# A Post-Synthetic Modification Approach to Expand MIL-101-NH₂ 2 Functionalization

Alain Vigroux, Christian Lherbet, Isabelle Fabing, Marie-Claire Barthélémy,

Christophe Laurent, Pascal Hoffmann

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Alain Vigroux, Christian Lherbet, Isabelle Fabing, Marie-Claire Barthélémy, Christophe Laurent, et al.. A Post-Synthetic Modification Approach to Expand MIL-101-NH 2 Functionalization. Chemistry, 2025, 7, pp.47. 10.3390/chemistry7020048 . hal-05009518

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Article

# A Post-Synthetic Modification Approach to Expand MIL-101-NH₂ Functionalization

Alain Vigroux ¹ID, Christian Lherbet ¹ID, Isabelle Fabing ¹ID, Marie-Claire Barthélémy ²ID, Christophe Laurent ²ID and Pascal Hoffmann <fnref n="1" />,* ID

**Abstract:** Considering the importance of organic functionalization of MOFs, we here report a simple, tunable and efficient one-step post-modification procedure for introducing amino and carboxylic groups into the mesoporous metal-organic framework Al- and Cr-MIL-101-NH₂ based on its reaction with alkyl bromides. This procedure allows also access to polyfunctionalized MIL-101 decorated with both carboxylic and primary amino groups. Other chemical functions, such as alcohols and alkynes, were also successfully introduced by this method.

**Keywords:** metal-organic frameworks; post-synthetic modification; PSM; (Al)MIL101-NH₂; (Cr)MIL101-NH₂; alkylation; alkyl halide

## 1. Introduction

Post-synthetic modification (PSM) of metal-organic frameworks (MOFs) is a process involving the conversion of pendent groups located at the surface and in the pores of MOFs, aiming to change their physical or chemical properties [1–7]. This process thus gives access to grafted MOFs that could not be prepared by direct synthesis from a modified ligand. In most cases, PSM is achieved by a chemical reaction directly on the crystalline MOF powder. The resulting post-modified MOF should retain its crystallinity in order to ensure its topological integrity, which can be confirmed by X-ray powder diffraction, in addition to other classical analysis methods, such as N₂ physisorption, TEM/SEM microscopy or NMR spectroscopies. In particular, ¹H-NMR, after MOF hydrolysis in acidic or basic conditions, is one of the most convenient methods used to identify the product(s) of PSMs, and also to calculate the yield and percentage of modification. Amino-functionalized MOFs, such as MOFs synthesized from 1,4-benzenedicarboxylate (BDC) and post-modified after nitration/reduction treatment [8], or MOFs directly synthesized from amino-1,4-benzenedicarboxylate (BDC-NH₂) like MIL-101-NH₂ [9] or IRMOF-3 [10], have often be used as starting materials for post-modifications due to the reactivity of the aniline functional group towards a variety of electrophiles. On this basis, PSM has been carried out (i) with alkyl/cyclic anhydrides or acyl chlorides to form amide bonds [11–14], (ii) with diphosgene and thiophosgene to form isocyanates and isothiocyanates [14], then converted to ureas or carbamates by reacting with amine or alcohol derivatives, (iii) with isocyanates to afford ureas [15,16], (iv) with aldehydes to obtain imines [17,18] that can be then reduced

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Academic Editor: Chun Cai

Received: 3 February 2025

Revised: 12 March 2025

Accepted: 25 March 2025

Published: 28 March 2025

**Citation:** Vigroux, A.; Lherbet, C.; Fabing, I.; Barthélémy, M.-C.; Laurent, C.; Hoffmann, P. A Post-Synthetic Modification Approach to Expand MIL-101-NH₂ Functionalization. *Chemistry* **2025**, *7*, 48. https://doi.org/10.3390/chemistry7020048

**Copyright:** © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

<footnote n="1">¹ Laboratoire de Synthèse et Physico-Chimie de Molécules d'Interêt Biologique LSPCMIB, Université de Toulouse, UMR CNRS UT 5068, 118 Route de Narbonne, 31062 Toulouse, France; alain.vigroux@univ-tlse3.fr (A.V.); christian.lherbet@univ-tlse3.fr (C.L.); isabelle.fabing@univ-tlse3.fr (I.F.)</footnote>

<footnote n="2">² Centre Interuniversitaire de Recherche et d'Ingénierie des Matériaux CIRIMAT, Université de Toulouse, UMR CNRS INP UT 5085, 118 Route de Narbonne, 31062 Toulouse, France; marie-claire.barthelemy@univ-tlse3.fr (M.-C.B.); christophe.laurent@univ-tlse3.fr (C.L.)</footnote>

