Input: Can individual molecules of indeno[1,2-a]fluorene switch between open-shell and closed-shell states?

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Paper Info

Title: Bistability between π-diradical open-shell and closed-shell states in indeno[1,2-a]fluorene
Publish Date: Unkown
Author List: Shantanu Mishra (from IBM Research Europe -Zurich), Manuel Vilas-Varela (from Department of Organic Chemistry, Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela), Leonard-Alexander Lieske (from IBM Research Europe -Zurich), Ricardo Ortiz (from Donostia International Physics Center (DIPC)), Igor Rončević (from Department of Chemistry, University of Oxford), Florian Albrecht (from IBM Research Europe -Zurich), Diego Peña (from Department of Organic Chemistry, Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela), Leo Gross (from IBM Research Europe -Zurich)

Figure

Fig. 1 | Non-benzenoid non-alternant polycyclic conjugated hydrocarbons.a, Classical nonbenzenoid non-alternant polycyclic conjugated hydrocarbons: pentalene, azulene and heptalene.b, Generation of indacenes and indenoindenes through benzinterposition and benzannelation of pentalene, respectively.Gray filled rings represent Clar sextets.c, Closed-shell Kekulé (left) and openshell non-Kekulé (right) resonance structures of QDMs.Note that meta-QDM is a non-Kekulé molecule.All indenofluorene isomers, being derived through benzannelation of indacenes, contain a central QDM moiety.d, Closed-shell Kekulé (top) and open-shell non-Kekulé (bottom) resonance structures of indenofluorenes.Compared to their closed-shell structures, 1 and 5 gain two Clar sextets in the openshell structure, while 2-4 gain only one Clar sextet in the open-shell structure.Colored bonds in d highlight the ortho-and para-QDM moieties in the two closed-shell Kekulé structures of 5. e, Scheme of on-surface generation of 5 by voltage pulse-induced dehydrogenation of 6 (C20H14).Structures 7 and 8 represent the two monoradical species (C20H13).
Fig. 2 | Characterization of open-shell indeno[1,2-a]fluorene on bilayer NaCl/Au(111).a, DFTcalculated wave functions of the frontier orbitals of 5OS in the triplet configuration for the spin up (occupied) level (isovalue: 0.002 e -Å -3 ).Blue and red colors represent opposite phases of the wave function.b, Corresponding DFT-calculated spin density of 5OS (isovalue: 0.01 e -Å -3).Blue and orange colors represent spin up and spin down densities, respectively.c, Probability density of the SOMOs of 5OS (isovalue: 0.001 e -Å -3 ).d, DFT-calculated bond lengths of 5OS.e, Constant-height I(V) spectra acquired on a species of 5 assigned as 5OS, along with the corresponding dI/dV(V) spectra.Open feedback parameters: V = -2 V, I = 0.17 pA (negative bias side) and V = 2 V, I = 0.17 pA (positive bias side).Acquisition position of the spectra is shown in Supplementary Fig.7.f, Scheme of many-body transitions associated to the measured ionic resonances of 5OS.Also shown are STM images of assigned 5OS at biases where the corresponding transitions become accessible.Scanning parameters: I = 0.3 pA (V = -1.2V and -1.5 V) and 0.2 pA (V = 1.3 V and 1.6 V). g, Laplace-filtered AFM image of assigned 5OS.STM set point: V = 0.2 V, I = 0.5 pA on bilayer NaCl, Δz = -0.3Å.The tip-height offset Δz for each panel is provided with respect to the STM setpoint, and positive (negative) values of Δz denote tip approach (retraction) from the STM setpoint.f and g show the same molecule at the same adsorption site, which is next to a trilayer NaCl island.The bright and dark features in the trilayer NaCl island in g correspond to Cl -and Na + ions, respectively.Scale bars: 10 Å (f) and 5 Å (g).
Fig. 3 | Characterization of closed-shell indeno[1,2-a]fluorene on bilayer NaCl/Au(111).a, DFTcalculated wave functions of the frontier orbitals of closed-shell 5 0 (isovalue: 0.002 e -Å -3 ).The wave functions shown here are calculated for the 5para geometry.b, DFT-calculated bond lengths of 5ortho (top) and 5para (bottom).c, Constant-height I(V) spectra acquired on a species of 5 assigned as 5para, along with the corresponding dI/dV(V) spectra.Open feedback parameters: V = -2 V, I = 0.15 pA (negative bias side) and V = 2.2 V, I = 0.15 pA (positive bias side).Acquisition position of the spectra is shown in Supplementary Fig. 7. d, Scheme of many-body transitions associated to the measured ionic resonances of 5para.Also shown are STM images of assigned 5para at biases where the corresponding transitions become accessible.Scanning parameters: I = 0.15 pA (V = -1.5 V) and 0.2 pA (V = 1.7 V). e, Laplace-filtered AFM image of assigned 5para.STM set point: V = 0.2 V, I = 0.5 pA on bilayer NaCl, Δz = -0.7 Å. f, Selected bonds labeled for highlighting bond order differences between 5para and 5ortho.For the bond pairs a/b, c/d and e/f, the bonds labeled in bold exhibit a higher bond order than their neighboring labeled bonds in 5para.g, Laplace-filtered AFM images of 5 on bilayer NaCl/Cu(111) showing switching between 5OS and 5para as the molecule changes its adsorption position.The faint protrusion adjacent to 5 is a defect that stabilizes the adsorption of 5. STM set point: V = 0.2 V, I = 0.5 pA on bilayer NaCl, Δz = -0.3Å. STM and STS data in c and d are acquired on the same species, while the AFM data in e is acquired on a different species.Scale bars: 10 Å (d) and 5 Å (e,g).
