Amorphous/crystalline HTiNbO_5-X membranes for efficient confined flow synthesis of acetate ester flavours

Domain: earth_science
Published: 2025-07-02
Editorial outcome: major_revision

Abstract
Ideallaminarmembranereactors(LMR)necessitatetherationalconstructionof2Dnanoconfinedchannelsandregulationofmicroenvironment.Theintrinsicstructure-activityrelationshipoflaminarmembranereactorsessentiallyremainsunclear.Herein,amorphous/crystallineHTiNbO 5-X nanosheets(NS)withabundantoxygenvacancy(V O)aresuccessfullypreparedandstackedas2Dsub-nanoconfinedmembraneflowreactorswithdifferentinterlayerspacings.Whentheinterlayerspacingisdecreasedto11.0Å,therepresentativeHTiNbO 5-X membraneexhibitsimpressiveconversionof≈100%within26.6sandturnovernumberofupto306.42fortheesterificationofbenzylalcoholat23°C.ThecombinationofstructuralcharacterizationsandtheoreticalcalculationsrevealsthatthesynergisticeffectofV Oandsub-nanoscaleconfinementgreatlypromotestheadsorptionandorbitalsymmetrymatchingofreactants,andreducestheoverallenergybarrier.Furthermore,theHTiNbO 5-X LMRisaccessibleforotheralcoholderivatives,indicatingtheefficientandgreensynthesisofacetateesterflavoursundermildconditions.Thisworkdemonstratesthepromisingpotentialofthemetaloxidenanosheetstocreateinorganiclaminarmembranereactorsforcontinuousorganicsynthesis.

Introduction
Efficient,environmental,andeconomicallyviablechemicalprocessesormethodologiesareingreatdemandforthosewidelyusedorganiccompounds. Acetate esters (e.g., benzyl acetate, anisyl acetate, cinnamylacetate)areextensivelyusedasflavoursandfragrancesinfood,cosmeticsandpharmaceuticalsindustrieswhichareinhighdemand(ashighas10,000tonsperannumforbenzylacetate)1.Besidesdirectextractionfromplantorfruitsources,theseesterflavoursaretypicallyobtainedthroughesterificationreactionsorenzymaticprocesses.Overthepastfewdecades,variouscatalyticmaterials,includingsolidacids,ionicliquidsandinorganicsalts,havebeenexploredtoreplaceor mineralacids(e.g.,H 2 SO 4 ) forserious corrosionand contaminationissues2,3.Recently,thegrowingtractionforsustainableprocessinghasresultedinatransitionfromconventionalbatchreactorstoadvancedcatalysisreactors4.Membranereactors,asacontinuousflowtechnology, offers many advantages including absence catalyst separation, precisetemperaturecontrolandreducedpowerconsumption5. Confinementcanplayadefiningroleininterfacepropertiesandchemical catalysis6. As the materials are assembled/confined to nanoscale,theirgeometricandelectronicstructuresintheconfinedstateoperateasthermodynamicallyandkineticallymorecriticalfactorsthanthoseinthebulkstate,whichcanresultinunusualphysicochemical and catalytic properties7. Over the past decade, tremendouseffortshavebeendevotedtopreparingvariousporousnanomaterialsfrom1Dto3D(e.g.,carbonnanotubes,grapheneoxide,metal-organicframeworks),whileonlyasmallportionofworkhavesuccessfully constructed nanoconfined systems or materials8–10. For example,Al/Ni-Pt/Tinanotubewasreportedtoshowremarkablyhigh efficiencyinnitrobenzenehydrogenationduetotheinstanttransferofintermediates and the tailored electronic properties of confined nanochannels9.However,thesematerialsmainlyparticipateincatalyticreactionsthroughbatchreactorsandthereactionefficienciesarestilllimitedbythedisorderedmotionofmoleculesandtheinefficientdiffusionofmoleculesbetweenthebulksolutionandthenanochannelsofporousmaterials,especiallyformolecular-scalechannels10. Moreover,currentstudyofcatalyticmaterialsaremainlyfocusedonthedesignofnanomaterialswithhierarchicalchannelsandthedegreeofconfinementforthesesystemsarelocalizedwithinseveraltotensofnanometers considering heat and mass transfer, and thereby the intrinsic structure−activity relationship of sub-nanoscale confinement has attracted intense interests6.

Innaturalenzymes,reactantsdiffuseintotheactivesiteswiththebindingsitesandcatalyticsitestobreakandformbonds11.Thesynergyofmultiple sites contribute to their extremely high activity and selectivity. There is a great challenge to apply this concepts into membrane flow reactors with confined channels in sub-nanometer scale,eventhoughitisattheforefrontofcatalyticchemistry.Recently,many 2D materials, such as graphene oxide (GO), covalent organic framework (COF), layered double hydroxide (LDH), and transition metal oxides/chalcogenides (TMO/C), have been employed for the fabrication of 2D material membranes, and these membranes have been effectively practiced in separation and purification12–16.Actually,2Dmaterialshaveatomic-levelthicknessesanduniquephysicochemicalproperties,andtheyarealsoverypromisingplatformstodevelopnewnanoconfinedflowreactorsfororganicsynthesis17,18.Forinstance,we have controlled the chemical structure of 2D graphene oxide membraneseffectively,andrealizedrapidKnoevenagelcondensationand synthesis of aspirin recently19,20. Through tuning the interlayer distances and interface properties of nanochannels, the intrinsic characteristicsof the reaction, e.g.,mass transfer,reaction kinetics, and selectivity, can be effectively dominated under mild process conditions. It is thus attractive to implement laminar membrane reactorsforcontinuouspharmaceuticalandfinechemicalsynthesis18.However,thedifficultyinpreparingofuniform,largesizedandultrathin 2D nanosheets (e.g., COF, LDH) to create effective confined nanochannelsgreatlyrestrictthedevelopmentofLMR17.Inaddition,thecurrentlyreported2Dmaterialslackproperandstablecatalyticactivesitesforspecificreactions(esterificationinthiswork).Incontrast to 2D carbonaceous materials like GO with abundant oxygen-containinggroups,2Dmetalliccompounds(e.g.,TMO)aredifficultto modulate the microenvironment nearby catalytic sites21. Oxygen vacancies in TMO have demonstrated to be beneficial for many applications due to their unsaturated coordination and distinct reactivity22. However, achieving precise control of these defects remains a significant challenge, and the role of vacancies to the adsorptionandactivationofreactants,especiallyunder2Dconfinedconditions,remainslargelyunknown23.

Here,wereportanoutstandinglaminarmembranereactorspreparedbyamorphous/crystallineHTiNbO 5-X nanosheetsenrichedwithoxygenvacancies,whichenablesrapidandefficientsynthesisofacetateesterflavours(Fig.1a,b).TheBrønstedacidsitesandoxygenvacancies are engineered onto the HTiNbO 5-X nanosheets by acid etching (Fig. 1c–f). The sub-nanoconfined channels of HTiNbO 5-X membranes are controlled from 14.4 to 11.0Å by mild thermal treatment(Fig.1g,h).Asaresult,alcoholmoleculesmovethroughthe sub-nanoconfinedchannelsdirectionallyandreactwithaceticanhydride (Ac 2 O) molecules efficiently under mild conditions (Fig. 1i, j). Whentheinterlayerspacingisdecreasedto11.0Å,theesterificationof benzyl alcohol (BnOH) is realized with conversion of ≈ 100% in an unparalleledshorttimeandturnovernumber(TON)ofupto28times higher than that of bulk reaction at 23°C (Fig. 1k). The synergy of multiple sites and confined spatial structures are realized in this bioinspiredLMR,contributingtothemodulationofreactantadsorption,molecularpolarization,orbitalsymmetrymatchingandreactionthermodynamics.Wehaveadjustedthemembranethicknesses,pressuredifference, reaction temperatures and reactant concentrations, andfurtherexpandedthesubstratescopeandstabilitytest,proving therationalityandsuperiorityofthelaminarmembranereactorstoconventionalbatchreactors.

Results
ThesynthesisandcharacterizationofHTiNbO 5-X membrane
TheultrathinHTiNbO 5-X NSweresuccessfullyobtainedbycalcination,acidetching,andexfoliationsteps(Fig.1b)22,24.Itisnoteworthythat KTiNbO 5 wastreatedinHClaqueoussolutionformultipletimes.This stepnotonlyfacilitatedsufficientprotonationofKTiNbO 5 introducing Brønsted acid sites, but also created abundant oxygen vacancy (V O)25,26. After that, a small amount of tetrabutylammonium cations (TBA+)wasusedtoexpandtheinterlayerspacingofbulkHTiNbO 5-X for exfoliation and to stabilize the interlayer distances of HTiNbO 5-X membrane. The morphology of the samples was investigated by scanning electron microscopy (SEM), transmission electron microscopy(TEM)andatomicforcemicroscopy(AFM).BothKTiNbO 5 and bulkHTiNbO 5-X presentedcloselycompactedlayeredstructure(SupplementaryFig.1).Thesizeoftheselamellarparticlesreachesseveral micrometers.AsshowninSupplementaryFig.2,thecolloidaldispersionsoftheHTiNbO 5-X NSarestableoveronemonth,implyingitswelldispersionanduniformity.TheTEMimagesofHTiNbO 5-X NSdepicted inFig.1candSupplementaryFig.3clearlyshowalargearea2Dultrathinnatureandtheaveragesizeisabout0.5±0.1μm,indicatingits suitabilityforconstructinglaminarmembranereactors.Energydispersive X-ray spectroscopy (EDX) elemental mapping of the HTiNbO 5-X nanosheetsrevealstheuniformdistributionsofTi,Nband Oacrossthesample,confirmingthesuccessfulsynthesisofHTiNbO 5-X nanosheets (SupplementaryFig.4and SupplementaryTable 1).The thickness ofthe exfoliated HTiNbO 5-X nanosheets wasmeasured by AFM with the corresponding height profile (≈1.2nm) presented in Fig. 1d. Considering the thickness of single-crystal nanosheet and surfaceadsorptionofsolventsorguestspecies(TBA+cations),theaspreparedHTiNbO 5-X nanosheetsconsistofmonolayer22,24.ThemicrostructureofthesampleswerealsoinvestigatedbypowderX-raydiffraction(XRD).InSupplementaryFig.5a,allthecharacteristicpeaksoftheKTiNbO 5 areindexedtoalayeredstructurewithanorthorhombic crystalKTiNbO 5 phase (JCPDS 72-1076).Interestingly,the characteristic diffraction peaks for bulk HTiNbO 5-X show obvious shift after replacementofK+withH+,whiletheintensityofHTiNbO 5-X nanosheets becomeveryweak.Theweakandabsenceofcharacteristicpeaksfor HTiNbO 5-X nanosheetsindicates the decreased crystallinityandpresenceoftheamorphousphases27,28.

ThesurfacepropertieswereidentifiedbytheFouriertransform infrared (FTIR), pyridine FTIR spectra and NH 3 temperature programmeddesorption(TPD).AsshowninSupplementaryFig.5b,it wasrevealedthatbothHTiNbO 5-X NSandbulkHTiNbO 5-X hadtwo distinctive signals at3600–3100cm−1 and 1600cm−1 which can be assignabletothestretchingmodesandbendingmodesofhydroxyl groups (OH), respectively29–33. This indicates that there is a considerableamountofhydroxylgroupsonthesurfacesofHTiNbO 5-X nanosheets.Theaciditydistributionwasinvestigatedusingpyridine FTIRspectroscopy.AsshowninFig.1eandSupplementaryFig.6a–c, the absorption bands at 1445–1454cm−1 indicate the presence of coordinatelybondedpyridineatLewisacidsites,whilethebandsat 1546cm−1 are assigned to pyridine adsorbed at Brønsted acid sites32–34.ThepyridineFTIRspectraprovethatHTiNbO 5-X NShave both Lewis acid and Brønsted acid sites. Even after evacuation at 200°C, the absorption bands of Brønsted acid sites could still be detectedandtheBrønsted/Lewisacidratiois0.184forHTiNbO 5-X nanosheets,indicatingthesesampleshavegoodstabilityandcatalytic potential (Supplementary Table 2).The overall acidity of the sampleswasfurtherprobedbyNH 3 TPD(Fig.1fandSupplementary Fig.6d).ForbulkHTiNbO 5-X ,desorptionofNH 3 occurredfrom150 to650°C,indicatingawiderangeofacidsites33,34.Thebroaddesorptionsignalcouldbedividedintotwopeakscenteredat208and 525°C, representing sites of medium and strong acidity. For HTiNbO 5-X nanosheets, the peaks in the range of 200-400°C belongs to sites of medium acidity, and peaks centered at 492°C represents strong acidity sites. The strong acidity sites should be ascribed to Brønsted acid sites at Ti(OH)Nb sites, and a slight decrease of peaks centered at 492°C is found for HTiNbO 5-X nanosheets since bulk HTiNbO 5-X was soaked in TBAOH dilute solution for exfoliation. The overall acidity of these samples was calculated in the following order: KTiNbO 5 (0.013mmol/g) <HTiNbO 5-X nanosheets (3.885mmol/g) <bulk HTiNbO 5-X (4.567mmol/g). These results consolidate that HTiNbO 5-X nanosheetshaveabundantBrønstedacidsitesandLewisacidsitesinduced byacidtreatment.

The2DHTiNbO 5-X laminarmembraneswerepreparedbystacking HTiNbO 5-X nanosheetsontoanylonsubstratethroughvacuumfiltration(SupplementaryFig.7).Itwasdemonstratedthattheinterlayerspacingofthelayeredmetaloxidecanbeadjustedbychangingthe cationsandthermaltreatment18.Theprotonsarepartiallyexchanged byappropriateorganiccations(TBA+),leadingtochemicalexfoliation of bulk HTiNbO 5-X and modulation of interlayer distance of the HTiNbO 5-X membranes.Theas-preparedmembraneswereairdriedat roomtemperature(RT)orthermallytreatedinvacuumovenatcertain temperature,whicharenamedY°Cdry(whereYisthecorresponding temperature). In the Supplementary Fig. 8a, the XRD patterns of HTiNbO 5-X membranes in dry-states exhibit sharp (002) diffraction peaks,whichalsoindicatesthattheHTiNbO 5-X membranespossessed a highly ordered stacking arrangement. Using the Bragg’s law, the interlayer distances of the dried HTiNbO 5-X membranes were decreasedfrom1.37nmto1.02nmafterincreasingtheheat-treatment temperature. With increasing calcination temperature, the H 2 O graduallyevaporatesfromtheinterlayerandtheTBA+cationscanturn into different geometric configuration and sizes (Supplementary Fig. 9). This can be evidenced by the weakening of the infrared absorption peak at 3600–3100cm−1 and 1600cm−1 with increasing temperature(SupplementaryFig.8b).AsdisplayedinSupplementary Figs.10and11,bothSEMimagesandTEMimagesofthecross-section of membranes revealed the well-ordered lamellar structure of the HTiNbO 5-X membrane.InSupplementaryFig.11,thealternatingdark andlightpatternshowstheaveragethicknessofonelayeroflamellaris 0.7nm, which matches the theoretical thickness of the HTiNbO 5-X nanosheet.Theesterificationofbenzylalcoholwithaceticanhydride wascarriedoutasthemodelreactiontostudythecatalyticproperties ofHTiNbO 5-X membranes.Beforethereaction,correspondingmolecular sizes are all predicted (Supplementary Figs. 9, 12). Through comparison and analysis, the thicknesses of molecules involved in esterification are all less than that of TBA+ cations.Thus, the membranes are effectively developed into different interlayer spacings allowingthecontinuousflowofreactantsandproducts.

ThecatalysisperformanceofHTiNbO 5-X membrane
Theesterificationofbenzylalcoholwithaceticanhydridewascarried outinamicrofiltrationdevice(SupplementaryFig.7b).Afterclamping HTiNbO 5-X membranes, the reaction solution of alcohol and acetic anhydride permeates through the HTiNbO 5-X membranes driven by thepressuredifference(0.9atm),andthereactantsreactwithinthe two-dimensionalsub-nanochannelsatRT,andtheproductsflowinto thecollectionbottlewiththesolvent.Asmentionedabove,fivetypes ofHTiNbO 5-X membraneswithdifferentinterlayerdistanceswereutilizedfortheconfinedbenzylacetatesynthesis.Aftermorethan12hof reaction,thereaction-stateinterlayerspacingofmembraneswastestedbyXRDimmediately.IntheFig.1handSupplementaryTable3,the interlayer spacings of the reaction-state HTiNbO 5-X membranes decreasemonotonically,andarecalculatedtobe14.4,12.3,12.1,11.9 and11.0ÅbyBragg’slaw,respectively.TheXRDpatternsofHTiNbO 5-X membranes in both dry-state and reaction-state exhibit strong diffractionpeak(002),confirmingthattheirorderlylayeredstructures are maintained in the process of reactions. The composition and conversionefficiencyofthepermeationsolutionwasdeterminedby1H NMRspectroscopy(Fig.2aandSupplementaryFig.13).Surprisingly, thecharacteristicsignalsofbenzylalcoholfadedawayalongwiththe interlayer spacings decreasing, whereas those for benzyl acetate enhanced and the conversion ofbenzylalcohol graduallyimproved from28.2%to100%(Fig.2a,b).Whentheinterlayerspacingturnedto 11.0Å, the characteristic signals of benzyl alcohol completely disappeared,andnearlycompleteconversion(≈100%)wasachievedat 23°C in a very short reaction time of 26.6s. Additionally, the flow volumeofthereactionsolutionwasobservedtobelinearwithtime, reflecting that the volumetric flow rate was steady (Supplementary Fig. 14). It was found that the velocity of the permeation solution graduallydecreasedwiththedecreasingoftheinterlayerspacingofthe HTiNbO 5-X membranes,whereasreactiontime(t R)werecalculated tobeincreasedfrom12.8sto26.6s.Theslightlyincreaseinreaction timeisattributedtothemoreseverespatialconstraintstothereaction solution.

Consideringthatthereactiontimeincreaseswiththedecrease of interlayer spacings, the increased conversion in HTiNbO 5-X membranesmayberelatedtobothreactiontimeandconfinement effects. Thereby, the reaction time of reaction solution in the HTiNbO 5-X laminar membranes were further studied by adjusting themembranethicknesses,andthecorrespondingconversionsof benzylalcoholweretested.TheHTiNbO 5-X membraneswithdifferentloadingswerethermallytreatedinsametemperature(60°Cdry) to maintain at a nearly constant interlayer spacing (d=12.1Å) but differentthicknessesinFig.2c.Thevolumeofthereactionmixture passing through is still linearly related to reaction time, and the velocity was decreased with the increased membrane thicknesses (SupplementaryFig.15).Asthethicknessesincreasedfrom2.6μmto 10.4μm,theconversionsofbenzylalcoholimprovedfrom23.6%to 100%, but thereactiontime greatly increasedfrom7.9s to63.5s. This is mainly attributed to the weakened confinement effect. Moreover,theeffectofreactiontimesontheconversionisfurther investigated by adjusting the operating pressure difference (Supplementary Fig. 16). When the pressure difference decreased to 0.3atm and 0.6atm, the reaction mixture had a lower flux and a higherreactiontimethroughtheHTiNbO 5-X membranes(d=14.4Å). Eventhoughthereactiontimegreatlyincreasedto27.5sand48.1s, theconversionsofbenzylalcoholonlyimprovedto53.2%and65.6% (Supplementary Fig. 16b). This results indicates that extending reaction time slightly increase benzyl alcohol conversion, but reducing interlayer spacing significantly promotes esterification reactivity.Besides,theconfinedreactionsofHTiNbO 5-X membranes are also performed at different temperatures in Supplementary Fig.17.Whenthetemperaturecomesto30°C,theconversionwas greatlyimprovedfrom20.4%forHTiNbO 5-X membranes(d=14.4Å) to 58.3% for HTiNbO 5-X membranes (d=11.0Å) in Supplementary Figs.18,19.Butthereactiontimewascalculatedtoshowslightdifference from 13.7s to14.3s. These results all proved that the prolonged reaction time has a slight impact on the conversion, whereasinterlayerspacinghasamoresignificantimpact.