<footnote>* Correspondence: pascal.hoffmann@univ-tlse3.fr</footnote>
to amines, or (v) with tert-butyl nitrite and trimethylsilyl azide to convert the amino group to an azide group [19–22] that can subsequently be involved in a CuAAC reaction (“click” chemistry) by reacting with alkyne derivatives [23]. Non-exhaustively, other reactants able to react with the amino group were used, such as cyanuric chloride [24], nitrogen monoxide [25], aziridine [26,27], 1,3-propane sultone [26,27], sodium nitrite in the presence of aqueous acid (diazotization) [28], alkenes containing electron withdrawing groups [29] and others. Surprisingly, the use of alkyl halides, and in particular alkyl bromides, has been little exploited to post-modify amino-functionalized MOFs [30–32]. In this work, we show how this basic reaction between MIL-101-NH₂ and alkyl bromides, involving a bimolecular nucleophilic substitution mechanism (SN2), allows access to a series of post-modified MOFs, namely **Cr-** and **Al-MOFn** (*n* = 2–9) with diverse amino and carboxylic groups, and also to polyfunctionalized MOFs (**Cr-** and **Al-MOF2/7**, Scheme 1) with both acid and primary amino groups.

<figure><img src="image_3.png" /><figcaption>**Scheme 1.** Access to post-modified amino (●) and carboxylic (●) M-MOFs (M = Al or Cr). Path *a*: 2-bromoethylamine●HBr or N-Boc-2-bromoethylamine; Path *b*: 3-bromopropylamine●HBr; Path *c*: N-methyl-3-bromoethylamine●HBr; Path *d*: bromoacetic acid; Path *e*: 3-bromopropionic acid; Path *f*: methyl 4-bromobutyrate; Path *g*: 2-bromoethylamine●HBr; Path *h*: N-Boc-2-bromoethylamine and bromoacetic acid.</figcaption></figure>

## 2. Materials and Methods

### 2.1. Synthesis of Al-MIL-101-NH₂ (Al-MOF1)

Al-MIL-101-NH₂ was prepared according to a slightly modified procedure described by Hartmann and Fischer [33]. In a 100 mL round bottom flask, 272 mg (1.5 mmol) of 2-aminoterephthalic acid was dissolved in 60 mL of DMF under magnetic stirring and heated to 110 °C (oil bath). Then, 724 mg (3 mmol) of AlCl₃·6H₂O was added to the solution in 7 equal portions with a time delay of 15 min between additions. After the last portion was added, the temperature was kept at 110 °C for 3 h under magnetic stirring, and for an additional 16 h without stirring. After cooling to room temperature, the yellow solid was isolated by filtration on fritted-glass (porosity 3), washed with 20 mL of DMF and 20 mL of ethanol, and then washed (“evacuated”) by Soxhlet extraction with ethanol (130 mL) for
96 h. The yellow powder was then dried for 24 h at 85 °C to obtain Al-MOF1, which was
stored in a desiccator until use.

2.2. *Synthesis of Cr-MIL-101-NH<sub>2</sub> (Cr-MOF1)*

Cr-MIL-101-NH₂ was prepared according to a procedure described by Lin *and coll.* [34]. Chromium(III) nitrate nonahydrate (99%, 808 mg, 2 mmol), 2-aminoterephthalic acid (365.9 mg, 2 mmol) and sodium hydroxide (200 mg, 5 mmol) were dispersed in deionized water (15 mL) in a 60 mL Schott vial. The solution was stirred for 5 min at room temperature, and then heated at 150 °C in an oven for 12 h. After cooling, the green precipitate was collected by centrifugation, washed with DMF (3 × 10 mL) at room temperature, and then with hot ethanol (30 mL) at 100 °C for 24 h in a 60 mL Schott vial. The precipitate was filtered over fritted-glass (porosity 3), dried at 80 °C in air and stored in a desiccator until use.