NMR (300 MHz, CDCl3) δ: 7.51 (m, 2H), 7.40 -7.28 (m, 5H), 7.27 -7.20 (m, 2H), 7.13 (d, J = 7.7 Hz, 1H), 2.07 (s, 3H), 1.77 (s, 3H) ppm. 13C NMR-DEPT (75 MHz, CDCl3, 1:1 mixture of atropisomers) δ: 141.2 (C), 141.1 (C), 140.0 (C), 139.4 (2C), 137.5 (C), 137.4 (C), 136.0 (3C), 134.8 (C), 134.5 (C), 134.1 (C), 134.0 (C), 133.7 (C), 133.6 (C), 131.6 (CH), 131.2 (CH), 131.1 (CH), 130.7 (CH), 129.8 (CH), 129.7 (CH), 129.5 (CH), 129.4 (CH), 129.0 (CH), 128.9 (CH), 128.7 (2CH), 128.6 (2CH), 127.2 (CH), 127.1 (CH), 127.0 (CH), 126.9 (CH), 126.7 (CH), 126.6 (CH), 20.6 (CH3), 20.5 (CH3), 17.7 (CH3), 17.5 (CH3) ppm.MS (APCI) m/z (%): 327 (M+1, 100).HRMS: C20H16Cl2; calculated: 327.0702, found: 327.0709.
NMR (500 MHz, CDCl3) δ: 7.93 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.47 (ddd, J = 8.4, 7.2, 1.1 Hz, 1H), 7.42 (dd, J = 8.1, 7.0 Hz, 1H), 7.35 (m, 2H), 4.22 (s, 3H), 4.02 (s, 3H).ppm. 13C NMR-DEPT (125 MHz, CDCl3) δ: 144.1 (C), 143.3 (C), 142.3 (C), 141.9 (C), 141.8 (C), 141.2 (C), 138.2 (C), 136.5 (C), 127.0 (CH), 126.9 (CH), 126.7 (CH), 126.6 (CH), 125.3 (CH), 125.2 (CH), 123.6 (CH), 122.2 (CH), 119.9 (CH), 118.4 (CH), 37.4 (CH2), 36.3 (CH2).ppm.MS (APCI) m/z (%): 254 (M+, 88).HRMS: C20H14; calculated: 254.1090, found: 254.1090.

abstract

Indenofluorenes are non-benzenoid conjugated hydrocarbons that have received great interest owing to their unusual electronic structure and potential applications in nonlinear optics and photovoltaics. Here, we report the generation of unsubstituted indeno[1,2-a]fluorene, the final and yet unreported parent indenofluorene regioisomer, on various surfaces by cleavage of two C-H bonds in 7,12-dihydro indeno[1,2-a]fluorene through voltage pulses applied by the tip of a combined scanning tunneling microscope and atomic force microscope.
On bilayer NaCl on Au(111), indeno[1,2a]fluorene is in the neutral charge state, while it exhibits charge bistability between neutral and anionic states on the lower work function surfaces of bilayer NaCl on Ag(111) and Cu(111). In the neutral state, indeno[1,2-a]fluorene exhibits either of two ground states: an open-shell π-diradical state, predicted to be a triplet by density functional and multireference many-body perturbation theory calculations, or a closedshell state with a para-quinodimethane moiety in the as-indacene core.
Switching between open-and closed-shell states of a single molecule is observed by changing its adsorption site on NaCl. The inclusion of non-benzenoid carbocyclic rings is a viable route to tune the physicochemical properties of polycyclic conjugated hydrocarbons (PCHs) . Non-benzenoid polycycles may lead to local changes in strain, conjugation, aromaticity, and, relevant to the context of the present work, induce an open-shell ground state of the corresponding PCHs .
Many nonbenzenoid PCHs are also non-alternant, where the presence of odd-membered polycycles breaks the bipartite symmetry of the molecular network . Figure shows classical examples of non-benzenoid non-alternant PCHs, namely, pentalene, azulene and heptalene. Whereas azulene is a stable PCH exhibiting Hückel aromaticity ([4n+2] π-electrons, n = 2), pentalene and heptalene are unstable Hückel antiaromatic compounds with [4n] π-electrons, n = 2 (pentalene) and n = 3 (heptalene).
Benzinterposition of pentalene generates indacenes, consisting of two isomers s-indacene and as-indacene (Fig. ). Apart from being antiaromatic, indacenes also contain proaromatic quinodimethane (QDM) moieties (Fig. ) , which endows them with potential open-shell character. While the parent s-indacene and asindacene have never been isolated, stable derivatives of s-indacene bearing bulky substituents have been synthesized .
A feasible strategy to isolate congeners of otherwise unstable non-benzenoid non-alternant PCHs is through fusion of benzenoid rings at the ends of the π-system, that is, benzannelation. For example, while the parent pentalene is unstable, the benzannelated congener indeno[2,1-a]indene is stable under ambient conditions (Fig. ) .
However, the position of benzannelation is crucial for stability: although indeno[2,1a]indene is stable, its regioisomer indeno[1,2-a]indene (Fig. ) oxidizes under ambient conditions . Similarly, benzannelation of indacenes gives rise to the family of PCHs known as indenofluorenes (Fig. ), which constitute the topic of the present work.
Depending on the benzannelation position and the indacene core, five regioisomers can be constructed, namely, indeno [ Practical interest in indenofluorenes stems from their low frontier orbital gap and excellent electrochemical characteristics that render them as useful components in organic electronic devices .
The potential open-shell character of indenofluorenes has led to several theoretical studies on their use as non-linear optical materials and as candidates for singlet fission in organic photovoltaics . Recent theoretical work has also shown that indenofluorene-based ladder polymers may exhibit fractionalized excitations.
Fundamentally, indenofluorenes represent model systems to study the interplay between aromaticity and magnetism at the molecular scale . Motivated by many of these prospects, the last decade has witnessed intensive synthetic efforts toward the realization of indenofluorenes. Derivatives of 1-4 have been realized in solution , while 1-3 have also been synthesized on surfaces and characterized using scanning tunneling microscopy (STM) and atomic force microscopy (AFM), which provide information on molecular orbital densities , molecular structure and oxidation state .
With regards to the open-shell character of indenofluorenes, 2-4 are theoretically and experimentally interpreted to be closed-shell, while calculations indicate that 1 and 5 should exhibit open-shell ground states . Bulk characterization of mesitylsubstituted 1, including X-ray crystallography, temperature-dependent NMR, and electron spin resonance spectroscopy, provided indications of its open-shell ground state .
Electronic characterization of 1 on Au(111) surface using scanning tunneling spectroscopy (STS) revealed a low electronic gap of 0.4 eV (ref. ). However, no experimental proof of an openshell ground state of 1 on Au(111), such as detection of singly occupied molecular orbitals (SOMOs) or spin excitations and correlations due to unpaired electrons , was shown.