Incomparison,HTiNbO 5-X nanosheetswerealsoutilizedasheterogenouscatalystsforbenzylacetatesynthesis.Thebulkreactionwas conductedunderthesameconditions.AsshownintheFigs.1k,2d,the catalyticperformanceforHTiNbO 5-X nanosheetsislimitedbythedisorderedmotionofmolecules.Throughincreasingthereactiontime from24hto48h,thereactionefficienciesofHTiNbO 5-X nanosheetsin the bulk system are raised from 21.3% to 38.4%. However, this enhancementisstillinferiortothatoftheconfinedsystem.ThecatalystdosageofHTiNbO 5-X NSinbulkconditionis10mg,whereasthatof HTiNbO 5-X membranes in confined system is calculated to be only 1.68mg. CombiningwiththeoverallacidityprobedbyNH 3 TPD,the turnovernumberforHTiNbO 5-X membranesat23°Cincreasesfrom 86.41 to 306.42 as the interlayer spacings decrease (Fig. 2d). The optimumresultsareabout28timeshigherthanthatofbulkreaction (10.96). Over the pasttwo decades, various homogeneous and heterogeneouscatalysts,includingsolid-acids,inorganicsaltsandionic liquids,havebeenappliedtobenzylacetatesynthesis(Supplementary Table4).Inordertoachieveabettercatalyticperformance,mostof thereportedworksadoptedhighreactiontemperatureorextended reactiontimeorcatalystdosages,andtherewerefewstudiesforthe efficientsynthesisofbenzylacetate(Fig.2e).Ulteriorly,threetypesof commercial solid acid catalysts, HZSM-5 (zeolite molecular sieves), H 3 PW 12 O 40 ·xH 2 O(heteropolyacids)andamberlyst-15(acidicresins), werepurchasedforcomparison.Underthepremiseofthesameconcentrations, the performances of H 3 PW 12 O 40 ·xH 2 O and amberlyst-15 aresuperiortoHZSM-5and HTiNbO 5-X nanosheets in the bulk reaction (Supplementary Table 5).Thisismainlyattributedtotheirstrongeracidity.However, theH 3 PW 12 O 40 ·xH 2 Owasdissolvedintheproductbenzylacetate,and the collected benzylacetate exhibits a light golden colour (Supplementary Fig. 46). The Amberlyst-15 ion-exchange resins were easily separated from solutions, but the collected benzyl acetate shows a noticeableorangecolorafterreaction.Thismaybeduetotheunstable structure of the amberlyst-1535,36. These results demonstrate the advantagesofHTiNbO 5-X membranesincatalystseparationandproductpurity.

StructuralanalysisofHTiNbO 5-X nanosheets
SincetheHTiNbO 5-X membranesarefabricatedbyvacuumfiltrationof HTiNbO 5-X nanosheets, the origin of its outstanding performance shouldberelatedtothestructuresofHTiNbO 5-X nanosheets.Togain furtherinsightsintotheelectronicstructureandchemicalstatesfor HTiNbO 5-X membranes,severalotheranalyticaltechniques,including X-ray photoelectron spectroscopy (XPS) and Raman spectra, were performed.TheXPSdataforKTiNbO 5 showscharacteristicTi2ppeaks forTi4+andNb3dpeaksforNb5+,butinthecaseofbulkHTiNbO 5-X and HTiNbO 5-X nanosheets these peaks shift to lower binding energy (SupplementaryFig.20).ThislikelyresultsfromthepresenceofNb4+ andTi3+duetotheacidetching37–40.Inaddition,O1scanbedivided intotwofitting peaks.Asshownin SupplementaryFig.21,the main peakoflatticeoxygensareshiftedfrom530.3eVto529.7eV,whichcan beascribedtotheoxygendefectsorvacanciespresentinthelatticeof HTiNbO 5-X 40. The shoulder peak at 531.3eV typically corresponds to adsorbedoxygenaroundoxygenvacancysites27,38.AsforHTiNbO 5-X membranes, the position of these peaks hold the stable during the vacuumthermaltreatment(SupplementaryFig.22).Notably,whenthe temperature increases, the content of oxygen vacancies gradually decreases from 29.2% to 22.5% (Supplementary Table 6). To gain insightsintotheroleofoxygenvacancy,thenanosheetsofHTiNbO 5-X membranesafterthermaltreatmentat100°Cwerecollectedforbulk reaction.Underthesamedosages,theperformancesofthenanosheets decreasesfrom21.3%to8.6%.Thus,itcanbeconfirmedthatoxygen vacancies play a key role during the reaction process. The Raman spectra were further collected to identify structural changes of HTiNbO 5-X membranes,becauseitisverysensitivetothestructureand bondorderofmetaloxides,especiallyintheregionrelatingtometal- oxygenstretchingmodes(SupplementaryFig.23)41,42.TheRamanshift intherangeof590–720cm–1belongstothestretchingvibrationofthe Ti–O–TibondintheTiO 6 octahedron,andtheshiftintherangeof480- 570cm–1belongstothestretchingvibrationoftheNb–O–Nbbondin theNbO 6 octahedron41.ItisworthnotingthatthepeaksforHTiNbO 5-X nanosheetsandHTiNbO 5-X membranesbothshowedevidentlybroad andenhancedabsorptionataround885and934cm–1,andthesepeak istypicallyregardedastheunsaturatedTi=OandNb=Osurfacegroups, compared with the shift of KTiNbO 5. The above results suggest the preparedHTiNbO 5-X nanosheetshavepartialstructuralchangeswhich canbeattributedtoacidetching,andtherebythemetaloccupationat tetrahedralandoctahedralsitesmighthaveslightdifferences38,41.

Ulteriorly,theselectedareaelectrondiffraction(SAED)patternof HTiNbO 5-X nanosheetsshowscleardiffractionrings(Fig.3a),indicating that the HTiNbO 5-X nanosheets areetched by hydrochloric acid resulting partially disordered atomic arrangement26,27. Notably, the High-resolution TEM image (HRTEM) reveals that the prepared HTiNbO 5-X nanosheets are typically composed of amorphous and crystalline domains (Fig. 3b). The amorphous structuralregions are relativelylargerthancrystallineregions,demonstratingthelowcrystallinity of HTiNbO 5-X nanosheets (Supplementary Fig. 24).This is consistentwithXRDresults(SupplementaryFig.5a).Additionally,lowtemperatureelectronparamagneticresonance(EPR)wasemployedto validatethegenerationofNb4+/Ti3+/V Opairssincethistechnologywas verysensitivetoparamagneticspeciescontainingunpairedelectrons (Fig.3candSupplementaryFig.25).FromFig.3c,itcanbeseenthat HTiNbO 5-X nanosheetsshowdistinctiveEPRsignalsataboutg=2.253 and g=2.028 assigned to Nb4+ and Ti3+, respectively43–45. In Supplementary Fig. 25, signal with g=4.252 could be assigned to Nb3+ species43.Afterthat,theindicatorofgvaluesat2.067and2.002should beattributedtothecorrespondingoxygenvacanciesinthelattices37. The abundant oxygen vacancies break the octahedral symmetry of NbO 6 and TiO 6 , which derive Nb4+ and Ti3+ with unpaired electron. Besides,thethermogravimetricanalysis(TGA)curveshowsthatthe HTiNbO 5-X nanosheetshasasmallmasslossinnitrogenatmosphere, but the decomposition rate is decreased in oxygen atmosphere (Fig.3d).Thisfeaturealsoservesasanindirectevidencefortheexis- tencetheoxygenvacancy,inagreementwiththeXPS,Raman,EPRand HRTEMfindingsabove.Thecreatedoxygendefectsashighlyactive low-coordination sites can break the inherent crystal arrangement causingamorphousdomainsandreadjustthelocalelectronstructure (SupplementaryFig.26)28,29.Assuch,theadsorptionandactivationof reactants may be optimized and thus boosting the reaction performance.

Theoreticalcalculationforcatalyticmechanism
Inviewoftheextensiveoxygenvacanciesintheconfinednanochannel, an effective modulation of interface properties of HTiNbO 5-X membranes is expected. Before theoretical calculations, we undertook Ramanstudiestounderstandtheintricateinteractionbetweenreactant molecules and oxygen vacancies (Supplementary Fig. 27). The strongelectrophilicpropertiesoftheoxygenvacancyarebeneficialto itsadsorptionwithoxygencontaininggroupsofaceticanhydrideand benzyl alcohol. As the experiment progresses, benzyl alcohol and aceticanhydridemoleculesgraduallymovethroughandreactwithin theHTiNbO 5-X membranes.InSupplementaryFig.27,thepeakofNb=O graduallyshiftedfrom940cm-1to948cm-1,whereasotherpeaksshow noobviousshift.Thiscanbeattributedtotheadsorptionofreactant moleculesatoxygenvacanciesaroundNbsites21.Therefore,theoxygen vacancies at Nb sites were considered for calculation29,30. The potentialdistributionisexploredbyelectrostaticpotentialsimulation tostudythesurfaceelectronicstatelikebondingnatureofHTiNbO 5-X nanosheets with reactant molecules (Supplementary Fig. 26). The obviouspotentialdifferencecanbeseenaroundtheoxygenvacancy, revealingtheformationoflocalpolarizationandconstructingstrong localelectricfield46,47.Thestrongelectrophilicpropertiesoftheoxygen vacancy are beneficialtomolecular polarization and transition state stabilization48.Thus,theadsorptionenergies(E ads)ofBnOHandAc 2 O intercalating between the nanosheets of HTiNbO 5 (no defects) and HTiNbO 5-X werebothcalculatedusingdensityfunctionaltheory(DFT). Consideringthereaction-stateinterlayerspacing(11.0Å)andthickness ofmonolayernanosheets(0.7nm),theinterlayerfreedistances(d free) istypicallyregardedastheunsaturatedTi=OandNb=Osurfacegroups, compared with the shift of KTiNbO 5. The above results suggest the preparedHTiNbO 5-X nanosheetshavepartialstructuralchangeswhich canbeattributedtoacidetching,andtherebythemetaloccupationat tetrahedralandoctahedralsitesmighthaveslightdifferences38,41.

Ulteriorly,theselectedareaelectrondiffraction(SAED)patternof HTiNbO 5-X nanosheetsshowscleardiffractionrings(Fig.3a),indicating that the HTiNbO 5-X nanosheets areetched by hydrochloric acid resulting partially disordered atomic arrangement26,27. Notably, the High-resolution TEM image (HRTEM) reveals that the prepared HTiNbO 5-X nanosheets are typically composed of amorphous and crystalline domains (Fig. 3b). The amorphous structuralregions are relativelylargerthancrystallineregions,demonstratingthelowcrystallinity of HTiNbO 5-X nanosheets (Supplementary Fig. 24).This is consistentwithXRDresults(SupplementaryFig.5a).Additionally,lowtemperatureelectronparamagneticresonance(EPR)wasemployedto validatethegenerationofNb4+/Ti3+/V Opairssincethistechnologywas verysensitivetoparamagneticspeciescontainingunpairedelectrons (Fig.3candSupplementaryFig.25).FromFig.3c,itcanbeseenthat HTiNbO 5-X nanosheetsshowdistinctiveEPRsignalsataboutg=2.253 and g=2.028 assigned to Nb4+ and Ti3+, respectively43–45. In Supplementary Fig. 25, signal with g=4.252 could be assigned to Nb3+ species43.Afterthat,theindicatorofgvaluesat2.067and2.002should beattributedtothecorrespondingoxygenvacanciesinthelattices37. The abundant oxygen vacancies break the octahedral symmetry of NbO 6 and TiO 6 , which derive Nb4+ and Ti3+ with unpaired electron. Besides,thethermogravimetricanalysis(TGA)curveshowsthatthe HTiNbO 5-X nanosheetshasasmallmasslossinnitrogenatmosphere, but the decomposition rate is decreased in oxygen atmosphere (Fig.3d).Thisfeaturealsoservesasanindirectevidencefortheexis- tencetheoxygenvacancy,inagreementwiththeXPS,Raman,EPRand HRTEMfindingsabove.Thecreatedoxygendefectsashighlyactive low-coordination sites can break the inherent crystal arrangement causingamorphousdomainsandreadjustthelocalelectronstructure (SupplementaryFig.26)28,29.Assuch,theadsorptionandactivationof reactants may be optimized and thus boosting the reaction performance.

Theoreticalcalculationforcatalyticmechanism
Inviewoftheextensiveoxygenvacanciesintheconfinednanochannel, an effective modulation of interface properties of HTiNbO 5-X membranes is expected. Before theoretical calculations, we undertook Ramanstudiestounderstandtheintricateinteractionbetweenreactant molecules and oxygen vacancies (Supplementary Fig. 27). The strongelectrophilicpropertiesoftheoxygenvacancyarebeneficialto itsadsorptionwithoxygencontaininggroupsofaceticanhydrideand benzyl alcohol. As the experiment progresses, benzyl alcohol and aceticanhydridemoleculesgraduallymovethroughandreactwithin theHTiNbO 5-X membranes.InSupplementaryFig.27,thepeakofNb=O graduallyshiftedfrom940cm-1to948cm-1,whereasotherpeaksshow noobviousshift.Thiscanbeattributedtotheadsorptionofreactant moleculesatoxygenvacanciesaroundNbsites21.Therefore,theoxygen vacancies at Nb sites were considered for calculation29,30. The potentialdistributionisexploredbyelectrostaticpotentialsimulation tostudythesurfaceelectronicstatelikebondingnatureofHTiNbO 5-X nanosheets with reactant molecules (Supplementary Fig. 26). The obviouspotentialdifferencecanbeseenaroundtheoxygenvacancy, revealingtheformationoflocalpolarizationandconstructingstrong localelectricfield46,47.Thestrongelectrophilicpropertiesoftheoxygen vacancy are beneficialtomolecular polarization and transition state stabilization48.Thus,theadsorptionenergies(E ads)ofBnOHandAc 2 O intercalating between the nanosheets of HTiNbO 5 (no defects) and HTiNbO 5-X werebothcalculatedusingdensityfunctionaltheory(DFT). Consideringthereaction-stateinterlayerspacing(11.0Å)andthickness ofmonolayernanosheets(0.7nm),theinterlayerfreedistances(d free) of 4Å were taken to simulate the adsorption behavior of confined reaction (Supplementary Figs. 28, 29). For bulk reaction, the 40Å vacuumspaceisusedtosimulatethesurfaceenvironment,ensuring thatthe slabmodelremains sufficientlyisolated15,49. This distance is largeenoughcomparedtothesizeofthereactants(benzylalcohol: 4.02×7.00×9.10Å;aceticanhydride:4.01×5.34×8.72Å)intheSupplementaryFig.12.Thecalculatedresultsprovedthattheadsorption energy(d free=40Å)ofBnOHandAc 2 OinHTiNbO 5-X werebothhigher than that of HTiNbO 5, indicating the strong adsorption on oxygen vacancy(E ads=−0.800eVforBnOH,E ads=−0.584eVforAc 2 O).Interestingly,theseenergieswerefurtherimprovedgreatlywhenthed free decreasedto4Å,especiallyforHTiNbO 5-X (E ads=−1.270eVforBnOH, E ads=−1.133eVforAc 2 O).Specifically,benzylalcoholandaceticanhydrideexhibitstrongelectrostaticinteractionswithoxygenvacanciesin HTiNbO 5-X membranes through benzene ring, hydroxyl oxygen and carbonyloxygen,whereasinHTiNbO 5 membranes,theinteractionsare mediatedbyweakhydrogenbonds(Fig.3e,f,SupplementaryFigs.28, 29). Therefore, the synergistic effects of oxygen vacancies and confinement effect are identified, which benefits to the adsorption and activationofthereactants.

ATRFTIRmeasurementswereperformedtogainfurtherinsights intothereactionprogression(SupplementaryFig.30).Theseinvestigations enabled the monitoring of the chemical transformations occurringwithintheHTiNbO 5-X membranes.Afteraspecifictimeof reaction(0h,0.5h,1hand12h),reaction-statemembraneswerecollectedandtestedbyATR FTIR spectra immediately. For acid anhydride, the peaks at 1756cm−1 and 1828 cm−1 are assigned to the stretchingmodeofC=O.Astheexperimentprogresses,thesepeaks areredshiftedto1752cm−1and1822cm−1,whichshouldattributetotheprotonation ofacetic anhydrides50,51. After12h of confined flow reaction,benzylacetate(product)isenrichedinsidethemembrane. The stretching mode of C=O and C-O for the ester is significantly enhancedataround1709cm−1and1232cm−1.Thesearedirectobservationsofreactionintermediatesandproducts.