2.3. MOFs Post-Synthetic Modifications

All post-synthetic modified MOF were prepared using a Monowave 50 apparatus
(Anton Paar, Graz, Austria) and a conventional heating synthesis reactor (see procedures,
data and spectra in the Supplementary Materials). Al-MOF2 was also prepared following a
classical procedure (see Supplementary Materials). PSM-yields were determined by NMR
and LC-MS as follows: an MOF sample (≈10 mg) was suspended in D₂O (deuterium oxide,
1 mL), and a solution of 40 wt% NaOD (deuterated sodium hydroxide) in D₂O (2 µL) was
added. For aluminum MOFs (Al-MOF), the NaOD/D₂O solution was allowed to stand
at room temperature for 2 h, and the terephthalate derivatives (deprotonated forms) were
then analyzed by ¹H-NMR recorded on a Bruker Advance 300 spectrometer (Billerica,
MA, USA) at 300 MHz. The residual proton signal of the deuterated water was used as
an internal reference (δ = 4.79 ppm). For chromium MOFs (Cr-MOF), the NaOD/D₂O
solution was allowed to stand at room temperature for 16 h, then centrifuged for 2 min at
10,000 rpm (Thermo Scientific Biofuge Fresco HeraeusTM centrifuge, Waltham, MA, USA)
and filtered on a short column of alumina (aluminum oxide 90 active neutral from Merck
(Merck KGaA, Darmstadt, Germany) to remove paramagnetic chromium salts, and the
terephthalate derivatives (deprotonated forms) were then analyzed by ¹H-NMR recorded
on a Bruker Advance 300 spectrometer at 300 MHz. In most of the cases, yields were
calculated by comparing the integrations of the more deshielded aromatic proton doublets
of unmodified ligand (BDC²⁻-NH₂, δ = 7.69) and modified ligand, but integration of other
aromatic protons can be considered (if overlapping for example) for yield determination.

2.4. LC-MS *Yields Determination*

NaOD/D₂O solutions used for NMR analyses were also used for LC-MS. The samples
were analyzed by analytical UPLC (UPLC Acquity Waters, PDA/MS detector, Waters
Corporation, Milford, MA, USA) with a C18 column (BEH C18, 1.7 µm, 2.1 mm × 100 mm).
Water with 0.1% formic acid (A) and methanol with 0.1% formic acid (B) were used as
mobile phases, with a flow rate of 0.3 mL·min⁻¹, using the following elution method: 0 min,
5% B; 5 min, 100% B; 7 min, 100% B, then returned to initial conditions. The SQD was
operated in an electrospray negative or positive ion mode by applying a voltage of 3.5 kV
to the ESI capillary and the cone voltage was set at 30 V. The yields were calculated from
integration of the peaks in the 254 nm chromatograms.
**3. Results and Discussion**

**3.1. Post-Modification with Amino Groups**

The amino group, especially primary amino group, is probably the most important re-
active group for further chemical modifications of MOFs. The reaction of Al-MIL-101-NH₂
towards 2-bromoethylamine hydrobromide as alkyl halide was first investigated as initial
reaction (path *a*, Scheme 1). The starting MOF Al-MIL-101-NH₂ (**Al-MOF1**) was prepared
from 2-aminoterephthalic acid (H₂BDC-NH₂) and aluminum chloride hexahydrate in DMF,
evacuated and activated according to a slightly modified procedure [33], and characterized
by powder X-ray diffraction, FT-IR and BET surface area measurement. BET surfaces of
2700 m²·g⁻¹ were routinely obtained from independent experiments, values in good agree-
ment with previous reported data [33]. Post-synthetic modification was then accomplished
by reacting **Al-MOF1** with 2-bromoethylamine hydrobromide in toluene, an aprotic solvent
suitable for SN2 reactions that gave the best results for our study. When performed at 110 °C
(toluene reflux) under atmospheric pressure, followed by ethanol Soxhlet-extraction and
drying, the expected ethyl amino-modified MOF, as di-hydrobromide salt (**Al-MOF2**), was
obtained, with no noticeable secondary products. Conversion yields for post-modifications
were estimated both from the LC-MS chromatogram of the NaOH-digested products of a
sample of **Al-MOF2** (Figure S7, ESI), and by ¹H-NMR after its hydrolysis with aqueous
sodium deuteroxide by comparing the ratio of aromatic proton doublets at δ = 7.69 of
unmodified ligand BDC²⁻-NH₂ and δ = 7.75 ppm of modified ligand 2-((2-aminoethyl)
amino)terephthalate (BDC²⁻-NH-(CH₂)₂-NH₂) (Figure 1). Conversions of ≈35–40% were
routinely obtained from several independent experiments. Compared to the parent ligand,
a deshielded chemical shift was observed for aromatic protons in *ortho* (*Hc*') and *meta* (*Ha*')
position, relative to the amino group in the modified ligand, while the *para* proton (*Hb*')
was slightly more shielded (Figure 1). In addition to the aromatic protons, two triplets at
2.82 and 3.27 ppm corresponding to the ethylene groups (*Hd*′ and *He*′) became apparent in
the spectrum. For an unambiguous structure determination, a pure sample of the modified
ligand 2-((2-aminoethyl)amino)terephthalic acid (H₂BDC-NH-(CH₂)₂-NH₂) was isolated
from NaOH-digestion of approximatively 100 mg of **Al-MOF2** by semi-preparative HPLC,
and characterized by ¹H-NMR, IR and MS analysis (Figures S1–S3, ESI).