In this work, we report the generation and characterization of unsubstituted 5. Our research is motivated by theoretical calculations that indicate 5 to exhibit the largest diradical character among all indenofluorene isomers . The same calculations also predict that 5 should possess a triplet ground state.
Therefore, 5 would qualify as a Kekulé triplet, of which only a handful of examples exist . However, definitive synthesis of 5 has never been reported so far. Previously, Dressler et al. reported transient isolation of mesityl-substituted 5, where it decomposed both in the solution and in solid state , and only the structural proof of the corresponding dianion was obtained.
On-surface generation of a derivative of 5, starting from truxene as a precursor, was recently reported . STM data on this compound, containing the indeno[1,2-a]fluorene moiety as part of a larger PCH, was interpreted to indicate its open-shell ground state. However, the results did not imply the ground state of unsubstituted 5. Here, we show that on insulating surfaces 5 can exhibit either of two ground states: an open-shell or a closed-shell.
We infer the existence of these two ground states based on high-resolution AFM imaging with bond-order discrimination and STM imaging of molecular orbital densities . AFM imaging reveals molecules with two different geometries. Characteristic bond-order differences in the two geometries concur with the geometry of either an open-or a closed-shell state.
Concurrently, STM images at ionic resonances show molecular orbital densities corresponding to SOMOs for the open-shell geometry, but orbital densities of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) for the closed-shell geometry. Our experimental results are in good agreement with density functional theory (DFT) and multireference perturbation theory calculations.
Finally, we observe switching between open-and closed-shell states of a single molecule by changing its adsorption site on the surface. Synthetic strategy toward indeno[1,2-a]fluorene. The generation of 5 relies on the solution-phase synthesis of the precursor 7,12-dihydro indeno[1,2-a]fluorene (6). Details on synthesis and characterization of 6 are reported in Supplementary Figs.
. Single molecules of 6 are deposited on coinage metal (Au(111), Ag(111) and Cu(111)) or insulator surfaces. In our work, insulating surfaces correspond to two monolayer-thick (denoted as bilayer) NaCl on coinage metal surfaces. Voltage pulses ranging between 4-6 V are applied by the tip of a combined STM/AFM system, which result in cleavage of one C-H bond at each of the pentagonal apices of 6, thereby leading to the generation of 5 (Fig. ).
In the main text, we focus on the generation and characterization of 5 on insulating surfaces. Generation and characterization of 5 on coinage metal surfaces is shown in Supplementary Fig. . ). Blue and orange colors represent spin up and spin down densities, respectively. c, Probability density of the SOMOs of 5OS (isovalue: 0.001 e -Å -3 ).
d, DFT-calculated bond lengths of 5OS. e, Constant-height I(V) spectra acquired on a species of 5 assigned as 5OS, along with the corresponding dI/dV(V) spectra. Open feedback parameters: V = -2 V, I = 0.17 pA (negative bias side) and V = 2 V, I = 0.17 pA (positive bias side). Acquisition position of the spectra is shown in Supplementary Fig. . f, Scheme of many-body transitions associated to the measured ionic resonances of 5OS.
Also shown are STM images of assigned 5OS at biases where the corresponding transitions become accessible. Scanning parameters: I = 0.3 pA (V = -1.2 V and -1.5 V) and 0.2 pA (V = 1.3 V and 1.6 V). g, Laplace-filtered AFM image of assigned 5OS. STM set point: V = 0.2 V, I = 0.5 pA on bilayer NaCl, Δz = -0.3
Å. The tip-height offset Δz for each panel is provided with respect to the STM setpoint, and positive (negative) values of Δz denote tip approach (retraction) from the STM setpoint. f and g show the same molecule at the same adsorption site, which is next to a trilayer NaCl island. The bright and dark features in the trilayer NaCl island in g correspond to Cl -and Na + ions, respectively.
Scale bars: 10 Å (f) and 5 Å (g). To experimentally explore the electronic structure of 5, we used bilayer NaCl films on coinage metal surfaces to electronically decouple the molecule from the metal surfaces. Before presenting the experimental findings, we summarize the results of our theoretical calculations performed on 5 in the neutral charge state (denoted as 5 0 ).
We start by performing DFT calculations on 5 0 in the gas phase. Geometry optimization performed at the spin-unrestricted UB3LYP/6-31G level of theory leads to one local minimum, 5OS, the geometry of which corresponds to the open-shell resonance structure of 5 (Fig. , the label OS denotes open-shell).
The triplet electronic configuration of 5OS is the lowest-energy state, with the openshell singlet configuration 90 meV higher in energy. Geometry optimization performed at the restricted closed-shell RB3LYP/6-31G level reveals two local minima, 5para and 5ortho, the geometries of which (Fig. ) exhibit bond length alternations in line with the presence of a para-or an ortho-QDM moiety, respectively, in the as-indacene core of the closed-shell resonance structures of 5 (Fig. ) .
Relative to 5OS in the triplet configuration, 5para and 5ortho are 0.40 and 0.43 eV higher in energy, respectively. Additional DFT results are shown in Supplementary Fig. . To gain more accurate insights into the theoretical electronic structure of 5, we performed multireference perturbation theory calculations (Supplementary Fig. ) based on quasi-degenerate second-order n-electron valence state perturbation theory (QD-NEVPT2).
In so far as the order of the ground and excited states are concerned, the results of QD-NEVPT2 calculations qualitatively match with DFT calculations. For 5OS, the triplet configuration remains the lowest-energy state, with the open-shell singlet configuration 60 meV higher in energy. The energy differences between the open-and closed-shell states are substantially reduced in QD-NEVPT2 calculations, with 5para and 5ortho only 0.11 and 0.21 eV higher in energy, respectively, compared to 5OS in the triplet configuration.
We also performed nucleus-independent chemical shift calculations to probe local aromaticity of 5 in the openand closed-shell states. While 5OS in the triplet configuration exhibits local aromaticity at the terminal benzenoid rings, 5OS in the open-shell singlet configuration, 5para and 5ortho all display antiaromaticity (Supplementary Fig. ).