Torevealtheunderlyingmechanismsofbulkandconfinedreactions,weinvestigatedthefreeenergyofthereactionpathsthrough DFTcalculations,basedonthespatialconfinementandthechemical structureofcatalysts.Theesterificationinboththebulkandconfined systemsisdividedintothefollowingthreesteps,thatisprotonation, nucleophilic addition, and deprotonation. As illustrated in Supplementary Fig. 31, Brønsted acid sites on the surface of HTiNbO 5-X nanosheetsareemployedastheprotondonor,andtheaceticanhydridesareeasilyprotonatedtothefirstintermediate(IM1)inbothbulk andconfinedsystemsduetothegoodelectronegativityofcarbonyl oxygen. This could promote the electron-withdrawing property of oxygenatomweakeningC-Obond,andfurtherincreasesthepositive chargeonthecarbonatom.Subsequently,thelonepairelectronsof alcohol hydroxyl oxygen in benzyl alcohol attack the empty antibonding π* orbital of carbon atom to generate the second intermediate (IM2) through the first transition state (TS1). Notably, the GibbsfreeenergiesfromIM1toTS1aredemonstrateasthemaximum energybarrierinboththebulkandconfinedsystems.Theenergies fromIM1toTS1forthebulkandconfinedconditionsrespectivelyare calculatedtobe42.0kJ/moland28.8kJ/mol,demonstratingagreat decreaseoftheenergybarrier(Fig.4c,d).Forthebulkreaction,the energybarriermainlyderivesfromthedisorderedmotionandinefficientdiffusionofmoleculestoactivesitesreflectedbyitslowturnover number (SupplementaryFig. 35). In order toobtainhigher reaction efficiency, the reaction time and temperature need to be increased (Fig. 4a, b). For the confined reaction, as the channel dimension decreases to nanoscale (especially angstrom scale), the disordered motionsofreactantmoleculesaregreatlyconstrained.Innucleophilic additionreactions,thesymmetrymatchofmolecularorbitalsdetermineswhetherthereactioncanproceedefficiently,mainlyinvolving thedirectionoforbitalinteractionbetweenthenucleophileandthe substrate.Thishasbeenconfirmedbythehigherconversionrateofthe confinedreaction(Fig.4b).Theconversionareraisedfrom7.8%(24h) inbulksystemto56.2%inconfinedsystemat10°C.Thisvalueisclose totheconversion(58.4%)ofbulkreactionat60°C(Fig.4a).Asshown in the Supplementary Fig. 32, the reactants are reorganized and becomemoreorderlywithinthe2Dconfinedsub-nanochannels.When the interlayer distance decreases from 14.4Å to 11.0Å, the best symmetric matching state between the highest occupied molecular orbital(HOMO)ofbenzylalcoholandthelowestunoccupiedmolecular orbital(LUMO)ofprotonatedacetic anhydride is achieved, favoringthenucleophilicadditionreaction.Besidestheconfinement effect,theintrinsicchemicalandelectronicstructureofcatalystscan alsoaffectthemolecularreactivity.Specifically,theoxygenvacancies onthesurfaceofHTiNbO 5-X nanosheetsareconsideredasLewisacid sitesthatalsocanattractcarbonyloxygenorhydroxyloxygenassisting molecular polarization, and promote the formation of IM2, as evidenced by the increased adsorption energy of HTiNbO 5-X membrane to BnOH and Ac 2 O. As shown in Supplementary Figs. 33, 34, LewisacidsitesatNbsitesofHTiNbO 5-X nanosheetsarealsocounted asactivesitesforcalculation.Inthiscase,thefreeenergyfromIM1to TS1alsodeliversanobviousdecreasefrom47.7kJ/molto39.8kJ/mol forconfinedconditions.Comparedtothatofbulksystem,thelower activationenergybarriersforreactionsintheconfinedspacegiverise toahigher-efficiencyreactionperformanceinevitably.

Todeterminethegeneralityandexpansibilityofmembranereaction,wefurtheradjustthereactantconcentrations,andexpandsolvents and alcohol derivatives using HTiNbO 5-X membranes (d=11.0Å) as mentionedabove.InSupplementaryFig.36,theflowvolumesarelinear withtime,andthepermeanceofreactionsolutionfallslightlywiththe concentration increasing (0.1, 0.2, 0.6 and 1.0M). The experimental resultsshowthattheconversionofconfinedreactiondecreasesgraduallywhentheconcentrationscometo0.6Mand1.0M(Supplementary Table 7). This should be ascribed to the saturation of active sites to reactantmolecules,sincethecatalystdosageofHTiNbO 5-X membranes is only 1.68mg. For bulk reactions, the conversion of benzyl alcohol delivers a completely opposite trend, mainly because the increased probabilityofmolecularcollisionathighconcentrations.Inspiteofthat, theperformancesofconfinedreactionarestillsuperiortothatofthe bulkreactionatthesameconcentrations.Inaddition,wehavemadea comparisonofdifferentsolventsintermsofboilingpoint,conversion andflowrateofthereactionsolution.Whencyclohexane,tolueneand chloroformareusedassolvents,theyalsoexhibitgoodconversionrates bothinbulkandconfinedreactions(SupplementaryTables8,9).However, flow rates for cyclohexane and toluene are much smaller than acetonitrileinconfinedreactions,andthereactiontimearesignificantly longer(SupplementaryFig.37).Thiscanbeattributedtothelargersize of cyclohexane and toluene, which obstructs their flow within the membranes(SupplementaryFig.38). Moreover,theHTiNbO 5-X membranesarealsoappliedtootheralcoholderivativesforcorresponding acetateesterflavours,becausetheseesterflavourshaveattractedspecial interestsinmanyindustrialsectors(Fig.5,SupplementaryFigs.39–44, SupplementaryTable11).FromtheFig.5andSupplementaryTable10, thesealcoholderivativesexhibiteddifferentcatalyticactivitiesbecause of the differences in molecular size, geometric configuration and nucleophilicity.Theperformanceof1-phenylethylalcoholandisoamyl alcoholwasunsatisfactory,whichwasspeculatedtobesterichindrance effectofmoleculesthemselvesandmismatchbetween2Dnanochannel andreactants.Obviously,boththeconversionandreactiontimeofthe confined reaction exceed that of bulk reaction, implying HTiNbO 5-X membranesareextendabletootherdifferentalcohols.

To determine the stability of the membranes, the HTiNbO 5-X membranesaretestedforfourcyclesofrecyclabilitytest.Asshownin SupplementaryFig.45,themembraneexhibitedhighstabilityinboth thepermeanceandconversionofthesolution.Theconversionofbenzyl alcoholremainedunchangedatalmost100%foralloperationcycles.In SupplementaryFig.46,weconductedacontinuousconfinedreaction forevaluatingreactivityandpracticalityofthemembrane.Aftermore than13daysofreaction,theproductswerecollectedinSupplementary Fig.46a.Accordingtothetheoreticalexpectedproductquality,theyield wascalculatedabout87.5%.Thelossofproductsmainlycomesfromthe processes of filtration reaction and sample collection. The products werealsoanalyzedby1HNMRspectroscopy,andcharacteristicsignals of benzyl alcohol completely disappeared which means a 100% conversion.Thebenzylacetatecollectedbytheconfinedreactionisalmost colorless.Togaininsightsintostabilityofoxygenvacancy,XPSspectra ofHTiNbO 5-X membraneswereperformedafterthelong-termstability test.AsshowninSupplementaryFig.47,O1scanbedividedintothree fitting peaks that is lattice oxygen at 530.4eV, oxygen vacancy at 531.3eV and organic oxygen at 532.9eV. Due to the relatively mild reactionconditions,thesignalpeakofoxygenvacanciesdidnotshow anysignsofweakeningordisappearing.Therefore,itcanbeconfirmed thatHTiNbO 5-X membranesareverystableduringthereactionprocess.

Methods
Materials
Niobiumpentoxide(Nb 2 O 5 ,AR),titaniumdioxide(TiO 2 ,AR)andcinnamylalcohol(>98.0%)werecommerciallysuppliedbySigma-Aldrich. Potassiumcarbonate(K 2 CO 3 ,AR),aceticanhydride(>99%),acetonitrileandhydrochloricacid(HCl)weresuppliedbySinopharmChemical Reagent.Amberlyst-15(Acidsiteså4.7eq/kg)wassuppliedbyAladdin. HZSM-5(MoleratioofSiO 2 /Al 2 O 3 ≈38-40)andH 3 PW 12 O 40 ·xH 2 O(AR) was supplied by Macklin. Benzyl alcohol (>99.0%), 4-methylbenzyl alcohol (>99.0%), 4-methoxybenzyl alcohol (>98.0%), phenylethyl alcohol(>98.0%),1-phenylethylalcohol(>98.0%),3-methyl-1-butanol (>99.0%)andtetrabutylammoniumhydroxide(TBAOH,10wt%)were purchasedfromTCI.Dimethylsulfoxide-d6(99.8atom%D,contains 0.03%v/vTMS)waspurchasedfromJ&KScientific.Deionizedwater (resistivityabove18MΩ∙cm)wascollectedfromaMili-QBiocelsystem. All solvents and reagents were used as received from commercial suppliersunlessotherwiseindicated.

PreparationofHTiNbO 5-X nanosheetsandHTiNbO 5-X membranes
The HTiNbO 5-X nanosheets were prepared by heating, acid etching, protonation,andexfoliation.K 2 CO 3 (10.64g),TiO 2 (6.15g),andNb 2 O 5 (10.23g)weremixedinthemortar.Themixturewasannealedinthe muffle furnace at 1000°C for 4h. After that, the solid sample was collectedandgroundintopowder.Theobtainedpowderwasannealed foranother20hourstofabricatelayeredKTiNbO 5 .TheKTiNbO 5 (2g) wasstirredinHCl(500mL,1M)solutionfor3day,andthesolidproductwasrecoveredbycentrifugation,washedthoroughlywithdeionizedwatertoremoveexcessacidandthendriedundervacuum.The bulkHTiNbO 5-X wasobtainedviaprotonexchangeandacidetchingof KTiNbO 5 with HCl aqueous solution for three times. To prepare HTiNbO 5-X nanosheets, HTiNbO 5-X (500mg) was soaked in TBAOH dilutesolution(100mL,1wt%)for6h,andredispersedinto500mL deionizedwater,andthenexfoliatedintonanosheetsbymechanical shaking for two weeks. To obtain monolayer HTiNbO 5-X nanosheet dispersion(≈0.6mg/mL),theabovesolutionwascentrifugedat3000 revolutions per minute (845×g, 5min) to remove unstripping HTiNbO 5-X . The HTiNbO 5-X nanosheet dispersion was centrifuged at 12000revolutionsperminute(13523×g,8min)toobtainHTiNbO 5-X nanosheetspowder.TheHTiNbO 5-X nanosheetpowderwasthermally treatedinvacuumovensat60°Cfor12h.
TheHTiNbO 5-X membraneswerefabricatedbyvacuumfiltration oftheHTiNbO 5-X nanosheetdispersion.20mLHTiNbO 5-X nanosheet dispersion(≈0.6mg/mL)wasdilutedto100mL(≈0.12mg/mL),after homogeneous dispersion, and was filtrated with a nylon membrane (47mm in diameter,pore sizeof0.22μm) asthe substrate.The aspreparedHTiNbO 5-X membraneswere air-dried at23°Cfor 12h.To regulate interlayer spacing, the membranes were further thermally treated in vacuum ovens at certain temperature (i.e., 40°C, 60°C, 80°Cor100°C)for12h.Themembraneswithdifferentthicknesses (HTiNbO 5-X loadings)werealsopreparedtoinvestigatetheircatalytic activity.

CatalyticevaluationofHTiNbO 5-X membranesfortheconfined reaction
The catalytic reaction was performed in microfiltration devices at room temperature (23°C) with a measuring cylinder diameter of15mm.First,HTiNbO 5-X membraneswerecuttooctagonalshape and fixed onto the surface of a porous glass support, clamping theuppermeasuringcylinderandtheglasssupporttoensuresealing. Then, acetonitrile (CH 3 CN) solution containing alcohol (0.2M) and acetic anhydride (0.3M) was added to the measuring cylinder, and the measuring cylinder was covered with aluminum foil. The solutionflowedthroughinterlayer2Dnanochannelsofthemembranes driven by a pressure difference (0.9atm), the reactants reacted in the interlayer, and the products flowed out with the solvent. After removing the solvent from the mixture obtained through membranes by rotary evaporation, dissolving the concentrate with DMSO-D6, analyzing its composition by 1H NMR spectroscopy, and calculating the conversion, the reactivity of membrane reactor was compared.
The relevant comparative experiments included the membrane interlayerdistances,membranethicknesses(HTiNbO 5-X NSloadings), reactiontemperatures,pressuredifferences,reactantconcentrations, solvents and substrates, and overall experiments were conducted analogously.

CatalyticevaluationofHTiNbO 5-X nanosheetsforthebulk reaction
Thecatalyticreactionwasperformedin25mLglassflasks.HTiNbO 5-X nanosheetpowder(10mg)wasaddedtoacetonitrilesolution(10mL) ofalcohol(0.2M)andaceticanhydride(0.3M),andthereactionflask wasthensealed,stirredandheatedatcertaintemperatures(i.e.,10°C, 23°C,40°Cor60°C)for72h.Every24hours,aspecificvolume(1mL) of reaction solution was taken out for testing. After removing the solidsbyfilterationandremovingthesolventbyrotaryevaporation, theobtainedconcentratewasdissolvedinDMSO-D6andanalyzedby 1HNMRspectroscopy.
The relevant comparative experiments included the reaction temperatures,reactantconcentrations,solvents and substrates, and overallexperimentswereconductedanalogously.

Recyclabilitytest
The experimental procedures were the same as confined reaction: HTiNbO 5-X membranes(d=11.0Å),benzylalcohol(0.2M)andacetic anhydride(0.3M)inacetonitrile(10mL).Afterthecompletefiltration of 10mL of reaction solution (about 100h), substances flowing through the membranes were collected and analyzed by 1H NMR spectroscopyforeachcycle.Acetonitrile(2mL)wasutilizedtorinse thebottomsurfaceofthemembraneanddissolvethesubstances.The solventwasremovedunderreducedpressureonarotaryevaporator andtheobtainedconcentratewasdissolvedinDMSO-D6.Afterthat, theHTiNbO 5-X membranes(d=11.0Å)wastestedforanothercycle,by adding acetonitrile solution (10mL) of alcohol (0.2M) and acetic anhydride(0.3M).