<figure><img src="image_4.png" /><figcaption>**Figure 1.** The ¹H-NMR spectra (300 MHz) of the NaOD/D₂O-digested **Al-MOF2** prepared from **Al-MOF1** and 2-bromoethylamine hydrobromide in toluene at 110 °C.</figcaption></figure>
The powder X-ray diffraction (PXRD) pattern of the modified MOF Al-MOF2 was found in accordance with the basic framework of MIL-101-family structures, but with a severe loss in crystallinity compared to the starting MOF Al-MOF1 (Figure 2), as evidenced by the total signal loss in the 2–7 degree range. This decrease in crystallinity, evidenced on the PXRD spectrum by a decrease in peak intensity associated with an increase in peak width, is often observed during MOF post-synthetic modifications, particularly on MOFs of the MIL-101-family. As expected, the ethylamino groups within the pores of Al-MOF2, combined with loss of crystallinity, lead to a marked decrease in its BET specific surface area as compared to Al-MOF1, from 2700 to 146 m²·g⁻¹ (Figure S4, ESI). Upon a simple treatment of di-hydrobrominated Al-MOF2 with a solution of triethylamine in chloroform, free amino Al-MOF3 was obtained. When the yellow powder of the later MOF was suspended in an acetonic solution of ninhydrin, a chemical commonly used to detect primary and secondary amines, the color of the resulting still insoluble powder changed gradually to deep-purple, the maximum coloration being reached within one hour (Figure S5, ESI), demonstrating the presence of reactive amino groups. In the same conditions, the color of Al-MIL-101-NH₂ (Al-MOF1) remained unchanged, even after hours. To further demonstrate the reactivity of the primary amine groups in the post-modified MOF, Al-MOF3 was allowed to react with *p*-tolylisocyanate in refluxing toluene, and, as expected, the corresponding urea formed with a rather good yield of 74% (Figure S6, ESI).

<figure><img src="image_5.png" /><figcaption>**Figure 2.** PXRD patterns simulated (1.54056 Å) from the crystal data of Cr-MIL-101, and recorded for a sample of Al-MOF1 (Al-MIL-101-NH₂) and post-modified Al-MOF2.</figcaption></figure>

For various potential applications of post-synthetically modified MOFs, it remains necessary to control the degree of rafting to accurately modulate the effectively available chemical functions. On this basis, the reaction of Al-MIL-101-NH₂, on a 100-mg MOF scale, with 2-bromoethylamine hydrobromide as model reaction, was further investigated by varying the reaction temperature above toluene boiling point (110 °C) in synthesis reactors under generated pressure (performed in Monowave 50 apparatus, Anton Paar). As expected, increased PSM-yields, from 57% at 110 °C up to 88% at 140 °C, were obtained by increasing the temperature in toluene (Figure 3). All these reactions yielding to di-hydrobrominated amino Al-MOF2 were found to be generally clean, even at a high temperature, with no significant formation of polyalkylated or polymerized products. This absence of secondary products is explained by the fact that the process used, which consists
of using 2-bromoethylamine hydrobromide without the addition of any base, releases one molar equivalent of hydrobromic acid during the reaction, which protonates the amino group of the terephthalate, thus, inhibiting any subsequent N-alkylation/polymerization reaction.

<figure><img src="image_6.png" /><figcaption>**Figure 3.** (Left panel) The 7.0–8.0 ppm-range ¹H-NMR spectra (300 MHz) of the digested Al-MOF2 prepared from Al-MOF1 and 2-bromoethylamine hydrobromide in toluene at different temperatures. (Right panel) PSM-yields as a function of temperature: (green) yields calculated by NMR from the ratio of doublets at δ = 7.69 ppm of unmodified ligand BDC²⁻-NH₂ and δ = 7.75 ppm of modified ligand BDC²⁻-NH-(CH₂)₂-NH₂; (blue) yields calculated by UPLC from peak area integration of crude mixtures chromatograms.</figcaption></figure>