The choice of the insulating surface determines the charge state of 5: while 5 adopts neutral charge state on the high work function bilayer NaCl/Au(111) surface (irrespective of its openor closed-shell state, Supplementary Fig. ), 5 exhibits charge bistability between 5 0 and the anionic state 5 -1 on the lower work function bilayer NaCl/Ag(111) and Cu(111) surfaces (Supplementary Figs. ).
In the main text, we focus on the characterization of 5 on bilayer NaCl/Au(111). Characterization of charge bistable 5 is reported in Supplementary Figs. . We first describe experiments on 5 on bilayer NaCl/Au(111), where 5 exhibits a geometry corresponding to the calculated 5OS geometry, and an open-shell electronic configuration.
We compare the experimental data on this species to calculations on 5OS with a triplet configuration, as theory predicts a triplet ground state for 5OS. For 5OS, the calculated frontier orbitals correspond to the SOMOs ψ1 and ψ2 (Fig. ), whose spin up levels are occupied and the spin down levels are empty.
Figure shows the DFT-calculated bond lengths of 5OS, where the two salient features, namely, the small difference in the bond lengths within each ring and the notably longer bond lengths in the pentagonal rings, agree with the open-shell resonance structure of 5 (Fig. ). Figure shows an AFM image of 5 adsorbed on bilayer NaCl/Au(111) that we assign as 5OS, where the bond-order differences qualitatively correspond to the calculated 5OS geometry (discussed and compared to the closed-shell state below).
Differential conductance spectra (dI/dV(V), where I and V denote the tunneling current and bias voltage, respectively) acquired on assigned 5OS exhibit two peaks centered at -1.5 V and 1.6 V (Fig. ), which we assign to the positive and negative ion resonances (PIR and NIR), respectively. Figure shows the corresponding STM images acquired at the onset (V = -1.2
V/1.3 V) and the peak (V = -1.5 V/1.6 V) of the ionic resonances. To draw a correspondence between the STM images and the molecular orbital densities, we consider tunneling events as many-body electronic transitions between different charge states of 5OS (Fig. ). Within this framework, the PIR corresponds to transitions between 5 0 and the cationic state 5 .
At the onset of the PIR at -1.2 V, an electron can only be detached from the SOMO ψ1 and the corresponding STM image at -1.2 V shows the orbital density of ψ1. Increasing the bias to the peak of the PIR at -1.5 V, it becomes possible to also empty the SOMO ψ2, such that the corresponding STM image shows the superposition of ψ1 and ψ2, that is, |ψ1| 2 + |ψ2| 2 (ref.
). Similarly, the NIR corresponds to transitions between 5 0 and 5 -1 . At the NIR onset of 1.3 V, only electron attachment to ψ2 is energetically possible. At 1.6 V, electron attachment to ψ1 also becomes possible, and the corresponding STM image shows the superposition of ψ1 and ψ2. The observation of the orbital densities of SOMOs, and not the hybridized HOMO and LUMO, proves the open-shell ground state of assigned 5OS.
Measurements of the monoradical species with a doublet ground state are shown in Supplementary Fig. . Unexpectedly, another species of 5 was also experimentally observed that exhibited a closedshell ground state. In contrast to 5OS, where the frontier orbitals correspond to the SOMOs ψ1 and ψ2, DFT calculations predict orbitals of different shapes and symmetries for 5para and 5ortho, denoted as α and β and shown in Fig. .
For 5ortho, α and β correspond to HOMO and LUMO, respectively. The orbitals are inverted in energy and occupation for 5para, where β is the HOMO and α is the LUMO. Fig. shows an AFM image of 5 that we assign as 5para. We experimentally infer its closed-shell state first by using qualitative bond order discrimination by AFM.
In high-resolution AFM imaging, chemical bonds with higher bond order are imaged brighter (that is, with higher frequency shift Δf) due to stronger repulsive forces, and they appear shorter . In Fig. , we label seven bonds whose bond orders show significant qualitative differences in the calculated 5ortho, 5para (Fig. ) and 5OS (Fig. ) geometries.
In 5para, the bonds b and d exhibit a higher bond order than a and c, respectively. This pattern is reversed for 5ortho, while the bond orders of the bonds a-d are all similar and small for 5OS. Furthermore, in 5para bond f exhibits a higher bond order than e, while in 5ortho and 5OS bonds e and f exhibit similar bond order (because they belong to Clar sextets).
Finally, the bond labeled g shows a higher bond order in 5para than in 5ortho and 5OS. The AFM image of assigned 5para shown in Fig. indicates higher bond orders of the bonds b, d and f compared to a, c and e, respectively. In addition, the bond g appears almost point-like and with enhanced Δf contrast compared to its neighboring bonds, indicative of a high bond order (see Supplementary Fig. for height-dependent measurements).
These observations concur with the calculated 5para geometry (Fig. ). Importantly, all these distinguishing bond-order differences are distinctly different in the AFM image of 5OS shown in Fig. , which is consistent with the calculated 5OS geometry (Fig. ). In the AFM images of 5OS (Fig. and Supplementary Fig. ), the bonds a-d at the pentagon apices appear with similar contrast and apparent bond length.
The bonds e and f at one of the terminal benzenoid rings also exhibit similar contrast and apparent bond length, while the central bond g appears longer compared to assigned 5para. Further compelling evidence for the closed-shell state of assigned 5para is obtained by STM and STS. dI/dV(V) spectra acquired on an assigned 5para species exhibit two peaks centered at -1.4 V (PIR) and 1.6 V (NIR) (Fig. ).
STM images acquired at these biases (Fig. ) show the orbital densities of β (-1.4 V) and α (1.6 V). First, the observation of α and β as the frontier orbitals of this species, and not the SOMOs, strongly indicates its closed-shell state. Second, consistent with AFM measurements that indicate good correspondence to the calculated 5para geometry, we observe β as the HOMO and α as the LUMO.
For 5ortho, α should be observed as the HOMO and β as the LUMO. We did not observe molecules with the signatures of 5ortho in our experiments. We observed molecules in open-(5OS, Fig. ) and closed-shell (5para, Fig. ) states in similar occurrence after their generation from 6 on the surface. We could also switch individual molecules between open-and closed-shell states as shown in Fig. and Supplementary Fig. .