Dataavailability
Thedatathatsupportthefindingsofthisworkareavailablewithinthe article,itssupplementaryinformationfile(SupplementaryFigs.1–47, SupplementaryTables1–11),aswellasthesourcedatafile.Thedataare alsoavailablefromthecorrespondingauthors.Sourcedataareprovidedwiththispaper.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Fang et al. present a laminar membrane reactor using HTiNbO5-X nanosheets enriched with oxygen vacancies. This study demonstrates high catalytic performance for the esterification of benzyl alcohol under mild conditions, achieving nearly 100% conversion within 26.6 seconds at 23°C, with a high turnover number of 306.42. The combination of oxygen vacancies and spatial confinement enhances reactant adsorption, improves orbital symmetry matching, and lowers the reaction’s energy barrier, as confirmed by both experimental results and DFT calculations. Additionally, the membrane reactor exhibits long-term stability, maintaining high conversion efficiency over 13 days of continuous use, highlighting its potential for practical applications. Overall, this is an interesting paper, but the following comments and questions should be addressed before this work can be considered for publication in Nature Communications:\n• The introduction provides a good background on catalytic materials and the advantages of 2D materials. However, it would be helpful to clearly define the study’s specific objectives and key research questions—particularly regarding the synergistic effects of oxygen vacancies and sub-nanoscale confinement.\n• Some technical terms, such as Brønsted acid site modulation and orbital symmetry matching, could benefit from brief explanations for clarity, considering Nature Communications’ broad audience.\n• While the DFT analysis is insightful, could the authors also include a kinetic model in Figure 1 that explicitly outlines the rate-limiting steps? This would enhance the mechanistic understanding.\n• The manuscript mentions the synergistic effect of oxygen vacancies and sub-nanoscale confinement but doesn’t discuss the actual mechanism. Could the authors provide a more detailed discussion on how these factors influence adsorption, orbital symmetry matching, and energy barrier reduction? A schematic diagram illustrating the proposed mechanism would be beneficial.\n• The authors should specify the exact conditions (temperature, duration, and concentration) used in the acid etching and exfoliation steps.\n• Have the authors explored regeneration methods after deactivation (e.g., washing or thermal treatment)?\n• The comparison with literature values is useful, but a direct catalytic activity comparison (e.g., turnover frequency) against commercial catalysts would strengthen the study’s industrial relevance. Additionally, how does this membrane reactor compare with previously reported catalytic systems such as COFs and LDHs in terms of reaction rates, TOF, and catalyst stability?\n• The presented DFT results suggest that decreasing the interlayer distance improves conversion. Have the authors attempted to reduce the interlayer spacing below 11.0 Å?\n• The authors should report their synthesis reproducibility (and batch-to-batch variation).\n• What is the distribution of the amorphous vs. crystalline phase percentage in the final nanosheets?\n• A discussion on how the distribution of Brønsted and Lewis acid sites impacts catalytic performance would be beneficial.", "reviewer_2": "This manuscript proposes a concept of using stacked two-dimensional (2D) amorphous/crystalline HTiNbO5−x nanosheets as sub-nanoconfined membrane reactors for the efficient synthesis of acetate ester flavors under mild conditions. The experimental results demonstrate that the esterification of benzyl alcohol achieves nearly 100% conversion within 26.6 seconds when the interlayer spacing is reduced to 11.0 Å, significantly outperforming conventional bulk reactions. The concept has been reported in the previous work (Adv. Mater. 2024, 36, 2310954; Matter 2023, 6, 1173; Adv. Sci. 2024, 11, 2308388). The manuscript suffers from significant shortcomings in mechanistic explanations, model construction, and experimental validation, which undermine the support for its core scientific claims. As it stands, the manuscript is not suitable for publication.\nDetailed Comments\n1. Insufficient Mechanistic Explanation and Lack of Direct Evidence\nThe authors attribute the enhanced performance to the synergistic effect of oxygen vacancies and sub-nanoscale confinement. However, the following issues remain unresolved:\na. Direct Role of Oxygen Vacancies Not Clearly Demonstrated: Although XPS and EPR characterizations suggest the presence of oxygen vacancies, no control experiments (e.g., synthesizing HTiNbO5-x membranes without oxygen vacancies) were conducted to confirm their necessity. Without such experiments, it is impossible to rule out the dominant role of other factors, such as surface acid sites or differences in interlayer mass transport.\nb. Lack of Empirical Evidence for Orbital Symmetry Matching: The manuscript claims that HOMO-LUMO symmetry matching (Fig. 1j) is responsible for the accelerated reaction, but no direct evidence (e.g., in situ spectroscopy such as Raman or XAS) is provided. Reliance solely on DFT calculations is insufficient to support this key mechanistic claim.\n2. Unclear Theoretical Model Construction\na. Questionable Validity of the Confined Reaction Model: The differences between the DFT models for \"confined reaction\" and \"bulk reaction\" are not clearly explained. For instance, when the interlayer spacing is reduced to 4 Å, how is the model's consistency with the actual material structure (e.g., oxygen vacancy distribution, surface functional groups) ensured? Are solvation effects or dynamic adsorption processes considered?\nb. Discrepancy Between Computational Parameters and Experimental Conditions: The manuscript does not clarify whether the interlayer spacings used in the calculations (e.g., 40 Å vs. 4 Å) correspond to the experimentally measured XRD data (e.g., 11.0 Å). If the model parameters do not match the experimental conditions, the computational results lose their explanatory power.\n3. Limitations in Material Characterization and Reactor Design\na. Lack of Verification of Interlayer Spacing Uniformity: While SEM and XRD data suggest an ordered layered structure, high-resolution characterization (e.g., HAADF-STEM) is needed to confirm the local uniformity of nanosheet stacking. Stacking defects or interlayer inhomogeneity could significantly affect the reproducibility of the reaction.\nb. Mass Transport Effects Not Excluded: The experimental results (e.g., the relationship between reaction time and interlayer spacing) may be dominated by mass transport rates rather than catalytic activity. Additional experiments (e.g., varying flow rates at fixed interlayer spacing) are needed to distinguish the contributions of mass transport and catalysis.", "reviewer_3": "The authors reported the creation of a HTiNbO5-x membrane for esterification of benzyl alcohol with acetic anhydride to yield benzyl acetate and other derivatives (depending on type of benzyl alcohol used). Comprehensive and complementary characterisation techniques were used to provide robust evidence that demonstrated the noteworthy esterification rates and turnover numbers. The mechanism underpinning delivery of such results were evaluated using suitable simulation methodology. Although the research and work merits publication in Nature Communication, there was a major flaw in the design of the experiments. The following questions and comments outline my concerns about experimental design associated with this paper:\n1) What is the motivation to develop a membrane for esterification of benzyl alcohol? Existing methods are already well-established and effective. Hence it was unclear why this work is important scientifically or industrially. The only segment of the manuscript that compared the performance of the current membranes with other catalysts was only limited to Lines 230 to 236. There were no analyses on why their membranes are better than existing catalysts beyond catalysis performance.\n2) Benzyl alcohol esterification is a well-established process in industry. However, why did the authors not compare outcomes from this work with already established processes? Comparisons were made with catalysts reported in scientific research (mostly used in labs) for e.g., ionic liquids, solid and inorganic acids, but there was no comparison with industrial processes. After all, the authors are in the opinion that their membranes outperform existing methods for benzyl alcohol esterification.\n3) Why did the authors use acetonitrile as the solvent and acetic anhydride for esterification in this work? BA is typically esterified in industry using acetic acid (as solvent and reagent for esterification), toluene, or hexane.\n4) Are the membranes single use? What is the cyclic catalytic performance of the membranes reported here?\nThe authors should carefully address these questions to improve the quality of the manuscript that is underpinned by solid, and interesting results before it can be published in Nat. Commun."}, "author_response": "Response to Reviewers\nReviewer #1\nFang et al. present a laminar membrane reactor using HTiNbO nanosheets enriched\n5-X\nwith oxygen vacancies. This study demonstrates high catalytic performance for the\nesterification of benzyl alcohol under mild conditions, achieving nearly 100%\nconversion within 26.6 seconds at 23°C, with a high turnover number of 306.42. The\ncombination of oxygen vacancies and spatial confinement enhances reactant adsorption,\nimproves orbital symmetry matching, and lowers the reaction’s energy barrier, as\nconfirmed by both experimental results and DFT calculations. Additionally, the\nmembrane reactor exhibits long-term stability, maintaining high conversion efficiency\nover 13 days of continuous use, highlighting its potential for practical applications.\nOverall, this is an interesting paper, but the following comments and questions should\nbe addressed before this work can be consideblue for publication in Nature\nCommunications:\nResponse: We are grateful to Reviewer 1 for the positive comment on the novelty of\nour work. We have carefully answeblue the Reviewer’s comments and provide\ncorresponding explanations and supplementary experiments in the revised manuscript,\nand believe the revised version is suitable for the publication in Nature\nCommunications.\nComment 1: The introduction provides a good background on catalytic materials and\nthe advantages of 2D materials. However, it would be helpful to clearly define the\nstudy’s specific objectives and key research questions—particularly regarding the\nsynergistic effects of oxygen vacancies and sub-nanoscale confinement.\nResponse: We express our gratitude to the reviewer for this important suggestion. In\nthe introduction, we provide a further explanation of oxygen vacancies and sub-\nnanoscale confinement, and cite some relevant references. (Please see the blue text of\nthe introduction)\nOn Page 5:\n2D metallic compounds (e.g., TMO) are difficult to modulate the microenvironment\nnearby catalytic sites.21 Oxygen vacancies in TMO have demonstrated to be beneficial\nfor many applications due to their unsaturated coordination and distinct reactivity.22\nHowever, achieving precise control of these defects remains a significant challenge,\nand the role of vacancies to the adsorption and activation of reactants, especially under\n2D confined conditions, remains largely unknown.23\nRelated references in the revised manuscript is given as follows:\n21. Verma, R. et al. Defects tune the acidic strength of amorphous aluminosilicates. Nat.\nCommun. 15, 6899 (2024).\n22. Yang, M. et al. Disorder engineering in monolayer nanosheets enabling\nphotothermic catalysis for full solar spectrum (250-2500 nm) harvesting. Angew. Chem.\nInt. Ed. 58, 3077-3081 (2019).\n23. Bi, F. et al. Engineering triple O-Ti-O vacancy associates for efficient water-\nactivation catalysis. Nat. Commun. 16, 851 (2025).\nComment 2: Some technical terms, such as Brønsted acid site modulation and orbital\nsymmetry matching, could benefit from brief explanations for clarity, considering\nNature Communications’ broad audience.\nResponse: Thank you very much for your good comment! We have revised the\nmanuscript. The discussion about the Brønsted acid site modulation and orbital\nsymmetry matching has been added in the Introduction and the Results. In Fig. S26, we\nprovide a detailed introduction to the structures of Brønsted acids and Lewis acids.\nBrønsted acids can donate protons (H⁺) to activate substrates, enhancing electrophilicity\nor stabilizing intermediates. In our work, Brønsted acids on the surface of HTiNbO\n5-X\nnanosheets are employed to protonate carbonyl oxygen of acetic anhydrides. Unlike\nBrønsted acids (proton donors), Lewis acids focus on electron-pair interactions. In\norganic reactions, Lewis acids can activate reactants, stabilize intermediates or\ntransition states by accepting electron pairs.\nIn nucleophilic addition reactions, the symmetry match of molecular orbitals\ndetermines whether the reaction can proceed efficiently, mainly involving the direction\nof orbital interaction between the nucleophile and the substrate. In Fig. 4c and 4d, the\nGibbs free energies from IM1 to TS1 are demonstrate as the maximum energy barrier\nin both the bulk and confined systems. The lone pair electrons of alcohol hydroxyl\noxygen in benzyl alcohol attack the empty antibonding 𝜋* orbital of carbon atom of\nprotonated acetic anhydrides to generate the second intermediate (IM2) through the first\ntransition state (TS1). In Fig. S32, HOMO of the benzyl alcohol and the LUMO of\nprotonated acetic anhydride were calculated in the nanochannels with different\ninterlayer spacing. The symmetry match of molecular orbitals determines whether the\nreaction can proceed efficiently. Similarly, the lone pair electron coordination between\ncarbonyl oxygen (C=O) and Lewis acid can blueuce the electron density of carbonyl\ncarbon, making it more susceptible to attack by nucleophiles such as alcohols and\namines. (Please see the blue text of the Results)\nOn Page 15:\nAs illustrated in Fig. S31, Brønsted acid sites on the surface of HTiNbO nanosheets\n5-X\nare employed as the proton donor, and the acetic anhydrides are easily protonated to the\nfirst intermediate (IM1) in both bulk and confined systems due to the good\nelectronegativity of carbonyl oxygen.\nOn Page 16:\nSpecifically, the oxygen vacancies on the surface of HTiNbO NS are consideblue as\n5-X\nLewis acid sites that also can attract carbonyl oxygen or hydroxyl oxygen assisting\nmolecular polarization.\nOn Page 16:\nIn nucleophilic addition reactions, the symmetry match of molecular orbitals\ndetermines whether the reaction can proceed efficiently, mainly involving the direction\nof orbital interaction between the nucleophile and the substrate.\nWhen the interlayer distance decreases from 14.4 Å to 11.0 Å, the best symmetric\nmatching state between the highest occupied molecular orbital (HOMO) of benzyl\nalcohol and the lowest unoccupied molecular orbital (LUMO) of protonated acetic\nanhydride is achieved, favoring the nucleophilic addition reaction.\nComment 3: While the DFT analysis is insightful, could the authors also include a\nkinetic model in Figure 1 that explicitly outlines the rate-limiting steps? This would\nenhance the mechanistic understanding.\nResponse: We thank the reviewer for the valuable suggestion. The model snapshots for\nthe HOMO of the benzyl alcohol and the LUMO of protonated acetic anhydride\nconfined in the 2D nanochannels are shown in the Fig. 1j. The confinement effect of\n2D channels can promote the nucleophilic addition reaction, and significantly blueuce\nthe energy barriers. We also include the kinetic model in Fig. S32, Figures 4c and 4d,\nwhich clearly depict the energy profiles for both the bulk and confined reactions. In\nboth cases, the IM1 → TS1 transition is identified as the rate-determining step, as TS1\nexhibits the highest activation energy. Specifically, the activation energy for TS1 is 42.0\nkJ/mol in the bulk and 28.8 kJ/mol under confinement, compablue to the much lower\nactivation energy of TS2 (11.4 kJ/mol in bulk and 13.1 kJ/mol in confinement).\nAlthough confinement blueuces the activation energy of TS1, it does not change the\nfact that TS1 remains the slowest and rate-limiting step due to its higher energy barrier\nrelative to TS2. The calculated results show that the symmetry matching for the frontier\norbitals of the reactants is enhanced as the interlayer spacing decreased in Fig. S32 and\nthe Fig. 1j.\nComment 4: The manuscript mentions the synergistic effect of oxygen vacancies and\nsub-nanoscale confinement but doesn’t discuss the actual mechanism. Could the\nauthors provide a more detailed discussion on how these factors influence adsorption,\norbital symmetry matching, and energy barrier blueuction? A schematic diagram\nillustrating the proposed mechanism would be beneficial.\nResponse: Thanks for your wise and crucial suggestions, this comment is valuable and\nvery helpful for revising and improving our paper. The synergistic effect of oxygen\nvacancies and subnanoscale confinement occurs at different stages of the reaction and\nis discussed in different parts of the article. We think there are three main reasons for\nthe improved catalytic performance of HTiNbO membranes.\n5-X\n1) Enhanced reactants accessibility: For the conventional bulk reaction, only the\nreactants extremely close to HTiNbO NS can be catalyzed and the reactants need to\n5-X\ndiffuse to the surface. In contrast, for the confined reaction, all the reactants flow\nthrough the 2D transport channels between adjacent HTiNbO NS, under the drive of\n5-X\nthe pressure difference. Therefore, the accessibility of reactants to catalytic sites will be\ndramatically increased during catalysis within the HTiNbO membranes, which may\n5-X\nbe beneficial to the esterification.\n2) Increased reactants adsorption: The strong electrophilic properties of the oxygen\nvacancy are beneficial to molecular polarization and transition state stabilization (Rf.48:\nJ. Am. Chem. Soc. 2019, 141, 14878-14888). The adsorption energies of BnOH and\nAc O intercalating between the nanosheets of HTiNbO (no defects) and HTiNbO\n2 5 5-X\nwere both calculated using density functional theory (Fig. 3e and 3f). Due to the oxygen\nvacancies and confinement effect of 2D channels, the adsorption energy of BnOH and\nAc O are increased for HTiNbO membranes (Rf.16: Nat. Commun. 2022, 13, 4010).\n2 5-X\nThereby, the synergistic effects of oxygen vacancies and confinement effect are\nidentified, which benefits to the adsorption and protonation of reactants. This has\ndiscussed in the section of “Theoretical calculation for catalytic mechanism”.\n3) Blueuced energy barrier: It has discussed in the section of “Theoretical calculation\nfor catalytic mechanism”, that confinement effects for HTiNbO membranes can\n5-X\nsignificantly blueuce the energy barrier. The confinement effect of 2D channels can\npromote the nucleophilic addition reaction. The Gibbs free energies from IM1 to TS1\nare demonstrate as the maximum energy barrier in both the bulk and confined systems\n(Fig. 4c and 4d). The energies from IM1 to TS1 for the bulk and confined conditions\nrespectively are calculated to be 42.0 kJ/mol and 28.8 kJ/mol, demonstrating a great\ndecrease of the energy barrier. For the bulk reaction, the energy barrier mainly derives\nfrom the disordeblue motion and inefficient diffusion of molecules reflected by its low\nturnover number. The calculated results show that the symmetry matching for the\nfrontier orbitals of the reactants is enhanced as the interlayer spacing decreased in Fig.