However, all the post-modified aluminum MOFs obtained at these different temper-
atures showed a strong loss of crystallinity, as attested by their PXRD spectra, similar or
worse than that obtained at 110 °C (Figure 2), suggesting a marked degradation, or even
collapse, of the framework. Consequently, the ethylamino post-synthetic modification start-
ing from the same amino alkyl bromide derivative, 2-bromoethylamine hydrobromide, was
carried out on the most rugged chromium MOF of the MIL family, i.e., Cr-MIL-101-NH₂ (Cr-
MOF1). This amino Cr-MOF, like Cr-MIL-101, has the same topology as Al-MIL-101-NH₂,
but with trimeric chromium(III) octahedral clusters interconnected by BDC-NH₂ ligands,
possesses a high porosity with a high BET surface, unsaturated open metal sites, and is,
above all, known to be extremely stable, in particular in neutral or acidic aqueous media
compared to its iron and aluminum isoreticular MOFs, which are more prone to hydroly-
sis [35,36]. Therefore, all these properties make this chromium MOF attractive for many
applications, such as gas storage or catalysis [37]. Cr-MOF1 was first prepared from
2-aminoterephthalic acid (H₂BDC-NH₂) and chromium nitrate in hydrothermal con-
ditions, as already described [34]. Its crystalline structure was confirmed by PXRD
(Figure 4), and from N₂ sorption isotherm a BET specific surface of 1620 m²·g⁻¹ was
calculated in agreement with previous reported data [34,38]. The reaction of Cr-MOF1 with
2-bromoethylamine hydrobromide was then performed at 120 °C in toluene under gener-
ated pressure (in an Anton Paar Monowave 50 synthesis reactor) and the expected modified
MOF, Cr-MOF2, was successfully obtained, with a PSM-yield estimated by ¹H-NMR in
the range of 62–67% from three independent experiments (Figure S17, ESI); that is, of
the same order of magnitude than that obtained with the aluminum MOF (around 57%).
However, the NMR spectrum was found to be less clean than that obtained with its alu-
minum counterpart, which could be due to amine grafting on coordinatively unsaturated
chromium centers, or the formation of metal-catalyzed by-products. The PXRD pattern of
Cr-MOF2 was found to be in agreement with the basic three-dimensional architecture of
MIL-101-family structures (Figure 4), also with a marked decrease in crystallinity, but not
as great as that observed with aluminum MOF Al-MOF2 (Figure 2). The Cr-MOF samples
exhibit an N₂ sorption isotherm, firstly with some degree of adsorption in the low-pressure
domain, thus revealing some microporosity as in Type I isotherms, and secondly with a
narrow hysteresis loop at relative pressures from about 0.4 to 1.0 (Figure 5), which points to
a Type IV isotherm. Therefore, the isotherm could be described as composite between Types
I and IV, which are two of the six types of isotherms recognized by the IUPAC classification
and characteristic of microporous (pore size below 2 nm) and mesoporous (pore size in
the range 2–50 nm) adsorbents, respectively [39]. Despite a slightly higher rate of grafting
for the chromium MOF, the decrease in the BET specific surface area was found to be less
marked compared to aluminum MOFs, from 1620 for **Cr-MOF1** m²·g⁻¹ (Figure S28, ESI) to
350 m²·g⁻¹ for **Cr-MOF2** (Figure 5).

<figure><img src="image_7.png" /><figcaption>**Figure 4.** PXRD patterns recorded for a sample of **Cr-MOF1** (Cr-MIL-101-NH2), amino (**Cr-MOF2** and **Cr-MOF4–6**) and carboxylic (**Cr-MOF7–9**) post-modified MOFs.</figcaption></figure>

The reactions of Al- and Cr-MIL-101-NH₂ with other alkyl bromides bearing amino
groups were also investigated (path *a–c*, Scheme 1). In our basic experimental con-
ditions, i.e., toluene as solvent at 120 °C in Anton Paar Monowave 50 synthesis re-
actors under generated pressure, 3-bromopropylamine hydrobromide and *N*-methyl-2-
bromoethylamine hydrobromide successfully reacted with Al- and Cr-MIL-101-NH₂, af-
fording the corresponding post-modified MOFs in approximatively 90% (**Al-MOF4**), 80%
(**Al-MOF5**), 62% (**Cr-MOF4**) and 70% (**Cr-MOF5**) yields, as estimated from ¹H-NMR
spectra (Figures 6, S18 and S19, ESI) and LC-MS chromatograms (Figures S8 and S9, ESI).