To this end, a change in the adsorption site of a molecule was induced by STM imaging at ionic resonances, which often resulted in movement of the molecule. The example presented in Fig. shows a molecule that was switched from 5para to 5OS and back to 5para. The switching is not directed, that is, we cannot choose which of the two species will be formed when changing the adsorption site, and we observed 5OS and 5para in approximately equal yields upon changing the adsorption site.
The molecule in Fig. is adsorbed on top of a defect that stabilizes its adsorption geometry on bilayer NaCl. At defect-free adsorption sites on bilayer NaCl, that is, without a third layer NaCl island or atomic defects in the vicinity of the molecule, 5 could be stably imaged neither by AFM nor by STM at ionic resonances (Supplementary Fig. ).
Without changing the adsorption site, the state of 5 (open-or closedshell) never changed, including the experiments on bilayer NaCl/Ag(111) and Cu(111), on which the charge state of 5 could be switched (Supplementary Figs. ). Also on these lower work function surfaces, both open-and closed-shell species were observed for 5 0 and both showed charge bistability between 5 0 (5OS or 5para) and 5 -1 (Supplementary Figs. ).
The geometrical structure of 5 -1 probed by AFM, and its electronic structure probed by STM imaging at the NIR (corresponding to transitions between 5 -1 and the dianionic state 5 -2 ), are identical within the measurement accuracy for the charged species of both 5OS and 5para. When cycling the charge state of 5 between 5 0 and 5 -1 several times, we always observed the same state (5OS or 5para) when returning to 5 0 , provided the molecule did not move during the charging/discharging process.
Based on our experimental observations we conclude that indeno[1,2-a]fluorene (5), the last unknown indenofluorene isomer, can be stabilized in and switched between an open-shell (5OS) and a closed-shell (5para) state on NaCl. For the former, both DFT and QD-NEVPT2 calculations predict a triplet electronic configuration.
Therefore, 5 can be considered to exhibit the spin-crossover effect, involving magnetic switching between high-spin (5OS) and low-spin (5para) states, coupled with a reversible structural transformation. So far, the spin-crossover effect has mainly only been observed in transition-metal-based coordination compounds with a near-octahedral geometry .
The observation that the switching between open-and closedshell states is related to changes in the adsorption site but is not achieved by charge-state cycling alone, indicates that the NaCl surface and local defects facilitate different electronic configurations of 5 depending on the adsorption site.
Gas-phase QD-NEVPT2 calculations predict that 5OS is the ground state, and the closed-shell 5para and 5ortho states are 0.11 and 0.21 eV higher in energy. The experiments, showing bidirectional switching between 5OS and 5para, indicate that a change in the adsorption site can induce sufficient change in the geometry of 5 (leading to a corresponding change in the ground state electronic configuration) and thus induce switching.
Switching between open-and closed-shell states in 5 does not require the breaking or formation of covalent bonds , but a change of adsorption site on NaCl where the molecule is physisorbed. Our results should have implications for single-molecule devices, capitalizing on the altered electronic and chemical properties of a system in π-diradical open-shell and closed-shell states such as frontier orbital and singlet-triplet gaps, and chemical reactivity.
For possible future applications as a single-molecule switch, it might be possible to also switch between open-and closed-shell states by changing the local electric field, such as by using chargeable adsorbates . Scanning probe microscopy measurements and sample preparation. STM and AFM measurements were performed in a home-built system operating at base pressures below 1×10 -10 mbar and a base temperature of 5 K. Bias voltages are provided with respect to the sample.
All STM, AFM and spectroscopy measurements were performed with carbon monoxide (CO) functionalized tips. AFM measurements were performed in non-contact mode with a qPlus sensor . The sensor was operated in frequency modulation mode with a constant oscillation amplitude of 0.5 Å. STM measurements were performed in constantcurrent mode, AFM measurements were performed in constant-height mode with V = 0 V, and I(V) and Δf(V) spectra were acquired in constant-height mode.
Positive (negative) values of the tip-height offset Δz represent tip approach (retraction) from the STM setpoint. All dI/dV(V) spectra are obtained by numerical differentiation of the corresponding I(V) spectra. STM and AFM images, and spectroscopy curves, were post-processed using Gaussian low-pass filters.
Au(111), Ag(111) and Cu(111) surfaces were cleaned by iterative cycles of sputtering with Ne + ions and annealing up to 800 K. NaCl was thermally evaporated on Au(111), Ag(111) and Cu(111) surfaces held at 323 K, 303 K and 283 K, respectively. This protocol results in the growth of predominantly bilayer (100)-terminated islands, with a minority of trilayer islands.
Sub-monolayer coverage of 6 on surfaces was obtained by flashing an oxidized silicon wafer containing the precursor molecules in front of the cold sample in the microscope. CO molecules for tip functionalization were dosed from the gas phase on the cold sample. Density functional theory calculations. DFT was employed using the PSI4 program package .
All molecules with different charge (neutral and anionic) and electronic (open-and closed-shell) states were independently investigated in the gas phase. The B3LYP exchangecorrelation functional with 6-31G basis set was employed for structural relaxation and singlepoint energy calculations. The convergence criteria were set to 10 −4 eV Å −1 for the total forces and 10 −6 eV for the total energies.
Multireference calculations. Multireference calculations were performed on the DFToptimized geometries using the QD-NEVPT2 level of theory , with three singlet roots and one triplet root included in the state-averaged calculation. A (10,10) active space (that is, 10 electrons in 10 orbitals) was used along with the def2-TZVP basis set .
Increasing either the active space size or expanding the basis set resulted in changes of about 50 meV for relative energies of the singlet and triplet states. These calculations were performed using the ORCA program package . Nucleus-independent chemical shift (NICS) calculations. Isotropic nucleus-independent chemical shift values were evaluated at the centre of each ring using the B3LYP exchangecorrelation functional with def2-TZVP basis set using the Gaussian 16 software package .
Starting materials (reagent grade) were purchased from TCI and Sigma-Aldrich and used without further purification. Reactions were carried out in flame-dried glassware and under an inert atmosphere of purified Ar using Schlenk techniques. Thin-layer chromatography (TLC) was performed on Silica Gel 60 F-254 plates (Merck).