\nS32. (Please see more details in the Fig. S35)\na\nProcesses of bulk reaction\nH\n②Protonation\nO O\n①Adsorption\nNb Ti Nb Nb Ti Nb\nV H IM1\nO\nO\nNb Ti Nb ③Nucleophilic addition\n⑤Deprotonation\nO ④Dissociation O\nNb Ti Nb Nb Ti Nb\nIM3 IM2\nb\nProcesses of confined reaction\n①Adsorption；②Protonation\nd\n③Nucleophilic addition\nFig. S35. Schematics of processes of bulk reaction and confined reaction. The\nsynergistic effects of oxygen vacancies and confinement effect promote the adsorption\nand protonation of reactants. The confinement effect of 2D channels promotes the\nnucleophilic addition reaction.\nComment 5: The authors should specify the exact conditions (temperature, duration,\nand concentration) used in the acid etching and exfoliation steps.\nResponse: Thank you for the helpful suggestion! The details of the experiment have\nbeen perfected and supplemented in the revised draft. (Please see the blue text of the\nMethods)\nOn Page 26:\nMaterials\nNiobium pentoxide (Nb O , AR), titanium dioxide (TiO , AR) and cinnamyl alcohol\n2 5 2\n(>98.0%) were commercially supplied by Sigma-Aldrich. Potassium carbonate\n(K CO , AR), acetic anhydride (>99%), acetonitrile and hydrochloric acid (HCl) were\n2 3\nsupplied by Sinopharm Chemical Reagent. Benzyl alcohol (>99.0%), 4-methylbenzyl\nalcohol (>99.0%), 4-methoxybenzyl alcohol (>98.0%), phenylethyl alcohol (>98.0%),\n1-phenylethyl alcohol (>98.0%), 3-methyl-1-butanol (>99.0%) and tetrabutyl\nammonium hydroxide (TBAOH, 10 wt %) were purchased from TCI. Dimethyl\nsulfoxide-d6 (99.8 atom% D, contains 0.03% v/v TMS) was purchased from J&K\nScientific. Amberlyst-15 (Acid sites＞4.7 eq/kg) was supplied by Aladdin. HZSM-5\n(Mole ratio of SiO /Al O ≈ 38-40) and H O PW ·xH O (AR) was supplied by\n2 2 3 3 40 12 2\nMacklin. Deionized water (resistivity above 18 MΩ∙cm) was collected from a Mili-Q\nBiocel system. All solvents and reagents were used as received from commercial\nsuppliers unless otherwise indicated.\nPreparation of HTiNbO nanosheets and HTiNbO membranes\n5-X 5-X\nThe HTiNbO nanosheets were prepablue by heating, acid etching, protonation, and\n5-X\nexfoliation. K CO (10.64 g), TiO (6.15 g), and Nb O (10.23 g) were mixed in the\n2 3 2 2 5\nmortar. The mixture was annealed in the muffle furnace at 1000 °C for 4 hours, and\nannealed for another 20 hours with an interval grinding treatment to fabricate layeblue\nKTiNbO . The KTiNbO (2 g) was stirblue in HCl (500 mL, 1 M) solution for 3 day,\n5 5\nand the solid product was recoveblue by centrifugation, washed thoroughly with\ndeionized water to remove excess acid and then dried under vacuum. The bulk\nHTiNbO was obtained via proton exchange and acid etching of KTiNbO with HCl\n5-X 5\naqueous solution for three times. To prepare HTiNbO nanosheets, HTiNbO (500\n5-X 5-X\nmg) was soaked in TBAOH dilute solution (100 mL, 1 wt %) for 6 h, and\nblueispersed into 500 mL deionized water, and then exfoliated into nanosheets by\nmechanical shaking for two weeks. To obtain monolayer HTiNbO nanosheet\n5-X\ndispersion (≈ 0.6 mg/mL), the above solution was centrifuged at 3000 revolutions\nfor 5 minutes to remove unstripping HTiNbO . The HTiNbO nanosheet\n5-X 5-X\ndispersion was centrifuged at 12000 revolutions for 8 minutes to obtain HTiNbO\n5-X\nnanosheets powder. The HTiNbO nanosheet powder was thermally treated in\n5-X\nvacuum ovens at 60 °C for 12 h.\nThe HTiNbO membranes were fabricated by vacuum filtration of the HTiNbO\n5-X 5-X\nnanosheet dispersion. 20 mL HTiNbO nanosheet dispersion (≈ 0.6 mg/mL) was\n5-X\ndiluted to 100 mL(≈ 0.12 mg/mL), after homogeneous dispersion, and was filtrated\nwith a nylon membrane (47 mm in diameter, pore size of 0.22 μm) as the substrate.\nThe as-prepablue HTiNbO membranes were air-dried at room temperature (23 °C)\n5-X\nfor 12 h. To regulate interlayer spacing, the membranes were further thermally treated\nin vacuum ovens at certain temperature (i.e., 40 °C, 60 °C, 80 °C or 100 °C) for 12 h.\nThe membranes with different thicknesses (HTiNbO loadings) were also prepablue\n5-X\nto investigate their catalytic activity.\nCatalytic evaluation of HTiNbO membranes for the confined reaction\n5-X\nThe catalytic reaction was performed in microfiltration devices at room temperature\n(23 °C) with a measuring cylinder diameter of 15 mm. First, HTiNbO membranes\n5-X\nwere cut to octagonal shape and fixed onto the surface of a porous glass support,\nclamping the upper measuring cylinder and the glass support to ensure sealing. Then,\nacetonitrile (CH CN) solution containing alcohol (0.2 M) and acetic anhydride (0.3\nwith aluminum foil. The solution flowed through interlayer 2D nanochannels of the\nmembranes driven by a pressure difference (0.9 atm), the reactants reacted in the\ninterlayer, and the products flowed out with the solvent. After removing the solvent\nfrom the mixture obtained through membranes by rotary evaporation, dissolving the\nconcentrate with DMSO-D6, analyzing its composition by 1H NMR spectroscopy, and\ncalculating the conversion, the reactivity of membrane reactor was compablue.\nThe relevant comparative experiments included the membrane interlayer distances,\nmembrane thicknesses (HTiNbO NS loadings), reaction temperatures, pressure\n5-X\ndifferences, reactant concentrations, solvents and substrates, and overall experiments\nwere conducted analogously.\nCatalytic evaluation of HTiNbO nanosheets for the bulk reaction\n5-X\nThe catalytic reaction was performed in 25 mL glass flasks. HTiNbO nanosheet\n5-X\npowder (10 mg) was added to acetonitrile solution(10 mL) of alcohol (0.2 M) and\nacetic anhydride (0.3 M), and the reaction flask was then sealed, stirblue and heated at\ncertain temperatures (i.e., 10 °C, 23 °C, 40 °C or 60 °C) for 72 h. Every 24 hours, a\nspecific volume (1 mL) of reaction solution was taken out for testing. After removing\nthe solids by filteration and removing the solvent by rotary evaporation, the obtained\nconcentrate was dissolved in DMSO-D6 and analyzed by 1H NMR spectroscopy.\nThe relevant comparative experiments included the reaction temperatures, reactant\nconcentrations, solvents and substrates, and overall experiments were conducted\nanalogously.\nComment 6: Have the authors exploblue regeneration methods after deactivation (e.g.,\nwashing or thermal treatment)?\nResponse: Thank you very much for your good comment! We feel deeply sorry that\nthe discussion of our manuscript is not clear enough in the results. In previous versions,\nwe conducted a continuous confined reaction for evaluating practicality and stability of\nthe membrane. After more than 13 days of reaction, the products (1.3709 g) were\ncollected in Fig. S46a, due to losses incurblue during the collection process. According\nto the theoretical expected product quality (1.566 g), the yield was calculated about\n87.5%. Besides, the products were also analyzed by 1H NMR spectroscopy, and there\nwas no characteristic signals of benzyl alcohol which means a 100% conversion. To\ngain insights into stability of oxygen vacancy, XPS spectra of HTiNbO membranes\n5-X\nalso were performed after the long-term stability test in Fig. S47.\nIn the revised draft, we conducted recyclability test in Fig. S45. The HTiNbO\n5-X\nmembranes was tested for four cycles by adding acetonitrile solution (10 mL) of alcohol\nand acetic anhydride. Following each cycle, substances flowing through the membranes\nwere collected and analyzed by 1H NMR spectroscopy. As shown in Fig. S45, the\nmembrane exhibited high stability in both the permeance and conversion of the solution.\nThe conversion of benzyl alcohol remained unchanged at almost 100% for all operation\ncycles. After more than 400 hours of cyclic experiments, the HTiNbO\n5-X\nmembranes\ndid not show any signs of deactivation. These results all indicate that the HTiNbO\n5-X\nmembranes have excellent stability. (Please see the blue text of the Results)\na\n12\n1st Cycle 2nd Cycle 3rd Cycle 4th Cycle\n10\n8\n)\nL\nm\n6\n(\nw\n4\no\nlF\n2\n0\n0 100 200 300 400\nTime (h)\nb\n100\n)\n% 80\n(\nn\no 60\nis\nr\ne\nv 40\nn\no\nC 20\n0\n1st Cycle 2nd Cycle 3rd Cycle 4th Cycle\nFig. S45. Recyclability test. (a) Flow curves of reaction solution through HTiNbO\n5-X\nmembranes (d=11.0 Å) over cycle times. (b) The conversion of reaction solution\nthrough HTiNbO membranes (d=11.0 Å) over cycle times.\n5-X\nOn Page 18:\nTo determine the stability of the membranes, the HTiNbO membranes are tested for\n5-X\nfour cycles of recyclability test. As shown in Fig. S45, the membrane exhibited high\nstability in both the permeance and conversion of the solution. The conversion of benzyl\nalcohol remained unchanged at almost 100% for all operation cycles. In Fig. S46, we\nconducted a continuous confined reaction for evaluating reactivity and practicality of\nthe membrane. After more than 13 days of reaction, the products were collected in Fig.\nS46a. According to the theoretical expected product quality, the yield was calculated\nabout 87.5%. The loss of products mainly comes from the processes of filtration\nreaction and sample collection. The products were also analyzed by 1H NMR\nspectroscopy, and characteristic signals of benzyl alcohol completely disappeablue\nwhich means a 100% conversion. The benzyl acetate collected by the confined reaction\nis almost colorless. To gain insights into stability of oxygen vacancy, XPS spectra of\nHTiNbO membranes were performed after the long-term stability test. As shown in\n5-X\nFig. S47, O 1s can be divided into three fitting peaks that is lattice oxygen at 530.4 eV,\noxygen vacancy at 531.3 eV and organic oxygen at 532.9 eV. Due to the relatively mild\nreaction conditions, the signal peak of oxygen vacancies did not show any signs of\nweakening or disappearing. Therefore, it can be confirmed that HTiNbO membranes\n5-X\nare very stable during the reaction process.\nOn Page 28:\nRecyclability test\nThe experimental procedures were the same as confined reaction: HTiNbO\n5-X\nmembranes (d=11.0 Å), benzyl alcohol (0.2 M) and acetic anhydride (0.3 M) in\nacetonitrile (10 mL). After the complete filtration of 10 mL of reaction solution (about\n100 h), substances flowing through the membranes were collected and analyzed by 1H\nNMR spectroscopy for each cycle. Acetonitrile (2 mL) was utilized to rinse the bottom\nsurface of the membrane and dissolve the substances. The solvent was removed under\nblueuced pressure on a rotary evaporator and the obtained concentrate was dissolved in\nDMSO-D6. After that, the HTiNbO membranes (d=11.0 Å) was tested for another\n5-X\ncycle, by adding acetonitrile solution (10 mL) of alcohol (0.2 M) and acetic anhydride\n(0.3 M).\nAfter reaction\nBefore reaction\n536 534 532 530 528 526\nFig. S47. O 1s XPS spectra of HTiNbO membranes (d=11.0 Å) before and after\n5-X\ncontinuous confined reaction.\nComment 7: The comparison with literature values is useful, but a direct catalytic\nactivity comparison (e.g., turnover frequency) against commercial catalysts would\nstrengthen the study’s industrial relevance. Additionally, how does this membrane\nreactor compare with previously reported catalytic systems such as COFs and LDHs in\nterms of reaction rates, TOF, and catalyst stability?\nResponse: Thank you very much for your good comment!\n).\nu.a(\nytisnetnI\nO 1s\nLattice O\nV 529.7 eV\nO\n531.5 eV\nV Lattice O\nO\n531.3 eV 530.4 eV\nOrganic C-O\n532.9 eV\nBinding energy (eV)\nThe esterification of alcohols with organic acids is a conversion of both environmental\nand industrial importance. In our work, the esterification of alcohols with acetic\nanhydride is used as a model reaction to test the improved performance. Conventionally,\nthe esterification of benzyl alcohol with acetic acid or acetic anhydride is performed in\nthe presence of mineral acids catalysts (e.g., H SO ). However, the inherent\n2 4\ndisadvantages related with the homogeneous system lie in separation and purification\nof the products, resulting in the environmental problems and economical\ninconveniences. In order to tackle these problems, a wide range of heterogeneous solid\nacid catalysts have been developed, such as zeolite molecular sieves, heteropoly acids,\nand acidic resins. In the revised essay, three types of commercial solid acid catalysts,\nHZSM-5 (zeolite molecular sieves), H O PW ·xH O (heteropoly acids) and\n3 40 12 2\namberlyst-15 (acidic resins), were purchased for comparison. Amberlyst-15 ion-\nexchange resins are Brønsted acidic catalysts with acid strength equivalent to 60%\nsulfuric acid. H\n12\n·xH\nacidity than common inorganic strong acids, such as HCl and HNO .\n3\na b c\nFig. R1. (a) Photograph of reaction solution with H\n12\n·xH\nreaction solution with amberlyst-15 ion-exchange resins. (c) Photograph of reaction\nsolution with HZSM-5.\nTable S5. Comparison of HTiNbO membranes (d=11.0 Å) with commercial solid\n5-X\nacid catalysts.\nEntry Catalyst Reactant Concentration Time Conversion (%)\n5-X\n5-X\n3 40 12 2\n5-X\n5-X\n3 40 12 2\n5-X\n5-X\n3 40 12 2\nBulk reaction condition: catalyst (10 mg), benzyl alcohol, acetic anhydride or acetic\nacid, CH CN (10 mL) at 23 °C. Confined reaction condition: HTiNbO membrane\n3 5-X\n(d=11.0 Å), benzyl alcohol, acetic anhydride or acetic acid, CH CN (10 mL) at 23 °C.\n3 40 12 2\nand amberlyst-15 are superior to HZSM-5 and HTiNbO nanosheets in the bulk\n5-X\nreaction (Table S5). This is mainly attributed to their stronger acidity. In comparison,\nthe catalytic activity of the HTiNbO membrane is superior to that of\n5-X\nH O PW ·xH O and amberlyst-15. The conversion rate the HTiNbO membrane\n3 40 12 2 5-X\nreaches 100% within 26.6 s and TON is 28 times higher than that of HTiNbO\n5-X\nnanosheets. It's worth noting that the catalyst dosage in bulk condition is 10 mg,\nwhereas that of in confined system is calculated to be only 1.68 mg. Besides, both\nH O PW ·xH O and amberlyst-15 exhibit poor activity for the esterification of acetic\n3 40 12 2\nacid and benzyl alcohol. The conversion rate of the HTiNbO membrane reaches 22.3 %\n5-X\nwithin 23.9 s. In the bulk system, the reaction is typically limited by temperature,\nstirring time and activity of the substrate itself. These results demonstrate the\nadvantages of HTiNbO membranes in conversion, catalyst dosage and reaction time.\n5-X\na b c\nFig. S45. (a) Photograph of benzyl acetate collected by continuous confined reaction of\nHTiNbO\n5-X\nmembrane. The mass of the collected benzyl acetate is 1.3709 g, and the\ncalculated yield is about 87.5%. Confined reaction condition: HTiNbO membranes\n5-X\n(d = 11.0 Å), benzyl alcohol (0.2 M) and acetic anhydride (0.3 M) in CH CN (30 mL)\n3\nat 23 °C (b) Photograph of benzyl acetate collected by bulk reaction with\nH\n12\n·xH\nreaction amberlyst-15 as catalyst.\nAfter reaction, the benzyl acetate produced by H O PW ·xH O and amberlyst-15 was\n3 40 12 2\ncollected separately. The H O PW ·xH O was dissolved in the product benzyl acetate,\n3 40 12 2\nand the collected benzyl acetate exhibits a light golden color (Fig. R1 and S46). By\ncontrast, benzyl acetate collected by the confined reaction is almost colorless. The\nindustrial application of heteropolyacid is limited by its difficulty in recovery and\nrecycling when used as a catalyst. The Amberlyst-15 ion-exchange resins were easily\nseparated from solutions, but the collected benzyl acetate shows a noticeable orange\ncolor after standing for a week. This signifies that the collected benzyl acetate contains\nimpurities, possibly due to the unstable structure of the amberlyst-15. According to\nprevious work, Amberlyst-15 have low thermal stability, and present a risk of leaching\nstyrene monomers, potential human carcinogens (Chem. Eng. J. 2023, 476, 146586).\nThese results have demonstrated the advantages of HTiNbO\n5-X\nmembrane reactors in\ncatalyst separation and product purity. (Please see the blue text of the Results)\nOn Page 11:\nUlteriorly, three types of commercial solid acid catalysts, HZSM-5 (zeolite molecular\nsieves), H O PW ·xH O (heteropoly acids) and amberlyst-15 (acidic resins), were\n3 40 12 2\npurchased for comparison. Under the premise of the same concentrations, the\nperformances of H O PW ·xH O and amberlyst-15 are superior to HZSM-5 and\n3 40 12 2\nHTiNbO nanosheets in the bulk reaction (Table S5). This is mainly attributed to their\n5-X\nstronger acidity. However, the H O PW ·xH O was dissolved in the product benzyl\n3 40 12 2\nacetate, and the collected benzyl acetate exhibits a light golden colour (Fig. S46). The\nAmberlyst-15 ion-exchange resins were easily separated from solutions, but the\ncollected benzyl acetate shows a noticeable orange color after standing for a week. This\nmay be due to the unstable structure of the amberlyst-15.35 These results demonstrate\nthe advantages of HTiNbO membranes in catalyst separation and product purity.\n5-X\nRelated references in the revised manuscript is given as follows:\n35. Sripada, S. et al. Continuous catalytic esterification using a solid acid activated\ncarbon monolith: Comparison of granular and monolith forms with a commercial\ncatalyst. Chem. Eng. J. 476, 146586 (2023).\n36. Su, F. et al. Advancements in solid acid catalysts for biodiesel production. Green\nChem. 16, 2934 (2014).\nIn the introduction, we write that “the difficulty in preparing of uniform, large sized and\nultrathin 2D nanosheets (e.g., COF, LDH) to create effective confined nanochannels\ngreatly restrict the development of LMR”. As far as we know, the 2D nanosheets (e.g.,\nCOF, LDH) are mainly used in bulk reactions (Appl. Catal. B: Environ. 2019, 243, 415–\n427; Angew. Chem. Int. Ed. 2022, 61, e202210447) or pervaporation membrane (J.\nMembr. Sci. 2024, 691, 122262) for different esters. If these materials can be\nsuccessfully prepablue into LMR, their catalytic activity will be greatly improved. In\nthe Table S4, we have made a detailed comparison of different materials for the\nacylation of benzyl alcohol. Our work demonstrates a promising potential of the metal\noxide nanosheets to create inorganic laminar membrane reactors for continuous organic\nsynthesis.\nThe TOF was also calculated from following equation. The TON of confined reactions\nis 28 times higher than that of bulk reaction, and the TOF of confined reactions is 6.3\ntimes higher than that of bulk reaction. (Please see the blue text of the SI)\nSupporting Information\nCalculation of turnover number (TON) and Turnover frequency (TOF).\nTON refers to the number of molecules converted/produced (N) per active site of the\ncatalyst surface (n). TOF refers to the number of molecules converted/produced (N) per\nactive site of the catalyst surface (n) per unit time (t). The active site number (n) can be\nobtained from mass of the catalyst and overall acidity (HTiNbO nanosheets, 3.885\n5-X\nmmol/g) based on the NH -TPD. The number of alcohol converted (N) can be obtained\n3\nfrom conversion rate, volume and concentration of the reaction solution.\nThe TON was calculated from equation\n𝑁\nTOF =\n𝑛\nThe TOF was calculated from equation\n𝑁\nTOF =\n𝑛×𝑡\nFor bulk reactions: HTiNbO nanosheet powder (10 mg), benzyl alcohol (0.2 M) in\n5-X\nacetonitrile (10 mL) at 23 °C. The conversion is 21.3 % after 24 h.\n𝑁 0.2𝑚𝑚𝑜𝑙/𝑚𝐿×10𝑚𝐿×21.3%\nTON = = = 10.96\n𝑛 3.885𝑚𝑚𝑜𝑙/𝑔×0.01𝑔\n𝑁 0.2𝑚𝑚𝑜𝑙/𝑚𝐿×10𝑚𝐿×21.3%\nTOF = = = 1.27×10−4 𝑠−1\n𝑛×𝑡 3.885𝑚𝑚𝑜𝑙/𝑔×0.01𝑔×24×3600𝑠\n= 0.76×10−2 𝑚𝑖𝑛−1\nFor confined reactions: HTiNbO membrane (1.68 mg), benzyl alcohol (0.2 M) in\n5-X\nacetonitrile (10 mL) at 23 °C. The reaction solution completely permeates through the\nmembranes after 106 h, and conversion of 100 % can be obtained.