Under the same conditions, when Al- or Cr-MIL-101-NH₂ were allowed to react with
the BOC-amino protected alkyl bromide *N*-Boc-2-bromoethylamine, MOFs **Al-MOF 6** and
**Cr-MOF6**, with the unblocked amine as the sole product, were obtained in approximatively
75% yield for both compounds (Figures 6 and S20, ESI), suggesting that a thermal, or an acid-
catalyzed de-BOC reaction occurred, probably due to an acid catalysis process generated
by HBr. In that case, it must be hypothesized that the post-modified amino-MOFs were
not obtained as di-hydrobromide salt, as in former reactions, but as mono-hydrobromide
salt. PXRD spectra show that there was a significant loss of MOF crystallinity for all amine
modified Cr-MOFs (Figure 4), and even more for aluminum MOFs, confirming the partial
degradation of the MOFs-network architecture in the presence of amine reagents. On the
other hand, all amino Cr-MOFs were found to retain a significant porosity, the total pore
volume ranging from of 0.15 to 0.25 cm³ g⁻¹. The corresponding specific surface areas
follow a similar evolution, from 166 to 374 m²·g⁻¹ (Figures 5 and S29, ESI).
<figure><img src="image_8.png" /><figcaption>**Figure 5.** N<sub>2</sub>-adsorption (○)-desorption (θ) isotherms of Cr-MOF2, Cr-MOF4, Cr-MOF5, Cr-MOF7, Cr-MOF8 and Cr-MOF2/7. The BET specific surface areas and pore volumes (V<sub>p</sub>) were calculated from the adsorption isotherms. The BET specific surface areas calculated from adsorption isotherms of Cr-MOF6, Cr-MOF9, Cr-MOF10 and Cr-MOF11 were 222, 847, 149 and 713 m<sup>2</sup>/g, respectively, with pore volumes of 0.16, 0.53, 0.11 and 0.47 cm<sup>3</sup>·g<sup>-1</sup>, respectively (Figure S29, ESI). Total pore volumes calculated from DFT analysis and micropore volumes calculated from t-plot analysis are given in Table S1 (ESI).</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>**Figure 6.** NMR of amino MOFs. The 6.95–7.85 ppm-range ¹H-NMR spectra (300 MHz) of digested Al-MOF1 and amino post-modified MOFs prepared from Al-MOF1 and 2-bromoethylamine hydrobromide (Al-MOF2), N-Boc-2-bromoethylamine (Al-MOF6), 3-bromopropylamine hydrobromide (Al-MOF4) and N-methyl-3-bromoethylamine hydrobromide (Al-MOF5). All reactions were carried out in toluene at 120 °C, except for Al-MOF2 (125 °C).</figcaption></figure>
## 3.2. *Post-Modification with Carboxylic Acids*

While the amino group reacts with electrophiles, the carboxyl group reacts, once activated, with nucleophiles. The ability to introduce these two complementary groups into the pores of MOFs should, therefore, facilitate access to a wide variety of functionalized MOF materials. On this basis, reactions of Al- and Cr-MIL-101-NH₂ with different commercially available bromocarboxylic acid derivatives, i.e., bromoacetic acid, 3-bromopropionic acid and 4-bromobutyric acid, were studied (path *d-f*, Scheme 1). When reactions starting from **Al-MOF1** were run in toluene at 120 °C, the expected post-modified MOFs, **Al-MOF7** and **Al-MOF8**, were obtained from bromoacetic acid (approx. 57% yield) and 3-bromopropionic acid (approx. 38% yield), respectively, as revealed by ¹H-NMR (Figures 7, S10 and S11, ESI). However, under the same conditions, no reaction occurred when **Al-MOF1** was allowed to react with 4-bromobutyric acid, as evidenced by NMR. In this case, it can be hypothesized that the aromatic amine function of the MIL-101-NH₂ framework catalyzes the cyclization reaction of the 4-bromobutyric acid into γ-butyrolactone, but no further experiments were run to verify the presence of the latter compound in the reaction mixture.

<figure><img src="image_10.png" /><figcaption>**Figure 7.** NMR of carboxylic Al-MOFs. The 6.95–7.90 ppm-range 1H-NMR spectra (300 MHz) of digested **Al-MOF1** and carboxylic post-modified MOFs prepared from **Al-MOF1** and bromoacetic acid (**Al-MOF7**), 3-bromopropionic acid (**Al-MOF8**) and methyl-4-bromobutyrate (**Al-MOF9**).</figcaption></figure>