Column chromatography was performed on silica gel (40-60 µm). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Varian Mercury 300 or Bruker Varian Inova 500 spectrometers. Mass spectrometry (MS) data were recorded in a Bruker Micro-TOF spectrometer. The synthesis of compound 6 was developed following the two-step synthetic route shown in Supplementary Fig. , which is based on the preparation of methylene-bridge polyarenes by means of Pd-catalyzed activation of benzylic C-H bonds .
Supplementary Figure | Synthetic route to obtain compound 6. The complex Pd2(dba)3 (20 mg, 0.02 mmol) was added over a deoxygenated mixture of 1,3-dibromo-2,4-dimethylbenzene (9, 100 mg, 0.38 mmol), boronic acid 10 (178 mg, 1.14 mmol), K2CO3 (314 mg, 2.28 mmol) and XPhos (35 mg, 0.08 mmol) in toluene (1:1, 10 mL), and the resulting mixture was heated at 90 °C for 2 h.
After cooling to room temperature, the solvents were evaporated under reduced pressure. The reaction crude was purified by column chromatography (SiO2; hexane:CH2Cl2 9:1) affording 11 (94 mg, 76%) as a colorless oil. The complex Pd(OAc)2 (7 mg, 0.03 mmol) was added over a deoxygenated mixture of terphenyl 11 (90 mg, 0.27 mmol), K2CO3 (114 mg, 0.83 mmol) and ligand L (26 mg, 0.06 mmol) in NMP (2 mL).
The resulting mixture was heated at 160 °C for 4 h. After cooling to room temperature, H2O (30 mL) was added, and the mixture was extracted with EtOAc (3x15 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The reaction crude was purified by column chromatography (SiO2; hexane:CH2Cl2 9:1) affording compound 6 (8 mg, 11%) as a white solid. in AFM imaging due to their reduced adsorption height compared to the rest of the carbon atoms.
We attribute this observation to the significantly different lattice parameter of Cu(111) (2.57 Å) compared to Au(111) and Ag(111) (2.95 Å and 2.94 Å, respectively) , such that the apical carbon atoms of the pentagonal rings of 5 adsorb on the on-top atomic sites on Au(111) and Ag(111), but not on Cu(111).
Our speculation is based on a previous study of polymers of 1 on Au(111) by Di Giovannantonio et al. , where both tilted and planar individual units of 1 were observed depending on whether the apical carbon atoms of the pentagonal rings in 1 adsorbed on the on-top or hollow sites of the surface, respectively.
Given the strong molecule-metal interaction, we found no electronic state signatures of 5 on all three metal surfaces. STM set point for AFM images: V = 0. e, Frontier orbital spectrum of 5 -1 . In the anionic state, ψ2 becomes doubly occupied and ψ1 is the SOMO. Filled and empty circles denote occupied and empty orbitals, respectively.
For each panel, zero of the energy axis has been aligned to the respective highest-energy occupied orbital.

Answer: Yes, individual molecules of indeno[1,2-a]fluorene can switch between open-shell and closed-shell states by changing their adsorption site on the surface.


Input: What are the symptoms of alpha thalassemia major?

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Thalassemia describes a group of inherited disorders characterized by reduced or absent amounts of hemoglobin, the oxygen-carrying protein inside the red blood cells. There are two basic groups of thalassemia disorders: alpha thalassemia and beta thalassemia. These conditions cause varying degrees of anemia, which can range from insignificant to life threatening.
All types of thalassemias are considered quantitative diseases of hemoglobin, because the quantity of hemoglobin produced is reduced or absent. Usual adult hemoglobin is made up of three components: alpha globin, beta globin, and heme. Thalassemias are classified according to the globin that is affected, hence the names alpha and beta thalassemia. Although both classes of thalassemia affect the same protein, the alpha and beta thalassemias are distinct diseases that affect the body in different ways.
Beta thalassemia may be the most best-known type of thalassemia and is also called Cooley's anemia. It is caused by a change in the gene for the beta globin component of hemoglobin. Beta thalassemia causes variable anemia that can range from moderate to severe, depending in part on the exact genetic change underlying the disease. Beta thalassemia can be classified based on clinical symptoms. Beta thalassemia major usually causes severe anemia that can occur within months after birth. If left untreated, severe anemia can result in insufficient growth and development, as well as other common physical complications that can lead to a dramatically decreased life-expectancy. Fortunately, in developed countries beta thalassemia is usually identified by screening in the newborn period, before symptoms have developed. Children who are identified early can be started on ongoing blood transfusion therapy as needed. Although transfusion therapy prevents many of the complications of severe anemia, the body is unable to eliminate the excess iron contained in the transfused blood. Over time, the excess iron deposits in tissues and organs, resulting in damage and organ failure. Another medication must be administered to help the body eliminate the excess iron and prevent iron-over-load complications. Beta thalassemia intermedia describes the disease in individuals who have moderate anemia that only requires blood transfusions intermittently, if at all.
Alpha thalassemia is the result of changes in the genes for the alpha globin component of hemoglobin. There are two main types of alpha thalassemia disease: hemoglobin H disease and alpha thalassemia major. The two diseases are quite different from beta thalassemia as well as from one another. Individuals with hemoglobin H disease can experience events of hemolytic anemia—anemia caused by the rapid breakdown of the red blood cells. These events are thought to be triggered by various environmental causes, such as infection and/or exposure to certain chemicals. Hemoglobin H disease is in most cases milder than beta thalassemia. It does not generally require transfusion therapy. Alpha thalassemia major is a very serious disease that results in severe anemia that begins even before birth. Most affected babies do not survive to be born or die shortly after birth.
The thalassemias are among the most common genetic diseases worldwide. Both alpha and beta thalassemia have been described in individuals of almost every ancestry, but the conditions are more common among certain ethnic groups. Unaffected carriers of all types of thalassemia traits do not experience health problems. In fact, the thalassemia trait is protective against malaria, a disease caused by blood-borne parasites transmitted through mosquito bites. According to a widely accepted theory, most genetic changes—mutations—that cause thalassemia occurred multiple generations ago. Coincidentally, these mutations increased the likelihood that carriers would survive malaria infection. Survivors passed the mutation onto their offspring, and the trait became established throughout areas where malaria is common. As populations migrated, so did the thalassemia traits.