\n𝑁 0.2𝑚𝑚𝑜𝑙/𝑚𝐿×10𝑚𝐿×100%\nTON = = = 306.42\n𝑛 3.885𝑚𝑚𝑜𝑙/𝑔×0.00168𝑔\n𝑁 0.2𝑚𝑚𝑜𝑙/𝑚𝐿×10𝑚𝐿×100%\nTOF = = = 8.03×10−4 𝑠−1\n𝑛×𝑡 3.885𝑚𝑚𝑜𝑙/𝑔×0.00168𝑔×106×3600𝑠\n= 4.82×10−2 𝑚𝑖𝑛−1\nComment 8: The presented DFT results suggest that decreasing the interlayer distance\nimproves conversion. Have the authors attempted to blueuce the interlayer spacing\nbelow 11.0 Å?\nResponse: Thank you very much for your good comment! The increased thermal\ntreatment gradually decreases the interlayer spacing of the HTiNbO membranes. As\n5-X\nfor the reaction-state d-spacing of 11.0 Å, the interlayer free distances is calculated to\nbe 4.0 Å after subtracting the thickness of monolayer nanosheets (≈0.7 nm) in the Fig.\nS28 and S29. As shown in the Fig. S12, the theoretically thicknesses of the molecules\ninvolved in esterification are about 4.0 Å. Thus, the interlayer free distances of\nHTiNbO membranes should be greater than 4.0 Å to allow the molecules to pass\n5-X\nthrough (Fig. R2).\nTo verify this, XRD patterns of HTiNbO membranes after thermal treatment at\n5-X\n120 °C were tested. Using the Bragg’s law, the interlayer distances of the dried\nHTiNbO\n5-X\nmembranes were 9.6 Å. After more than 10 hours of reaction, the interlayer\nspacings of the reaction-state HTiNbO\n5-X\nmembranes shift to 10.5 Å. Driven by the\npressure difference, the reactant molecules have to pass through the gaps inside the\nmembrane rather than 2D channel. The flow rate is too slow to collect the product.\na\nd= 14.4 Å d = 7.4 Å\nfree\n(XRD data)\ninterlayer free distances\n4.02×7.00×9.10 Å 4.01×5.34×8.72 Å\nb\nd = 4.0 Å\nd= 11.0 Å free\n(XRD data) interlayer free distances\n4.02×7.00×9.10 Å 4.01×5.34×8.72 Å\nFig. R2. Schematic diagram of the effective molecular transport pathways.\nReaction-state\nDry-state (120 °C)\n10.5 Å 9.6 Å\n)\n.\nu\n.\na\n(\ny\nt\ni\ns\nn\ne\nt\nn\nI\n5 6 7 8 9 10 11 12 13 14 15\nFig. R3. XRD patterns measublue for the dry-state and reaction-state of HTiNbO\n5-X\nmembranes.\nComment 9: The authors should report their synthesis reproducibility (and batch-to-\nbatch variation).\nResponse: Thank you very much for your good comment! The synthesis\nreproducibility is reflected in different parts of the article.\nIn the experimental section, we have taken into account the reproducibility of the\nmembranes. To confirm the uniformity of the stacking, HTiNbO\n5-X\nnanosheet\ndispersion was diluted to 100 mL (≈0.12 mg/mL), after homogeneous dispersion, and\nit was then filtrated with a nylon membrane. This can be confirmed through SEM (Fig.\nS10) and TEM data (Fig. S11). In the Fig. S8a and Fig. 1h, the XRD patterns of\nHTiNbO membranes exhibit sharp (002) diffraction peaks, confirming the uniform\n5-X\nstacking of nanosheets.\nFor catalytic performance tests, we conducted repeated experiments and provided error\nbars for most of the samples. Moreover, we performed continuous confined reaction for\nmore than 13 days in the previous manuscript, and conducted another four cycles of\nexperiments in the revised version (Fig. S45 and S46a). These results all confirm the\nreproducibility of our work.\na\n20 nm 5 nm\nb\n3.6 nm\n)\n.\nu\n.\na\n(\ny\nt\nis\nn 0.7 nm\ne\nt\nn\nI\nThickness (nm)\nFig. S11. (a) FIB-TEM image of the cross-section of HTiNbO membranes. (b) The\n5-X\nintensity profile according to the blue line in (a). The alternating dark and light pattern\nshows the average thickness of one layer of lamellar is about 0.7 nm, which matches\nthe theoretical thickness of the HTiNbO nanosheets.\n5-X\nOn Page 8:\nAs displayed in Fig. S10 and S11, both SEM images and TEM images of the cross-\nsection of membranes revealed the well-ordeblue lamellar structure of the HTiNbO\n5-X\nmembrane. In Fig. S11, the alternating dark and light pattern shows the average\nthickness of one layer of lamellar is 0.7 nm, which matches the theoretical thickness of\nthe HTiNbO nanosheet.\n5-X\nComment 10: What is the distribution of the amorphous vs. crystalline phase\npercentage in the final nanosheets?\nResponse: We thank the reviewer for the comment. Electron microscopy\ncharacterization has been extensively utilized to monitor and quantify the catalyst\nmicrostructures such as grain boundaries and amorphous domains (Nat Commun 2025,\n16, 897; Angew. Chem. Int. Ed. 2023, 62, e202216290; Angew. Chem. Int. Ed. 2019,\n58, 3077-3081). In order to show the statistics of the ratio of amorphous domains, we\nanalyzed two typical HRTEM images of HTiNbO nanosheets. The boundary between\n5-X\nthe crystalline region and the amorphous region is not very clear, which makes it very\ndifficult to accurately calculate the proportion of the two. As shown in the Fig. S24, the\ncrystalline regions occupy a small area of the nanosheet surface, approximately less\nthan one-fourth.\nThe amorphous regions may come from locally structural disorder around the oxygen\nvacancies, whereas oxygen vacancies are consideblue to be Lewis acid sites in Fig. S26.\nThe crystalline regions are coveblue with Brønsted acid sites. Thus, the distribution of\nthe crystalline and amorphous regions should be consistent with the distribution of\nBrønsted and Lewis acid sites. Pyridine infrablue spectroscopy is used to qualitatively\ndistinguish the relative content and distribution of Brønsted acid and Lewis acid sites\non the surface of materials. According to the pyridine FTIR spectra, the distribution of\nBrønsted and Lewis acids are summarized in Table. S2. After evacuation at 200 °C, the\nBrønsted/Lewis acid site ratio is 0.184 for HTiNbO\n5-X\nnanosheets. This results of\ninfrablue spectroscopy are close to that of HRTEM. (Please see the blue text of the\nResults)\na b c\nb\nc\n5 nm 1 nm 1 nm\nd e e f\nf\n5 nm 1 nm 1 nm\nFig. S24. Two typical HRTEM images of HTiNbO\n5-X\nnanosheets. Crystalline regions\nare circled with yellow lines, and amorphous regions are uncircled.\nOn Page 7:\nEven after evacuation at 200 °C, the absorption bands of Brønsted acid sites could still\nbe detected and the Brønsted/Lewis acid ratio is 0.184 for HTiNbO nanosheets,\n5-X\nindicating these samples have good stability and catalytic potential (Table S2).\nOn Page 13:\nNotably, the High-resolution TEM image (HRTEM) reveals that the prepablue\nHTiNbO nanosheets are typically composed of amorphous and crystalline domains\n5-X\n(Fig. 3b). The amorphous structural regions are relatively larger than crystalline regions,\ndemonstrating the low crystallinity of HTiNbO nanosheets, which was consistent\n5-X\nwith XRD results (Fig. S5a and S24).\nRelated references in the revised manuscript is given as follows:\n25. Wang, Y. et al. Ammonia electrosynthesis from nitrate using a stable\namorphous/crystalline dual-phase Cu catalyst. Nat. Commun. 16, 897 (2025).\nTable. S2. The distribution of Brønsted and Lewis acids.\nAcid site density (mmol/g, NH TPD)\nTemperature\nSample acid ratio\n(℃)\n(Pyridine IR)\nTotal Brønsted acid Lewis acid\n50 0.109 4.567 0.449 4.118\nBulk\n100 0.157 4.567 0.620 3.947\nHTiNbO\n5-X\n200 0.203 4.567 0.771 3.796\n50 0.105 3.885 0.369 3.516\nHTiNbO\n5-X\n100 0.166 3.885 0.553 3.332\nnanosheets\n200 0.184 3.885 0.603 3.282\nComment 11: A discussion on how the distribution of Brønsted and Lewis acid sites\nimpacts catalytic performance would be beneficial.\nResponse: Thank you very much for your good comment! Based on your kind advice,\nwe substantially revise the manuscript, strengthen some discussion and analysis. The\ncontribution of Brønsted and Lewis acid sites have discussed in the section of\n“Theoretical calculation for catalytic mechanism”. Both Brønsted acid and Lewis acid\nplay crucial roles at different stages of the reaction. The oxygen vacancies on the surface\nof HTiNbO NS are consideblue as Lewis acid sites in Fig. S26.\n5-X\n1) Increased reactants adsorption: The oxygen vacancies at Nb sites were consideblue\nfor calculation of adsorption energy. The calculated results proved that the adsorption\nenergy (d =40 Å) of BnOH and Ac O in HTiNbO were both higher than that of\nfree 2 5-X\nHTiNbO , indicating the strong adsorption on oxygen vacancy (E =−0.800 eV for\n5 ads\nBnOH, E =−0.584 eV for Ac O). In this case, the oxygen vacancies (Lewis acid sites)\nads 2\nare benefits to the adsorption and activation of the reactants.\n2) Blueuced energy barrier: In Fig. S31, Fig. 4c and 4d, Brønsted acid on the surface of\nHTiNbO nanosheets are employed as the proton donor, and the free energy of the\n5-X\nreaction paths are calculated by DFT. The energies from IM1 to TS1 for the bulk and\nconfined conditions respectively are calculated to be 42.0 kJ/mol and 28.8 kJ/mol. In\nFig. S33 and S34, Lewis acid at Nb sites of HTiNbO nanosheets are also counted as\n5-X\nactive sites for calculation. In this case, the free energy from IM1 to TS1 also delivers\nan obvious decrease from 47.7 kJ/mol to 39.8 kJ/mol for confined conditions. From the\nview point of energy barrier, the Brønsted acid plays a more important role in this case.\nFinally, thank you very much for your kind advice, which has greatly benefited\nour paper!\nReviewer #2\nThis manuscript proposes a concept of using stacked two-dimensional (2D)\namorphous/crystalline HTiNbO nanosheets as sub-nanoconfined membrane reactors\n5-X\nfor the efficient synthesis of acetate ester flavors under mild conditions. The\nexperimental results demonstrate that the esterification of benzyl alcohol achieves\nnearly 100% conversion within 26.6 seconds when the interlayer spacing is blueuced\nto 11.0 Å, significantly outperforming conventional bulk reactions. The concept has\nbeen reported in the previous work (Adv. Mater. 2024, 36, 2310954; Matter 2023, 6,\n1173; Adv. Sci. 2024, 11, 2308388). The manuscript suffers from significant\nshortcomings in mechanistic explanations, model construction, and experimental\nvalidation, which undermine the support for its core scientific claims. As it stands, the\nmanuscript is not suitable for publication.\nResponse: Thank you very much for your good comment! First of all, we sincerely\nthank you for your valuable advices, which is in favor of further improving quality of\nour paper. As we mentioned in the introduction section, the construction of laminar\nmembrane reactors (LMR) is one of the great challenges in material field. In the past\nfew years, there are many reports of LMR for water purification (Nat. Commun. 2024,\n15, 9607; Nat. Commun. 2024, 15, 391; Angew. Chem. Int. Ed. 2019, 58, 8134-8138),\nbut few studies for organic synthesis. In this context, our recent work mainly focused\non the membranes of graphene oxide (2D carbonaceous materials) for organic synthesis\n(Adv. Mater. 2024, 36, 2310954; Matter 2023, 6, 1173; Adv. Sci. 2024, 11, 2308388).\nBy comparison, 2D metallic compounds (e.g., TMO/C) are difficult to modulate the\nmicroenvironment and are rarely reported for organic synthesis. This work provides a\nnew insight to the rational design of LMR of metal oxide via synergistically surface\ndefect and spatial confinement strategies. We believe our manuscript meets the criteria\nof novelty and quality of “Nature Communications”. The additional experimental\nresults have been included in revised manuscript.\nRelated references\n1. Xiao, Q. et al. Ultrafast complete dechlorination enabled by ferrous oxide/graphene\noxide catalytic membranes via nanoconfinement advanced blueuction. Nat. Commun.\n15, 9607 (2024).\n2. Tian, M. et al. Overcoming the permeability-selectivity challenge in water\npurification using two-dimensional cobalt-functionalized vermiculite membrane. Nat.\nCommun. 15, 391 (2024).\n3. Chen, Y. et al. Confining free radicals in close vicinity to contaminants enables\nultrafast fenton-like processes in the interspacing of MoS membranes. Angewandte\nDetailed Comments\nComment 1: Insufficient Mechanistic Explanation and Lack of Direct Evidence\nThe authors attribute the enhanced performance to the synergistic effect of oxygen\nvacancies and sub-nanoscale confinement. However, the following issues remain\nunresolved:\nComment 1a: Direct Role of Oxygen Vacancies Not Clearly Demonstrated: Although\nXPS and EPR characterizations suggest the presence of oxygen vacancies, no control\nexperiments (e.g., synthesizing HTiNbO membranes without oxygen vacancies)\n5-X\nwere conducted to confirm their necessity. Without such experiments, it is impossible\nto rule out the dominant role of other factors, such as surface acid sites or differences\nin interlayer mass transport.\nResponse: We thank the reviewer for his/her comments. We have also noticed the\nquestion based on your kind comments, which is benefit for further understanding the\nkey role of oxygen vacancies. Oxygen vacancies in catalysts can blueuce the\ncoordination number of neighboring atoms and create enriched unsaturated sites\nessential for the adsorption and activation of reactant molecules. However, engineering\noxygen vacancies at a level where their types and relative abundances can be controlled\nand precisely identified remains a significant challenge.\nTo confirm the necessity of oxygen vacancies, the adsorption of reactants at oxygen\nvacancies was detected by Raman spectroscopy and XPS spectroscopy. After a specific\ntime of reaction (0 h, 0.5 h, 1 h and 12 h), reaction-state membranes were collected and\ntested by Raman spectra immediately. As the experiment progresses, benzyl alcohol\nand acetic anhydride molecules gradually move through and react within the sub-\nnanoconfined channels. In fig. S27, the peak of Nb=O shifted from 940 cm-1 to 948 cm-\n1. This can be attributed to the adsorption of reactant molecules at oxygen vacancies at\nNb sites. The strong electrophilic properties of the oxygen vacancy are beneficial to its\nadsorption with oxygen containing groups of acetic anhydride and benzyl alcohol.\n(Please see the blue text of the Results)\nConfined reaction-12 h\nTi=O Confined reaction-1 h\nConfined reaction-0.5 h\n) u . Confined reaction-0 h\nNb=O\n. Nb−O\na\n( Ti−O\ny\nt\ni\ns\nn\ne\nt\nn\nI\n948 940\n1200 1000 800 600 400 200\nRaman shift (cm-1)\nFig. S27. Raman spectra of HTiNbO membranes (d=11.0 Å) before and after\n5-X\nreaction. After a specific time of reaction (0 h, 0.5 h, 1 h and 12 h), reaction-state\nmembranes were collected and tested by Raman spectra immediately.\nH\n②Protonation\nO O\n①Adsorption\nNb Ti Nb Nb Ti Nb\nV H IM1\nO\nO\nNb Ti Nb ③Nucleophilic addition\n⑤Deprotonation\nO ④Dissociation O\nNb Ti Nb Nb Ti Nb\nIM3 IM2\nFig. R4. Processes of esterification reaction. Acetic anhydride molecules adsorb at the\noxygen vacancies, and are protonated by Bronsted acid nearby.\nOn Page 14:\nBefore theoretical calculations, we undertook in-situ Raman studies to understand the\nintricate interaction between reactant molecules and oxygen vacancies (Fig. S27). The\nstrong electrophilic properties of the oxygen vacancy are beneficial to its adsorption\nwith oxygen containing groups of acetic anhydride and benzyl alcohol. As the\nexperiment progresses, benzyl alcohol and acetic anhydride molecules gradually move\nthrough and react within the HTiNbO membranes. In fig. S27, the peak of Nb=O\n5-X\ngradually shifted from 940 cm-1 to 948 cm-1, whereas other peaks show no obvious shift.\nThis can be attributed to the adsorption of reactant molecules at oxygen vacancies at\nNb sites.21 Therefore, the oxygen vacancies at Nb sites were consideblue for\ncalculation.29,30\nSupporting Information\nIn situ Raman of HTiNbO membranes.\n5-X\nThe experimental procedures were the same as confined reaction: HTiNbO\n5-X\nmembranes (d = 11.0 Å), benzyl alcohol (0.2 M) and acetic anhydride (0.3 M) in\nCH CN. After a specific time of reaction (0 h, 0.5 h, 1 h and 12 h), reaction-state\n3\nmembranes were collected and tested by Raman immediately. The membranes were\ntransferblue onto the detection platform and then examined from 200 to 1200 cm-1 with\n532 nm laser irradiation.\nAccording to Raman spectroscopy, the oxygen vacancies are benefits to the adsorption\nand activation of the reactants. To quantitatively estimate the concentrations of oxygen\nvacancy, XPS spectra of HTiNbO\n5-X\nmembranes were performed and split after thermal\ntreatment at different temperatures. As shown in Fig. S22 and Table S6, O 1s can be\ndivided into two fitting peaks that is lattice oxygen and oxygen vacancy. The position\nof these peaks hold stable states during the vacuum thermal treatment of HTiNbO\n5-X\nmembranes. However, as the thermal treatment temperature increases, the content of\noxygen vacancies gradually decreases from 29.2% to 22.5%. This can be attributed that\nthe thermal treatment process results in partial loss of oxygen vacancies. This can also\nbe confirmed by the decreased mass loss in oxygen atmosphere (Fig. 3d) and increased\nBrønsted/Lewis acid ratio for HTiNbO\n5-X\nnanosheets (Table S2) with increasing of\ntemperature. To gain insights into the role of oxygen vacancy, the nanosheets of\nHTiNbO membranes after thermal treatment at 100 °C were collected for bulk\n5-X\nreaction. Under the premise of the same concentrations, the performances of the\nnanosheets decreases from 21.3% to 8.6%. For the bulk reaction, the energy barrier\nmainly derives from the disordeblue motion and inefficient adsorption of molecules to\nthe active sites. For the confined reaction, adsorption of molecules are promoted by\noxygen vacancies and confinement effect according to theoretical calculations.\nTherefore, it can be confirmed that oxygen vacancies play a key role during the reaction\nprocess. (Please see the blue text of the Results)\nRelated references\n1. Chen, K. et al. A facile approach for generating ordeblue oxygen vacancies in metal\noxides. Nat. Mater. (2025). https://doi.org/10.1038/s41563-025-02171-4.\n2. Yu, B. et al. Defect Engineering Enables Synergistic Action of Enzyme-Mimicking\nActive Centers for High-Efficiency Tumor Therapy. J. Am. Chem. Soc. 143, 8855-8865\n(2021).\n3. Lu, Y. et al. Tailoring competitive adsorption sites by oxygen-vacancy on cobalt\noxides to enhance the electrooxidation of biomass. Adv. Mater. 34, 2107185 (2022).\na b\nO 1s N 1s\n100 °C dry\n100 °C dry\n80 °C dry\n) . 80 °C dry ) .\nu u\n. .\na a\n( (\ny y 60 °C dry\nt t\nis 60 °C dry is\nn n\ne e\nt t\nn n\nI I 40 °C dry\n40 °C dry\nLattice O\nV O 529.7 eV 401.8 eV\n531.4 eV 23°C dry\n23 °C dry\n534 532 530 528 526 408 405 402 399 396\nBinding energy (eV) Binding energy (eV)\nFig. S22. (a) O 1s and (b) N 1s XPS spectra of HTiNbO membranes after thermal\n5-X\ntreatment at different temperatures.\nTable. S6. The XPS elemental composition analysis for HTiNbO membranes\n5-X\ntreating at different temperatures.\nEntry 23 °C dry 40 °C dry 60 °C dry 80 °C dry 100 °C dry\nC (atomic %) 44.16 44.23 44.02 43.91 44.13\nN (atomic %) 2.96 2.98 2.95 2.99 2.96\nNb (atomic %) 7.14 7.13 7.16 7.16 7.15\nTi (atomic %) 7.69 7.63 7.78 7.83 7.81\nO (atomic %) 38.05 38.03 38.10 38.11 37.95\nOxygen vacancy (%) 29.2 27.5 28.1 25.6 22.5\nLattice oxygen (%) 70.8 72.5 71.9 74.4 77.5\nTable. S2. The distribution of Brønsted and Lewis acids.\nAcid site density (mmol/g, NH TPD)\nTemperature\nSample acid ratio\n(℃)\n(Pyridine IR)\nTotal Brønsted acid Lewis acid\n50 0.109 4.567 0.449 4.118\nBulk\n100 0.157 4.567 0.620 3.947\nHTiNbO\n5-X\n200 0.203 4.567 0.771 3.796\n50 0.105 3.885 0.369 3.516\nHTiNbO\n5-X\n100 0.166 3.885 0.553 3.332\nnanosheets\n200 0.184 3.885 0.603 3.282\nOn Page 12:\nThe shoulder peak at 531.3 eV typically corresponds to adsorbed oxygen around\noxygen vacancy sites.27,38 As for HTiNbO membranes, the position of these peaks\n5-X\nhold the stable during the vacuum thermal treatment (Fig. S22). Notably, when the\ntemperature increases, the content of oxygen vacancies gradually decreases from 29.2%\nto 22.5% (Table S6). To gain insights into the role of oxygen vacancy, the nanosheets\nof HTiNbO membranes after thermal treatment at 100 °C were collected for bulk\n5-X\nreaction. Under the same dosages, the performances of the nanosheets decreases from\n21.3% to 8.6%. Thus, it can be confirmed that oxygen vacancies play a key role during\nthe reaction process.