However, a modified MOF with a butyric chain, **Al-MOF9**, that could not be prepared from 4-bromobutyric acid, was successfully obtained directly from the methyl ester derivative methyl-4-bromobutyrate. The acidity of the reaction mixture, due to the release of hydrobromic acid, is likely responsible for the hydrolysis of the ester function during the reaction process (Figures 7 and S12, ESI). The same reactions starting from bromoacetic acid and 3-bromopropionic acid were then performed on the chromium MOF **Cr-MOF1**, and as expected, the corresponding modified MOFs, namely **Cr-MOF7** and **Cr-MOF8**, were obtained with yields of 46% and 50% (Figures S21 and S22, ESI) and BET surfaces of 664 and 625 m²/g, respectively (Figure 5). On the other hand, reaction of **Cr-MOF1** with methyl-4-bromobutyrate yielded the corresponding carboxylic modified MOF **Cr-MOF9** in low yield (<20%), and a secondary product (around 10%) as indicated by the aromatic part of the NMR spectrum (Figure S23, ESI). All acidic-modified Al- or Cr-MOFs showed a slight loss of crystallinity, but much lower than in the case of amino-modified Al- or Cr-MOFs, as attested by their PXRD spectra (Figure 4 for Cr-MOFs). Acidic Cr-MOFs were
found to retain a significant porosity with a total pore volume in the 0.44–0.53 cm³ g⁻¹ range, and specific surface areas from 664 to 847 m²·g⁻¹ (Figures 5 and S29, ESI).

### 3.3. Polyfunctionalization

Polyfunctionalized MOFs would also be of interest for different purposes, for example, as simple models of enzyme catalytic sites. MOF-pores, decorated both with a primary amino group mimicking a lysine residue and a carboxylate group found in glutamate or aspartate residues, could act as an enzyme active site mimic that may perform acid-base catalyzed reactions, such as ester or amide hydrolysis [40,41]. On these bases, post-modified MOFs, Al-MOF2/7 and Cr-MOF2/7, have been prepared with both an ethyl amino group and an acetic group using the following two different methods: a one-pot procedure (path *h*, Scheme 1) mixing at 120 °C in toluene Al- or Cr-MOF1 [a] with N-Boc-2-bromoethylamine [b] and bromoacetic acid [c] using [a]/[b]/[c] proportions 1/3.45/7.20; and a sequential procedure (path *d* + *g*, Scheme 1) reacting the carboxylic MOF Al- or Cr-MOF7 with 7.5 eq. of 2-(aminoethyl)bromide hydrobromide. As expected, the ¹H-NMR spectra of an NaOD-digested sample of this trifunctionalized MOF (i.e., primary amino, carboxylic and unreacted terephthalic amino groups) display signals of both M-MOF2 and M-MOF7 (M = Al or Cr), in addition to the signals derived from the unreacted aminophthalate (Figures 8, S24 and S25, ESI). These results were confirmed by LC-MS analyses of the Al-MOF2/7 digested products (Figures S13 and S14, ESI). In these experimental conditions, PSM-yields calculated from NMR spectra were approx. 14% in amino groups and 76% in carboxylic groups for Al-MOF2/7 prepared with the one-pot procedure, and 14% (amino) and 46% (carboxylic) for the MOF obtained by the sequential procedure. For Cr-MOF2/7, PSM-yields calculated from NMR spectra were approximately 33% in amino groups and 45% in carboxylic groups using the one-pot procedure, and 26% (amino) and 33% (carboxylic) for the MOF obtained by the sequential procedure (Figures S24 and S25, ESI). Obviously, it is likely that these yields, as well as the amino/carboxylic groups' proportion, could be easily modulated by changing the experimental conditions, such as the temperature and the ratio of the starting alkyl bromide reactants.

<figure><img src="image_11.png" /><figcaption>**Figure 8.** The 6.95–7.90 ppm-range 1H-NMR spectra (300 MHz) of digested Al-MOF1 and post-modified MOFs prepared from Al-MOF1 and 2-bromoethylamine hydrobromide (Al-MOF2), from Al-MOF1 and bromoacetic acid (Al-MOF7), and from Al-MOF7 and 2-bromoethylamine hydrobromide (Al-MOF2/7) containing both ethyl amino and acetic groups.</figcaption></figure>
### 3.4. Post-Modification with Other Functional Groups