Beta thalassemia trait is seen most commonly in people with the following ancestry: Mediterranean (including North African, and particularly Italian and Greek), Middle Eastern, Indian, African, Chinese, and Southeast Asian (including Vietnamese, Laotian, Thai, Singaporean, Filipino, Cambodian, Malaysian, Burmese, and Indonesian). Alpha-thalassemia trait is seen with increased frequency in the same ethnic groups. However, there are different types of alpha thalassemia traits within these populations. The frequency of hemoglobin H disease and alpha thalassemia major depends on the type of alpha thalassemia trait. The populations in which alpha thalassemia diseases are most common include Southeast Asians and Chinese (particularly Southern Chinese).
It is difficult to obtain accurate prevalence figures for various types of thalassemia within different populations. This difficulty arises due to testing limitations in determining exact genetic diagnoses, as well as the fact that many studies have focused on small, biased hospital populations.
Two studies reflect prevalence figures that can be helpful counseling families and determining who to screen for beta thalassemia. Between the years of 1990 and 1996, the State of California screened more than 3.1 million infants born in the state for beta thalassemia. Approximately 1 in 114,000 infants had beta thalassemia major, with prevalence rates being highest among Asian Indians (about one in 4,000), Southeast Asians (about one in 10,000), and Middle Easterners (about one in 7,000). Another type of beta thalassemia disease, E/beta thalassemia, was represented in approximately one in 110,000 births, all of which occurred in families of Southeast Asian ancestry. Among Southeast Asians, the prevalence of E/beta thalassemia was approximately one in 2,600 births. This is in keeping with the observation that hemoglobin E trait carrier rates are relatively high within the Southeast Asian population: 16% in a study of 768 immigrants to California, and up to 25% in some specific Southeast Asian populations such as Cambodians. While these California studies address some of the limitations of earlier population studies, the pattern observed in California is expected to be different in other areas of the United States and the world. For example, Italians are underrepresented in this population when compared to the population of the East Coast of the United States.
Determining prevalence figures for alpha thalassemia is even more difficult due to increased limitations in diagnostic testing. All types of alpha thalassemia disease are most common among people of Southeast Asian and Chinese descent, for reasons that become clearer with an understanding of the underlying genetics of alpha thalassemia. One study of 500 pregnant women in Northern Thailand estimated a frequency of one in 500 pregnancies affected by alpha thalassemia major, for example. Prevalence of alpha thalassemia disease is significantly lower in the United States primarily because of immigration patterns; although at least one state, California, has observed growing hemoglobin H disease incidence rates that are high enough to justify universal newborn screening for the condition.
Humans normally make several types of the oxygen-carrying protein hemoglobin. An individual's stage in development determines whether he or she makes primarily embryonic, fetal, or adult hemoglobins. All types of hemoglobin are made of three components: heme, alpha (or alpha-like) globin, and beta (or beta-like) globin. All types of thalassemia are caused by changes in either the alpha- or beta-globin gene. These changes cause little or no globin to be produced. The thalassemias are, therefore, considered quantitative hemoglobin diseases. All types of thalassemias are recessively inherited, meaning that a genetic change must be inherited from both the mother and the father. The severity of the disease is influenced by the exact thalassemia mutations inherited, as well as other genetic and environmental factors. There are rare exceptions, notably with beta thalassemia, where globin gene mutations exhibit a dominant pattern of inheritance in which only one gene needs to be altered in order to see disease expression. Scientists continue to study the causes. For instance, a new mutation for alpha-thalassemia was discovered for the first time among Iranian patients in 2004.
BETA-THALASSEMIA. Most individuals have two normal copies of the beta globin gene, which is located on chromosome 11 and makes the beta globin component of normal adult hemoglobin, hemoglobin A. There are approximately 100 genetic mutations that have been described that cause beta thalassemia, designated as either beta0 or beta + mutations. No beta globin is produced with a beta0 mutation, and only a small fraction of the normal amount of beta globin is produced with a beta + mutation.
When an individual has one normal beta globin gene and one with a beta thalassemia mutation, he or she is said to carry the beta thalassemia trait. Beta thalassemia trait, like other hemoglobin traits, is protective against malaria infection. Trait status is generally thought not to cause health problems, although some women with beta thalassemia trait may have an increased tendency toward anemia during pregnancy.
When two members of a couple carry the beta thalassemia trait, there is a 25% chance that each of their children will inherit beta thalassemia disease by inheriting two beta thalassemia mutations, one from each parent. The clinical severity of the beta thalassemia disease—whether an individual has beta thalassemia intermedia or beta thalassemia major—will depend largely on whether the mutations inherited are beta0 thalassemia or beta + thalassemia mutations. Two beta0 mutations generally lead to beta thalassemia major, and two beta+ thalassemia mutations generally lead to beta thalassemia intermedia. Inheritance of one beta0 and one beta + thalassemia mutation tends to be less predictable.
Although relatively uncommon, there are other thalassemia-like mutations that can affect the beta globin gene. Hemoglobin E is the result of a substitution of a single nucleotide. This change results in a structurally altered hemoglobin that is produced in decreased amounts. Therefore, hemoglobin E is unique in that it is both a quantitative (i.e. thalassemia-like) and qualitative trait. When co-inherited with a beta thalassemia trait, it causes a disease that is almost indistinguishable from beta thalassemia disease. Large deletions around and including the beta globin gene can lead to delta/beta thalassemia or hereditary persistence of fetal hemoglobin (HPFH). Interestingly, delta/beta thalassemia trait behaves very similarly to beta thalassemia trait in its clinical manifestations. However, HPFH trait does not tend to cause hemoglobin disease when co-inherited with a second thalassemia or other beta globin mutation.
ALPHA-THALASSEMIA. Most individuals have four normal copies of the alpha globin gene, two copies on each chromosome 16. These genes make the alpha globin component of normal adult hemoglobin, which is called hemoglobin A. Alpha globin is also a component of fetal hemoglobin and the other major adult hemoglobin called hemoglobin A2. Mutations of the alpha globin genes are usually deletions of the gene, resulting in absent production of alpha globin. Since there are four genes (instead of the usual two) to consider when looking at alpha globin gene inheritance, there are several alpha globin types that are possible.