\nIn the calculation of adsorption energy, we have already consideblue the effects of\nsurface acid sites and interlayer distances. The surface acid sites of nanosheets of\nHTiNbO (no defects) are Brønsted acid sites. The calculated results proved that the\n5\nadsorption energy (d = 40 Å) of BnOH and Ac O in HTiNbO (no defects) were both\nfree 2 5\nsmaller than that of HTiNbO . The energies were further improved greatly when the\n5-X\nd decreased to 4 Å, both for HTiNbO and HTiNbO .\nfree 5 5-X\nComment 1b: Lack of Empirical Evidence for Orbital Symmetry Matching: The\nmanuscript claims that HOMO-LUMO symmetry matching (Fig. 1j) is responsible for\nthe accelerated reaction, but no direct evidence (e.g., in situ spectroscopy such as\nRaman or XAS) is provided. Reliance solely on DFT calculations is insufficient to\nsupport this key mechanistic claim.\nResponse: Thank you very much for your good comment! Firstly, thanks for reviewer’s\nvaluable advice, this suggestion is meaningful and very helpful for revising and\nimproving our paper, as well as the important guiding significance to our researches. In\nFig. 1j, the HOMO of the benzyl alcohol and the LUMO of protonated acetic anhydride\nare displayed. The protonated acetic anhydride is key reaction intermediates. In the\nComment 1a, Raman spectra have been used to detect the adsorption of reactants at\noxygen vacancies. In our research system, ATR FTIR spectra are more suitable for the\ninvestigation of reaction pathways (Angew. Chem. Int. Ed. 2025, 64, e202503901).\nATR FTIR spectroscopy can detect the reaction intermediates and products within the\nmembranes. After a specific time of reaction (0 h, 0.5 h, 1 h and 12 h), reaction-state\nmembranes were collected and tested by ATR FTIR spectra immediately. As the\nexperiment progresses, acetic anhydride molecules gradually move through the\nmembranes. For acid anhydride, the peaks at 1756 cm-1 and 1827 cm-1 are assigned to\nthe stretching mode of C=O. After more than 1 hour of filtration, these peaks are\ngradually blue shifted to 1752 cm-1 and 1822 cm-1, which should attribute to the\nprotonation of acetic anhydrides (Journal of Catalysis 2004, 228, 225-233; Surface\nScience 2007, 601, 1822-1830). After 12 hours of confined flow reaction, benzyl\nacetate (product) is enriched inside the membrane. The stretching mode of C=O and C-\nO for the ester is significantly enhanced at around 1709 cm-1 and 1232 cm-1. These are\ndirect observations of reaction intermediates and products. (Please see the blue text of\nthe Results)\n)\n.\nu\n.\na\n(\ne\nc\nn\na\nt\nt Confined reaction-12 h\ni\nm\nConfined reaction-1 h\ns Confined reaction-0.5 h\nn\na Confined reaction-0 h\nr Acetic anhydride\nT\nBenzyl alcohol\n4000 3500 3000 2500 2000 1500 1000 500\nWavenumber (cm-1)\n)\n.\nu\n.\na 1828 1756\n(\ne\nc\nn\na\nt\nt Red shift 1822\ni m C=O of ACO\n2\n1752\ns 1232\nn +H+ C=O of ester C−O of ester\na\nr\nT\n2000 1800 1600 1400 1200\nWavenumber (cm-1)\nFig. S30. ATR FTIR spectra of HTiNbO membranes (d=11.0 Å) before and after\n5-X\nreaction. After a specific time of reaction (0 h, 0.5 h, 1 h and 12 h), reaction-state\nmembranes were collected and tested by ATR FTIR spectra immediately.\nOn Page 15:\nATR FTIR measurements were performed to gain further insights into the reaction\nprogression (Fig. S30). These investigations enabled the in-situ monitoring of the\nchemical transformations occurring within the HTiNbO membranes. After a specific\n5-X\ntime of reaction (0 h, 0.5 h, 1 h and 12 h), reaction-state membranes were collected and\ntested by ATR FTIR spectra immediately. For acid anhydride, the peaks at 1756 cm-1\nand 1828 cm-1 are assigned to the stretching mode of C=O. As the experiment\nprogresses, these peaks are blue shifted to 1752 cm-1 and 1822 cm-1, which should\nattribute to the protonation of acetic anhydrides.49,50 After 12 hours of confined flow\nreaction, benzyl acetate (product) is enriched inside the membrane. The stretching mode\nof C=O and C-O for the ester is significantly enhanced at around 1709 cm-1 and 1232\ncm-1. These are direct observations of reaction intermediates and products.\nRelated references in the revised manuscript is given as follows:\n50. Collins, S. E. et al. Acylating capacity of the phosphotungstic Wells-Dawson\nheteropoly acid: intermediate reactive species. J. Phys. Chem. C 115, 700-709 (2011).\n51. Bachiller-Baeza, B. et al. FTIR and reaction studies of the acylation of anisole with\nacetic anhydride over supported HPA catalysts. J. Catal. 228, 225-233 (2004).\nSupporting Information\nIn situ ATR-FTIR of HTiNbO membranes.\n5-X\nTo better understand the intermediate products during the catalytic process, we carried\nout in situ ATR-FTIR experiments. The reaction-state membranes were transferblue\nonto the detection platform promptly. The spectrum was examined at certain time\nintervals (0 h, 0.5 h, 1 h and 12 h) with wavelengths from 400 to 4000 cm-1.\nComment 2: Unclear Theoretical Model Construction\nComment 2a: Questionable Validity of the Confined Reaction Model: The differences\nbetween the DFT models for \"confined reaction\" and \"bulk reaction\" are not clearly\nexplained. For instance, when the interlayer spacing is blueuced to 4 Å, how is the\nmodel's consistency with the actual material structure (e.g., oxygen vacancy\ndistribution, surface functional groups) ensublue? Are solvation effects or dynamic\nadsorption processes consideblue?\nResponse: We express our gratitude to the reviewer for this important suggestion. The\nbulk reaction is modeled using a slab model with a 40 Å vacuum space, which is a\nstandard approach for simulating reactions in surface environments. For the confined\nreaction, we use an interlayer spacing of 4 Å, which is consistent with experimental\nobservations. Specifically, the interlayer free distance (d ) is calculated to be 4 Å after\nfree\nsubtracting the monolayer nanosheet thickness (~0.7 nm) from the d-spacing of 11.0 Å,\naligning with reported values for nanoporous materials. This blueuction in interlayer\nspacing captures the effects of nanoscale confinement. While dynamic adsorption\nprocesses are not consideblue in the current model, we do account for solvation effects\nin the DFT calculations, which allows us to include the influence of solvent interactions\non the reaction mechanism.\nComment 2b: Discrepancy between computational parameters and experimental\nconditions: The manuscript does not clarify whether the interlayer spacings used in the\ncalculations (e.g., 40 Å vs. 4 Å) correspond to the experimentally measublue XRD data\n(e.g., 11.0 Å). If the model parameters do not match the experimental conditions, the\ncomputational results lose their explanatory power.\nResponse: Thanks for your wise and crucial suggestions, this comment is valuable and\nvery helpful for revising and improving our paper, as well as the important guiding\nsignificance to our researches. In the Fig. 1k and Fig. 4b, we compablue the catalytic\nperformance of bulk reactions (HTiNbO nanosheets) and confined reactions\n5-X\n(HTiNbO membranes, d=11.0 Å, d =4.0 Å). In the Fig. 3e and Fig. 3f, the\n5-X free\nadsorption energy of reactants in bulk states and confined states are calculated. The\ndetermination of interlayer spacing in the calculations is based on the following reasons.\nIn the Fig. 1h and Table S3, the interlayer spacing of the reaction-state HTiNbO\n5-X\nmembranes decreases monotonically. When the interlayer spacing turned to 11.0 Å,\nnearly complete conversion (≈100%) was achieved. Considering the thickness of\nmonolayer nanosheets (≈0.7 nm), interlayer free distances (d ) for reactant molecular\nfree\ntransport are determined to be approximately 4.0 Å. Thus, the 4 Å interlayer spacing in\nthe confined model is designed to represent nanoscale confinement and is consistent\nwith the experimentally observed interlayer free distance.\nFor bulk reaction, HTiNbO nanosheets as a heterogeneous catalyst were dispersed\n5-X\ninto the solution. In heterogeneous catalysis, reactants need to diffuse from the bulk\nsolution to the surface of the catalyst for reaction, and reactants are not subject to\nconfinement effects. Thus, the 40 Å vacuum space in the bulk model is used to simulate\nthe surface environment, ensuring that the slab model remains sufficiently isolated. This\ndistance is large enough compablue to the size of the reactants (benzyl alcohol:\n4.02×7.00×9.10 Å; acetic anhydride: 4.01×5.34×8.72 Å) in the Fig. S12. Therefore,\nwhile the interlayer spacing does not directly match the XRD data (bulk reaction), the\nmodel parameters are selected to effectively capture the key aspects of confinement and\nsurface interactions, which align with experimental observations in similar catalytic\nsystems.\nOn Page 15:\nConsidering the reaction-state interlayer spacing (11.0 Å) and thickness of monolayer\nnanosheets (0.7 nm), the interlayer free distances (d ) of 4 Å were taken to simulate\nfree\nthe adsorption behavior of confined reaction (Fig. S28 and S29). For bulk reaction, the\n40 Å vacuum space is used to simulate the surface environment, ensuring that the slab\nmodel remains sufficiently isolated.15,49 This distance is large enough compablue to the\nsize of the reactants (benzyl alcohol: 4.02×7.00×9.10 Å; acetic anhydride:\n4.01×5.34×8.72 Å) in the Fig. S12.\nComment 3: Limitations in Material Characterization and Reactor Design\nComment 3a: Lack of Verification of Interlayer Spacing Uniformity: While SEM and\nXRD data suggest an ordeblue layeblue structure, high-resolution characterization (e.g.,\nHAADF-STEM) is needed to confirm the local uniformity of nanosheet stacking.\nStacking defects or interlayer inhomogeneity could significantly affect the\nreproducibility of the reaction.\nResponse: We thank the reviewer for the valuable suggestion.\nFocused ion beam/scanning electron microscopy (FIB-SEM) techniques are used to the\npreparation of TEM section of HTiNbO\n5-X\nmembranes. As shown in the Fig.S11,\nHRTEM images demonstrate that the HTiNbO membranes possess a highly ordeblue\n5-X\nstacking arrangement. In the experimental section, we have taken into account the\nreproducibility of the experiment. To confirm the uniformity of the stacking, HTiNbO\n5-\nnanosheet dispersion was diluted to 100 mL (≈0.12 mg/mL), after homogeneous\nX\ndispersion, and it was then filtrated with a nylon membrane. This can be confirmed\nthrough SEM and XRD data. In the Fig. S8a and 1h, the XRD patterns of HTiNbO\n5-X\nmembranes exhibit sharp (002) diffraction peaks. In the Fig. S10, the cross-section\nimages of membranes reveal the well-ordeblue lamellar structure of the HTiNbO\n5-X\nmembranes. These results all indicate that the HTiNbO membranes possessed a\n5-X\nhighly ordeblue stacking arrangement. (Please see the blue text of the Results)\na\n20 nm 5 nm\nb\n3.6 nm\n)\n.\nu\n.\na\n(\ny\nt\nis\nn 0.7 nm\ne\nt\nn\nI\nThickness (nm)\nFig. S11. (a) FIB-TEM image of the cross-section of HTiNbO membranes. (b) The\n5-X\nintensity profile according to the blue line in (a). The alternating dark and light pattern\nshows the average thickness of one layer of lamellar is about 0.7 nm, which matches\nthe theoretical thickness of the HTiNbO\n5-X\nnanosheets. The interlayer distances is\ncalculated to be 0.9 nm, which is close to the XRD results (10.2 Å) of the dry-state of\nHTiNbO membranes.\n5-X\nOn Page 8:\nAs displayed in Fig. S10 and S11, both SEM images and TEM images of the cross-\nsection of membranes revealed the well-ordeblue lamellar structure of the HTiNbO\n5-X\nmembrane. In Fig. S11, the alternating dark and light pattern shows the average\nthickness of one layer of lamellar is 0.7 nm, which matches the theoretical thickness of\nthe HTiNbO nanosheet.\n5-X\nComment 3b: Mass Transport Effects Not Excluded: The experimental results (e.g.,\nthe relationship between reaction time and interlayer spacing) may be dominated by\nmass transport rates rather than catalytic activity. Additional experiments (e.g., varying\nflow rates at fixed interlayer spacing) are needed to distinguish the contributions of\nmass transport and catalysis.\nResponse: Thank you very much for your good suggestion! This comment is valuable\nand very helpful for revising and improving our paper, as well as the important guiding\nsignificance to our researches. We adjusted the flux of HTiNbO membranes (d=14.4\n5-X\nÅ) by adjusting the pressure differences, and tested the effect of different retention time\non the large interlayer spacing membrane reaction. The flow volume of the reaction\nsolution was still linear with time under different pressures (Fig. S16). When the\npressure difference decreased to 0.3 atm and 0.6 atm (Table. R1), the reaction mixture\nhad a lower flux but a higher reaction time through the HTiNbO membranes (d=14.4\n5-X\nÅ). However, compablue to the HTiNbO\n5-X\nmembranes (d=11.0 Å) at 0.9 atm, the\npermeation solution of HTiNbO membranes (d=14.4 Å) at 0.3 atm still had lower\n5-X\nconversion, even though the reaction time has almost doubled. This results indicates\nthat extending reaction time slightly increase benzyl alcohol conversion, but blueucing\ninterlayer spacing significantly promotes esterification reactivity. (Please see the blue\ntext of the Results)\nOn Page 10:\nMoreover, the effect of different reaction times on the conversion is further investigated\nby adjusting the operating pressure difference (Fig. S16). When the pressure difference\ndecreased to 0.3 atm and 0.6 atm, the reaction mixture had a lower flux and a higher\nreaction time through the HTiNbO membranes (d = 14.4 Å). Even though the\n5-X\nreaction time greatly increased to 27.5 s and 48.1 s, the conversions of benzyl alcohol\nonly improved to 53.2% and 65.6% (Fig. S16b). This results indicates that extending\nreaction time slightly increase benzyl alcohol conversion, but blueucing interlayer\nspacing significantly promotes esterification reactivity.\nTable. R1. The conversion of reaction solution through HTiNbO membranes (d =\n5-X\n14.4 Å) with different pressure differences and retention time.\nd=11.0 Å d=14.4 Å d=14.4 Å d=14.4 Å\n(0.9 atm) (0.3 atm) (0.6 atm) (0.9 atm)\nTime (s) 26.6 48.1 27.5 12.8\nPermeance\n0.314 0.279 0.488 1.047\n(L m-2 h-1 atm-1)\nConversion (%) 100 65.6 53.2 28.2\na\n20\n0.9 atm (11.0 Å)\n0.3 atm (14.4 Å)\n0.6 atm (14.4 Å)\n15\n0.9 atm (14.4 Å)\n)\nL\nm 10\n(\nw\no\nl 5\nF\n0\n0 10 20 30 40 50\nTime (h)\nb\n100\n)\n% 80\n(\nn\no\n60\ni\ns\nr\ne\nv 40\nn\no\nC 0.9 atm (11.0 Å)\n20 0.9 atm (14.4 Å)\n0.6 atm (14.4 Å)\n0.3 atm (14.4 Å)\n0\n10 20 30 40 50\nReaction time (s)\nFig. S16. (a) Flow curves of reaction solution through HTiNbO membranes (d =\n5-X\n14.4 Å) under different pressure differences. (b) The conversion of reaction solution\nthrough HTiNbO membranes (d = 14.4 Å) with different reaction time.\n5-X\nFinally, thank you very much for your guidance on our paper, which has been of\ngreat benefit to us!\nReviewer #3\nThe authors reported the creation of a HTiNbO membrane for esterification of benzyl\n5-X\nalcohol with acetic anhydride to yield benzyl acetate and other derivatives (depending\non type of benzyl alcohol used). Comprehensive and complementary characterisation\ntechniques were used to provide robust evidence that demonstrated the noteworthy\nesterification rates and turnover numbers. The mechanism underpinning delivery of\nsuch results were evaluated using suitable simulation methodology. Although the\nresearch and work merits publication in Nature Communication, there was a major flaw\nin the design of the experiments. The authors should carefully address these questions\nto improve the quality of the manuscript that is underpinned by solid, and interesting\nresults before it can be published in Nat. Commun.\nResponse: We are grateful to Reviewer 3 for your high evaluation of our work. We\nhave revised manuscript with additional experimental data to better support our findings,\nand have carefully prepablue detailed point-to-point responses to address each of\ncomments below.\nThe following questions and comments outline my concerns about experimental design\nassociated with this paper:\nComment 1: What is the motivation to develop a membrane for esterification of benzyl\nalcohol? Existing methods are already well-established and effective. Hence it was\nunclear why this work is important scientifically or industrially. The only segment of\nthe manuscript that compablue the performance of the current membranes with other\ncatalysts was only limited to Lines 230 to 236. There were no analyses on why their\nmembranes are better than existing catalysts beyond catalysis performance.\nResponse: Thanks for your wise and crucial suggestions, this comment is valuable and\nvery helpful for revising and improving our paper. Based on your good advice, we have\ncarefully studied lots of the reported literatures about membrane reactor and\nesterification of benzyl alcohol.\nSub-nanometer-confined reaction is the ultimate frontier of catalytic chemistry, yet it is\nchallenging to form the angstrom channels with distributed atomic catalytic centers\nwithin. Herein, amorphous/crystalline HTiNbO nanosheets with abundant oxygen\n5-X\nvacancy were successfully prepablue and stacked as 2D sub-nanoconfined membrane\nflow reactors. The Brønsted acid sites and oxygen vacancies are engineeblue onto the\nHTiNbO nanosheets by acid etching. The synergy of multiple sites and confined\n5-X\nspatial structures are realized in this laminar membrane reactor. Up to now, no works\nregarding these factors associates for organic reaction tuning have been reported. Thus,\nthis work is important scientifically.\nThe esterification of alcohols with acetic anhydride is used as a model reaction, because\nit is a conversion of both environmental and industrial importance. Conventionally, the\nesterification of benzyl alcohol with acetic acid or acetic anhydride is performed in the\npresence of mineral acids catalysts (e.g., H SO ). However, the inherent disadvantages\n2 4\nrelated with the homogeneous system lie in separation and purification of the products,\nresulting in the environmental problems and economical inconveniences. Over the past\nfew decades, various catalytic materials or systems have been exploblue to replace\nmineral acids (Angew. Chem. Int. Ed. 2009, 48, 168-171; Nat. Commun. 2014, 5, 3170;\nAdv. Mater. 2025, 37, 2413949; J. Am. Chem. Soc. 2023, 145, 15680-15687). In this\nwork, we report an outstanding laminar membrane reactors. The Brønsted acid sites and\noxygen vacancies are engineeblue into the 2D sub-nanoconfined channels.\nConsequently, the membrane reactor exhibits ≈ 100% conversion from benzyl alcohol\nto benzyl acetate within 26.6 s at 23 °C and 28 times higher TON than that of bulk\nreaction, and also shows satisfactory performance to other alcohol derivatives. This\nstrategy can provide a reference to other 2D materials and organic synthesis reactions.\nThus, this work has the potential for industrial applications.\nIn the introduction, we provide a further explanation of the importance of our work, and\ncite some relevant references. (Please see the blue text of the Introduction)\nRelated references\n1. Leng, Y. et al. Heteropolyanion-based ionic liquids: reaction-induced self-separation\ncatalysts for esterification. Angew. Chem. Int. Ed. 48, 168-171 (2009).\n2. Zhang, X. et al. Polystyrene sulphonic acid resins with enhanced acid strength via\nmacromolecular self-assembly within confined nanospace. Nat. Commun. 5, 3170\n(2014).\n3. Zhang, J. et al. Joule-heated interfacial catalysis for advanced electrified\nesterification with high conversion and energy efficiency. Adv. Mater. 37, 2413949\n(2025).