Following this simple procedure involving alkyl bromides, a terminal alkyne that may be used in the copper(I)-catalyzed azide–alkyne [3 + 2] cycloaddition (CuAAC, or “click chemistry”) to further connect other molecules was also introduced. However, when propargyl bromide alone was used in our standard experimental conditions (toluene, 120 °C), the desired alkyne-modified MOF was not obtained. In this case, the only product formed was that resulting from the expected reaction (i.e., **Al-MOF10**), but the hydrobromic acid released during the reaction has added to the triple bond of **Al-MOF10** leading finally to a vinyl bromide modified MOF. However by replacing toluene by *N*,*N*-dimethylformamide as solvent and in the presence of potassium carbonate to trap released hydrobromic acid, **Al-MOF10** was obtained in 80% yield (Scheme 2 and Figure S15, ESI). It should be noted that the presence of a small amount (approx. 4%) of an *N*-dialkylated product, i.e., the aniline amino group bearing two alkyne functions, was also identified in the LC-MS chromatogram of the digested products of **Al-MOF10**. In the same experimental conditions, **Cr-MOF10** was obtained but with a rather low PSM-yield (30%, Figure S26, ESI), a low specific surface (149 m²/g, Figure S29, ESI) and a significant loss of crystallinity (Figure S30, ESI). On the other hand, no reaction occurred in our standard conditions when 4-bromo-1-butyne was used as alkyl bromide. Here, it can be hypothesized that the basic aromatic amino group of **Al-MOF1** could catalyze the HBr elimination reaction from the starting bromo butyne, leading to 1-buten-3-yne.

<figure><img src="image_12.png" /><figcaption>**Scheme 2.** Access to post-modified alkyne (●) and alcohol (●) M-MOFs (M = Al or Cr).</figcaption></figure>

Modification of MOF with alcohol functions is of interest to further covalently link other organic molecules, but also to modify the inner and outer hydrophilic properties of MOF pores. From 3-bromo-1-propanol in toluene at 120 °C, post-modified **Al-MOF11** was obtained, but as a mixture of polypropyl ether derivatives, which is not devoid of interest, as revealed by the LC-MS chromatogram of the digested products (Figure S16, ESI). The expected post-synthetic modification leading to the amine-linked propanol chain was obtained in 22% yield, but was accompanied by other modifications leading to the formation of two, three and four consecutive ether chains in 12%, 3% and 1% yield, respectively. In contrast to previous reactions with amino alkyl bromides, which lead to unpolymerizable protonated amino functions, reactions with alcoholic alkyl bromides give primary hydroxylated MOFs that retain their nucleophilic properties, thus leading to polymerization reactions. The same reaction on **Cr-MOF1** gave the analogous chromium MOF **Cr-MOF11** with a PSM-overall yield of 40% (Figure S27, ESI), a BET specific surface of 713 m²/g (Figure S29, ESI) and a good crystallinity retention (Figure S30, ESI).

## 4. Conclusions

We have reported an effective, modulable and versatile methodology for post-synthetically introducing amino or carboxylic groups into MOFs of the MIL-101-NH₂ family. This method, based on condensation reactions with alkyl bromides without addition of base, releases one or two equivalents of hydrobromic acid, thus avoiding undesirable polyalkylation and polymerization reactions. Our results indicate that the chromium MOF is less affected by hydrolysis or degradation than its aluminum counterpart under all
post-modification reaction conditions, and that amines, although protonated, are more damaging for the framework than carboxylic acids. Complementary studies will be carried out to further investigate the stability of these modified MOFs, particularly in aqueous media, for their application as catalysts. This strategy also allows the two functional groups to be introduced into the MOF pores in varying proportions. The amino and carboxylic groups can be retained as is, for example, to act as mimics of enzyme amino-acid residues, or they can be modified independently of each other for other purposes. By using the same approach, it is also possible to introduce other functional groups such as alcohol and alkyne, but the corresponding alkylation are accompanied by secondary modifications resulting from dialkylation or polymerization reactions that are difficult to control.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry7020048/s1, post-modified MOFs syntheses, preparative purification and characterization of 2-((2-aminoethyl)amino) terephthalic acid, NMR spectra, LC-MS chromatograms, N₂-adsorption-desorption isotherms, PXRD spectra and other data.

**Author Contributions:** I.F. and M.-C.B.: Resources. A.V., C.L. (Christian Lherbet) and C.L. (Christophe Laurent): Conceptualization, Investigation, Writing—review and editing. P.H.: Conceptualization, Investigation, Writing—original draft, Writing—review and editing. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the "Centre National de la Recherche Scientifique" (CNRS, France) and by the "University Toulouse 3 Paul Sabatier" (France).

**Data Availability Statement:** The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding author.

**Acknowledgments:** The authors thank Fernanda Goncalves for the chromatographic analyses recorded on a UPC², which is part of the Integrated Screening Platform of Toulouse (PICT, IBISA). The authors thank Benjamin Duployer (CIRIMAT) for his help with the PXRD analyses. Technical assistance provided by the Institut de Chimie de Toulouse platform (Université Toulouse 3 Paul Sabatier, CNRS, France) is also gratefully acknowledged.

**Conflicts of Interest:** The authors declare no conflicts of interest.

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