\n4. Han, J. et al. An electrochemical design for catalytic dehydration: direct, room-\ntemperature esterification without acid or base additives. J. Am. Chem. Soc. 145, 15680-\n15687 (2023).\nOn Page 3:\nOver the past few decades, various catalytic materials, including solid acids, ionic\nliquids and inorganic salts, have been exploblue to replace mineral acids (e.g., H SO )\n2 4\nfor serious corrosion and contamination issues.2,3 Recently, the growing traction for\nsustainable processing has resulted in a transition from conventional batch reactors to\nadvanced catalysis reactors.4 Membrane reactors, as a continuous flow technology,\noffers many advantages including absence catalyst separation, precise temperature\ncontrol and blueuced power consumption.5\nRelated references in the revised manuscript is given as follows:\n4. Yao, P. et al. Greener and higher conversion of esterification via interfacial\nphotothermal catalysis. Nat. Sustain. 5, 348-356 (2022).\n5. Xiao, Q. et al. Ultrafast complete dechlorination enabled by ferrous oxide/graphene\noxide catalytic membranes via nanoconfinement advanced blueuction. Nat. Commun.\n15, 9607 (2024).\nOn Page 5:\n2D metallic compounds (e.g., TMO) are difficult to modulate the microenvironment\nnearby catalytic sites.21 Oxygen vacancies in TMO have demonstrated to be beneficial\nfor many applications due to their unsaturated coordination and distinct reactivity.22\nHowever, achieving precise control of these defects remains a significant challenge,\nand the role of vacancies to the adsorption and activation of reactants, especially under\n2D confined conditions, remains largely unknown.23\nRelated references in the revised manuscript is given as follows:\n21. Verma, R. et al. Defects tune the acidic strength of amorphous aluminosilicates. Nat.\nCommun. 15, 6899 (2024).\n22. Yang, M. et al. Disorder engineering in monolayer nanosheets enabling\nphotothermic catalysis for full solar spectrum (250-2500 nm) harvesting. Angew. Chem.\nInt. Ed. 58, 3077-3081 (2019).\n23. Bi, F. et al. Engineering triple O-Ti-O vacancy associates for efficient water-\nactivation catalysis. Nat. Commun. 16, 851 (2025).\nComment 2: Benzyl alcohol esterification is a well-established process in industry.\nHowever, why did the authors not compare outcomes from this work with already\nestablished processes? Comparisons were made with catalysts reported in scientific\nresearch (mostly used in labs) for e.g., ionic liquids, solid and inorganic acids, but there\nwas no comparison with industrial processes. After all, the authors are in the opinion\nthat their membranes outperform existing methods for benzyl alcohol esterification.\nResponse: Thank you very much for your good suggestions! This suggestion is\nmeaningful and very helpful for revising and improving our paper, as well as the\nimportant guiding significance to our researches.\nIn our work, the esterification of alcohols with acetic anhydride is used as a model\nreaction to test the improved performance. In Table S4, a comparison of catalytic\nperformance with other reported catalysts was made, which demonstrating the\nadvantages of our strategy. In the revised draft, the conversion and reaction time of\nHTiNbO membranes are comparable to commercial solid acid catalysts (Table S5).\n5-X\nConventionally, the esterification of benzyl alcohol with acetic acid or acetic anhydride\nis performed in the presence of mineral acids catalysts (e.g., H SO ). However, the\n2 4\ninherent disadvantages related with the homogeneous system lie in separation and\npurification of the products, resulting in the environmental problems and economical\ninconveniences. In order to tackle these problems, a wide range of heterogeneous solid\nacid catalysts have been developed, such as zeolite molecular sieves, heteropoly acids,\nand acidic resins. Thus, three types of commercial solid acid catalysts, HZSM-5 (zeolite\nmolecular sieves), H O PW ·xH O (heteropoly acids) and amberlyst-15 (acidic\n3 40 12 2\nresins), were purchased for comparison. Amberlyst-15 ion-exchange resins are\nBrønsted acidic catalysts with acid strength equivalent to 60% sulfuric acid.\nH O PW ·xH O is a typical heteropoly acid with significantly higher acidity than\n3 40 12 2\ncommon inorganic strong acids, such as HCl and HNO .\n3 40 12 2\nand amberlyst-15 are superior to HZSM-5 and HTiNbO nanosheets in the bulk\n5-X\nreaction (Table S5). This is mainly attributed to their stronger acidity. In comparison,\nthe catalytic activity of the HTiNbO membrane is superior to that of\n5-X\nH O PW ·xH O and amberlyst-15. The conversion rate the HTiNbO membrane\n3 40 12 2 5-X\nreaches 100% within 26.6 s and TON is 28 times higher than that of HTiNbO\n5-X\nnanosheets. It's worth noting that the catalyst dosage in bulk condition is 10 mg,\nwhereas that of in confined system is calculated to be only 1.68 mg. Besides, both\nH O PW ·xH O and amberlyst-15 exhibit poor activity for the esterification of acetic\n3 40 12 2\nacid and benzyl alcohol. The conversion rate of the HTiNbO membrane reaches 22.3 %\n5-X\nwithin 23.9 s. In the bulk system, the reaction is typically limited by temperature,\nstirring time and activity of the substrate itself. These results demonstrate the\nadvantages of HTiNbO\n5-X\nmembranes in conversion, catalyst dosage and reaction time.\na b c\nFig. R1. (a) Photograph of reaction solution with H\n12\n·xH\nreaction solution with amberlyst-15 ion-exchange resins. (c) Photograph of reaction\nsolution with HZSM-5.\nAfter reaction, the benzyl acetate produced by H O PW ·xH O and amberlyst-15 was\n3 40 12 2\ncollected separately. It is noteworthy that the H O PW ·xH O was dissolved in the\n3 40 12 2\nproduct benzyl acetate, and the collected benzyl acetate exhibits a light golden color\n(Fig. R2 and S46). By contrast, benzyl acetate collected by the confined reaction is\nalmost colorless. The industrial application of heteropolyacid is limited by its difficulty\nin recovery and recycling when used as a catalyst (Angew. Chem. Int. Ed. 2009, 48,\n168-171). The Amberlyst-15 ion-exchange resins were easily separated from solutions,\nbut the collected benzyl acetate shows a noticeable orange color after standing for a\nweek. This signifies that the collected benzyl acetate contains impurities, possibly due\nto the unstable structure of the amberlyst-15. According to previous work, Amberlyst-\n15 have low thermal stability, and present a risk of leaching styrene monomers, potential\nhuman carcinogens (Chem. Eng. J. 2023, 476, 146586). These results demonstrate the\nadvantages of HTiNbO membranes in catalyst separation and product purity. (Please\n5-X\nsee the blue text of the Results)\na b c\nFig. S46. (a) Photograph of benzyl acetate collected by continuous confined reaction of\nHTiNbO\n5-X\nmembrane. The mass of the collected benzyl acetate is 1.3709 g, and the\ncalculated yield is about 87.5%. Confined reaction condition: HTiNbO membranes\n5-X\n(d=11.0 Å), benzyl alcohol (0.2 M) and acetic anhydride (0.3 M) in CH CN (30 mL) at\n3\n23 °C (b) Photograph of benzyl acetate collected by bulk reaction with\nH\n12\n·xH\nreaction amberlyst-15 as catalyst.\nTable S5. Comparison of HTiNbO membranes (d = 11.0 Å) with commercial solid\n5-X\nacid catalysts.\nEntry Catalyst Reactant Concentration Time Conversion (%)\n5-X\n5-X\n3 40 12 2\n5-X\n5-X\n3 40 12 2\n5-X\n5-X\n3 40 12 2\nBulk reaction condition: catalyst (10 mg), benzyl alcohol, acetic anhydride or acetic\nacid, CH CN (10 mL) at 23 °C. Confined reaction condition: HTiNbO membrane (d\n3 5-X\n= 11.0 Å), benzyl alcohol, acetic anhydride or acetic acid, CH CN (10 mL) at 23 °C.\nUlteriorly, three types of commercial solid acid catalysts, HZSM-5 (zeolite molecular\nsieves), H O PW ·xH O (heteropoly acids) and amberlyst-15 (acidic resins), were\n3 40 12 2\npurchased for comparison. Under the premise of the same concentrations, the\nperformances of H O PW ·xH O and amberlyst-15 are superior to HZSM-5 and\n3 40 12 2\nHTiNbO nanosheets in the bulk reaction (Table S5). This is mainly attributed to their\n5-X\nstronger acidity. However, the H O PW ·xH O was dissolved in the product benzyl\n3 40 12 2\nacetate, and the collected benzyl acetate exhibits a light golden colour (Fig. S46). The\nAmberlyst-15 ion-exchange resins were easily separated from solutions, but the\ncollected benzyl acetate shows a noticeable orange color after standing for a week. This\nmay be due to the unstable structure of the amberlyst-15.35,36 These results demonstrate\nthe advantages of HTiNbO membranes in catalyst separation and product purity.\n5-X\nRelated references in the revised manuscript is given as follows:\n35. Sripada, S. et al. Continuous catalytic esterification using a solid acid activated\ncarbon monolith: Comparison of granular and monolith forms with a commercial\ncatalyst. Chem. Eng. J. 476, 146586 (2023).\n36. Su, F. et al. Advancements in solid acid catalysts for biodiesel production. Green\nChem. 16, 2934 (2014).\nComment 3: Why did the authors use acetonitrile as the solvent and acetic anhydride\nfor esterification in this work? BA is typically esterified in industry using acetic acid\n(as solvent and reagent for esterification), toluene, or hexane.\nResponse: Thank you very much for your good comment! Based on your kind advice,\nwe also notice this question and have provided the activity in different solvents. To\nbegin with, acetic acid was also used in esterification reactions. In Table S5, both\nHTiNbO NS and commercial solid acid catalysts exhibited very low catalytic activity\n5-X\nin the esterification of benzyl alcohol and acetic acid at 23 °C. According to literature\nreports, esterification of benzyl alcohol and acetic acid typically require heating and\nreflux conditions to proceed effectively. The esterification with acetic anhydride is\ncurrently the greener process in most impact categories (global warming, fossil\ndepletion and human toxicity potential) with the exception of the acid anhydride\nproduction (Green Chem., 2023, 25, 7292-7308). Therefore, the esterification of benzyl\nalcohol with acetic anhydride was carried out as the model reaction to study the\ncatalytic properties of HTiNbO membranes in our study.\n5-X\nIn traditional methods, water carrying agents (such as toluene, cyclohexane) are used\nto removing the by-products (H O) from the reaction system continuously, thus\n2\nbreaking thermodynamic equilibrium and enhancing the conversion of esterification.\nIn our work, the HTiNbO membranes can provide both high catalytic activity and\n5-X\nseparation performance. The by-products (such as CH COOH, H O) can promptly\n3 2\nflows out with the solvent and be selectively removed during the reaction, enabling\nthermodynamic equilibrium to effectively break (Nat. Commun. 2024, 15, 6837; J.\nMembr. Sci. 2019, 584, 268-281).\nNonetheless, we have made a detailed comparison of different solvents in terms of\nboiling point, solubility, conversion and flow rate of the reaction solution in Table S8\nand Table S9. Firstly, chloroform is not suitable for the control and study of reaction\ntemperature due to its volatility, although it has good catalytic activity. When\nacetonitrile, cyclohexane, toluene and chloroform are used as solvents, they exhibit\ngood conversion rates both in bulk and confined reactions. However, flow rates for\ncyclohexane and toluene are much smaller than acetonitrile in confined reactions, and\nthe reaction time are significantly longer (Fig. S37). This can be attributed to the larger\nsize of cyclohexane and toluene, which obstructs its flow within the membranes (Fig.\nS38). Without considering the flow rate of the solution, toluene is also a good choice as\na solvent. (Please see the blue text of the Results)\nTable S8. Optimization of solvents for the bulk reaction.\nBoiling Reaction Conversion of\nEntry Solvent Conversion of 48 h\npoint (°C) temperature (°C) 24 h\n6 1,4-Dioxane 101 °C 23 °C 4.5 % 6.9 %\nReaction condition: HTiNbO NS powder (10 mg), benzyl alcohol (0.2 M) and acetic\n5-X\nanhydride (0.3 M) in solvent (10 mL) at 23 °C.\nTable S9. The confined reactions with different solvents.\nReaction Conversion of\nEntry Solvent Time (s)\ntemperature (°C) confined reaction\n6 1,4-Dioxane 23 °C 43.3 22.3±1.2 %\nReaction condition: HTiNbO membrane (d = 11.9 Å), benzyl alcohol (0.2 M) and\n5-X\nacetic anhydride (0.3 M) in solvent (10 mL) at 23 °C.\nToluene\n) 5 Acetone\nL 1,4-Dioxane\nm\n4\n(\nw\n3\no\nl F 2\n1\n0\n0 10 20 30 40 50\nTime (h)\nFig. S37. The flow curves of reaction solution corresponding to HTiNbO membranes\n5-X\n(interlayer spacing of 11.9 Å) with different solvents.\na b c\n3.93×3.98×5.88 Å 4.56×6.04×6.43 Å 4.02×5.68×6.01 Å\nd e f\n4.02×6.52×8.19 Å 4.88×6.86×7.08 Å 4.88×5.85×6.36 Å\nFig. S38. Perspective view of six kinds of solvent molecules. (a) Acetonitrile. (b)\nChloroform. (c) Acetone. (d) Toluene. (e) Cyclohexane. (s) 1,4-Dioxane.\nOn Page 17:\nIn addition, we have made a comparison of different solvents in terms of boiling point,\nconversion and flow rate of the reaction solution. When cyclohexane, toluene and\nchloroform are used as solvents, they also exhibit good conversion rates both in bulk\nand confined reactions (Table S8 and S9). However, flow rates for cyclohexane and\ntoluene are much smaller than acetonitrile in confined reactions, and the reaction time\nare significantly longer (Fig. S37). This can be attributed to the larger size of\ncyclohexane and toluene, which obstructs their flow within the membranes (Fig. S38).\nComment 4: Are the membranes single use? What is the cyclic catalytic performance\nof the membranes reported here?\nResponse: Thank you very much for your good comment! We feel deeply sorry that\nthe discussion of our manuscript is not clear enough in the results. In previous versions,\nwe conducted a continuous confined reaction for evaluating practicality and stability of\nthe membrane. After more than 13 days of reaction, the products (1.3709 g) were\ncollected in Fig. S46a, due to losses incurblue during the collection process. According\nto the theoretical expected product quality (1.566 g), the yield was calculated about\n87.5%. The products were analyzed by 1H NMR spectroscopy, and characteristic\nsignals of benzyl alcohol completely disappeablue which means a 100% conversion.\nBesides, recyclability test of the catalyst was shown four times without detectible loss\nin activity.\nIn the revised draft, we conducted recyclability test in Fig. S45. The HTiNbO\n5-X\nmembranes was tested for four cycles by adding acetonitrile solution (10 mL) of alcohol\nand acetic anhydride. Following each cycle, substances flowing through the membranes\nwere collected and analyzed by 1H NMR spectroscopy. As shown in Fig. S45, the\nmembrane exhibited high stability in both the permeance and conversion of the solution.\nThe conversion of benzyl alcohol remained unchanged at almost 100% for all operation\ncycles. (Please see the blue text of the Results)\na\n12\n1st Cycle 2nd Cycle 3rd Cycle 4th Cycle\n10\n8\n)\nL\nm\n6\n(\nw\n4\no\nlF\n2\n0\n0 100 200 300 400\nTime (h)\nb\n100\n)\n% 80\n(\nn\no 60\nis\nr\ne\nv 40\nn\no\nC 20\n0\n1st Cycle 2nd Cycle 3rd Cycle 4th Cycle\nFig. S45. Recyclability test. (a) Flow curves of reaction solution through HTiNbO\n5-X\nmembranes (d=11.0 Å) over cycle times. (b) The conversion of reaction solution\nthrough HTiNbO membranes (d=11.0 Å) over cycle times.\n5-X\nThe oxygen vacancies are benefits to the adsorption and activation of the reactants. To\ngain insights into stability and role of oxygen vacancy, XPS spectra of HTiNbO\n5-X\nmembranes were performed after continuous confined reaction. As shown in Fig. S47,\nO 1s can be divided into three fitting peaks, that is lattice oxygen at 530.4 eV, oxygen\nvacancy at 531.3 eV and organic oxygen at 532.9 eV. Therefore, it can be confirmed\nthat the reactants adsorb on the catalyst surface and oxygen vacancies exist stably\nduring the reaction process.\nAfter reaction O 1s\nBefore reaction\nLattice O\n) V 529.7 eV\n. O\nu\n531.5 eV\n.\na\n(\ny\nt\ni\ns V Lattice O\nn O\ne 531.3 eV 530.4 eV\nOrganic C-O\nt\nn 532.9 eV\nI\n536 534 532 530 528 526\nBinding energy (eV)\nFig. S47. O 1s XPS spectra of HTiNbO membranes (d=11.0 Å) before and after\n5-X\ncontinuous confined reaction.\nOn Page 18:\nTo determine the stability of the membranes, the HTiNbO membranes are tested for\n5-X\nfour cycles of recyclability test. As shown in Fig. S45, the membrane exhibited high\nstability in both the permeance and conversion of the solution. The conversion of benzyl\nalcohol remained unchanged at almost 100% for all operation cycles. In Fig. S46, we\nconducted a continuous confined reaction for evaluating reactivity and practicality of\nthe membrane. After more than 13 days of reaction, the products were collected in Fig.\nS46a. According to the theoretical expected product quality, the yield was calculated\nabout 87.5%. The loss of products mainly comes from the processes of filtration\nreaction and sample collection. The products were also analyzed by 1H NMR\nspectroscopy, and characteristic signals of benzyl alcohol completely disappeablue\nwhich means a 100% conversion. The benzyl acetate collected by the confined reaction\nis almost colorless. To gain insights into stability of oxygen vacancy, XPS spectra of\nHTiNbO membranes were performed after the long-term stability test. As shown in\n5-X\nFig. S47, O 1s can be divided into three fitting peaks that is lattice oxygen at 530.4 eV,\noxygen vacancy at 531.3 eV and organic oxygen at 532.9 eV. Due to the relatively mild\nreaction conditions, the signal peak of oxygen vacancies did not show any signs of\nweakening or disappearing. Therefore, it can be confirmed that HTiNbO membranes\n5-X\nare very stable during the reaction process.\nOn Page 28:\nRecyclability test\nThe experimental procedures were the same as confined reaction: HTiNbO\n5-X\nmembranes (d=11.0 Å), benzyl alcohol (0.2 M) and acetic anhydride (0.3 M) in\nacetonitrile (10 mL). After the complete filtration of 10 mL of reaction solution (about\n100 h), substances flowing through the membranes were collected and analyzed by 1H\nNMR spectroscopy for each cycle. Acetonitrile (2 mL) was utilized to rinse the bottom\nsurface of the membrane and dissolve the substances. The solvent was removed under\nblueuced pressure on a rotary evaporator and the obtained concentrate was dissolved in\nDMSO-D6. After that, the HTiNbO membranes (d=11.0 Å) was tested for another\n5-X\ncycle, by adding acetonitrile solution (10 mL) of alcohol (0.2 M) and acetic anhydride\n(0.3 M).\nFinally, thank you very much for your patience and careful review, which has\ngreatly benefited our paper!"}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have properly addressed the reviewer's comments and questions. The manuscript can be recommended for publication in its current form.", "reviewer_2": "The Authors have addressed my concerns. The current version can be published in Nature communications.", "reviewer_3": "The authors have performed significant amount of high-quality experiments to clarify the initial doubts/ comments/ suggestions that all reviewers had for this research. The responses are highly detailed and answers all questions appropriately. I have no doubt that the quality of the manuscript is greatly improved now.\nPersonally, I am satisfied with the responses and the quality of the revised manuscript. I am in the opinion that this manuscript should be published in Nature Communications."}, "author_response": "Response: Thank you very much for your patience and recommending our\nwork for publication in Nature Communications.\nResponse: Thank you very much for your kind advice and recommending\nour work for publication in Nature Communications.\nResponse: Thank you very much for appreciating our work and\nrecommending it for publication in Nature Communications."}]

Decision letter