Absence of one alpha globin gene leads to a condition known as silent alpha thalassemia trait. This condition causes no health problems and can be detected only by special genetic testing. Alpha thalassemia trait occurs when two alpha globin genes are missing. This can occur in two ways. The genes may be deleted from the same chromosome, causing the 'cis' type of alpha thalassemia trait. Alternately, they may be deleted from different chromosomes, causing the 'trans' type of alpha thalassemia trait. In both instances, there are no associated health problems, although the trait status may be detected by more routine blood screening.
Hemoglobin H disease results from the deletion of three alpha globin genes, such that there is only one functioning gene. Typically, this can occur when one parent carries the silent alpha thalassemia trait, and the other parent carries the 'cis' type of the alpha thalassemia trait. In this situation, there is a 25% chance for hemoglobin H disease in each of such a couple's children.
Hemoglobin H disease-like symptoms can also be a part of a unique condition called alpha thalassemia mental retardation syndrome. Alpha thalassemia mental retardation syndrome can be caused by a deletion of a significant amount of chromosome 16, affecting the alpha globin genes. This is usually not inherited, but rather occurs sporadically in the affected individual. Affected individuals have mild hemoglobin H disease, mild-to-moderate mental retardation, and characteristic facial features. This syndrome can also occur as a sex-linked form in which a mutation is inherited in a particular gene on the X-chromosome. This gene influences alpha globin production, as well as various other developmental processes. Individuals affected with this form of the syndrome tend to have more severe mental retardation, delayed development, nearly absent speech, characteristic facial features, and genital-urinary abnormalities. The remaining discussion will focus only on aspects of hemoglobin H disease.
Alpha thalassemia major results from the deletion of all four alpha globin genes, such that there are no functioning alpha globin genes. This can occur when both parents carry the 'cis' type of the alpha thalassemia trait. In this situation, there is a 25% chance for alpha thalassemia major in each of such a couple's children.
Beta thalassemia major is characterized by severe anemia that can begin months after birth. In the United States and other developed countries beta thalassemia is identified and treated early and effectively. Therefore, the following discussion of symptoms applies primarily to affected individuals in the past and unfortunately in some underdeveloped countries now. If untreated, beta thalassemia major can lead to severe lethargy, paleness, and delays in growth and development. The body attempts to compensate by producing more blood, which is made inside the bones in the marrow. However, this is ineffective without the needed genetic instructions to make enough functioning hemoglobin. Instead, obvious bone expansion and changes occur that cause characteristic facial and other changes in appearance, as well as increased risk of fractures. Severe anemia taxes other organs in the body—such as the heart, spleen, and liver—which must work harder than usual. This can lead to heart failure, as well as enlargement and other problems of the liver and spleen. When untreated, beta thalassemia major generally results in childhood death, usually due to heart failure. In 2004, the first known heart attack associated with beta thalassemia major was reported. Fortunately, in developed countries diagnosis is usually made early, often before symptoms have begun. This allows for treatment with blood transfusion therapy, which can prevent most of the complications of the severe anemia caused by beta thalassemia major. Individuals with beta thalassemia intermedia have a more moderate anemia that may only require treatment with transfusion intermittently, such as when infections occur and stress the body. As a person with beta thalassemia intermedia gets older, however, the need for blood transfusions may increase to the point that they are required on a regular basis. When this occurs their disease becomes more similar to beta thalassemia major. Other genetic and environmental factors can influence the course of the disease as well. For example, co-inheritance of one or two alpha thalassemia mutations can tend to ameliorate some of the symptoms of beta thalassemia disease, which result in part from an imbalance in the amount of alpha- and beta-globin present in the red blood cells.
Hemoglobin h disease
Absence of three alpha globin genes causes an imbalance of alpha and beta globin proteins in the red blood cells. The excess beta globin proteins tend to come together to form hemoglobin H, which is unable to release oxygen to the tissues. In addition, hemoglobin H tends to precipitate out in the cells, causing damage to the red blood cell membrane. When affected individuals are exposed to certain drugs and chemicals known to make the membrane more fragile, the cells are thought to become vulnerable to breakdown in large numbers, a complication called hemolytic anemia. Fever and infection are also considered to be triggers of hemolytic anemia in hemoglobin H disease. This can result in fatigue, paleness, and a yellow discoloration of the skin and whites of eyes called jaundice. Usually, the anemia is mild enough not to require treatment. Severe anemia events may require blood transfusion, however, and are usually accompanied by such other symptoms as dark feces or urine and abdominal or back pain. These events are uncommon in hemoglobin H disease, although they occur more frequently in a more serious type of hemoglobin H disease called hemoglobin H/Constant Spring disease. Individuals effected with this type of hemoglobin H disease are also more likely to have enlargement of and other problems with the spleen.
Alpha thalassemia major
Because alpha globin is a necessary component of all major hemoglobins and some minor hemoglobins, absence of all functioning alpha globin genes leads to serious medical consequences that begin even before birth. Affected fetuses develop severe anemia as early as the first trimester of pregnancy. The placenta, heart, liver, spleen, and adrenal glands may all become enlarged. Fluid can begin collecting throughout the body as early as the start of the second trimester, causing damage to developing tissues and organs. Growth retardation is also common. Affected fetuses usually miscarry or die shortly after birth. In addition, women carrying affected fetuses are at increased risk of developing complications of pregnancy and delivery. Up to 80% of such women develop toxemia, a disturbance of metabolism that can potentially lead to convulsions and coma. Other maternal complications include premature delivery and increased rates of delivery by cesarean section, as well as hemorrhage after delivery.
Thalassemia may be suspected if an individual shows signs that are suggestive of the disease. In all cases, however, laboratory diagnosis is essential to confirm the exact diagnosis and to allow for the provision of accurate genetic counseling about recurrence risks and testing options for parents and affected individuals. Screening is likewise recommended to determine trait status for individuals of high-risk ethnic groups.
The following tests are used to screen for thalassemia disease and/or trait:
hemoglobin electrophoresis with quantitative hemoglobin A2 and hemoglobin F
free erythrocyte-protoporphyrin (or ferritin or other studies of serum iron levels)
A complete blood count will identify low levels of hemoglobin, small red blood cells, and other red blood cell abnormalities that are characteristic of a thalassemia diagnosis. Since thalassemia trait can sometimes be difficult to distinguish from iron deficiency, tests to evaluate iron levels are important. A hemoglobin electrophoresis is a test that can help identify the types and quantities of hemoglobin made by an individual. This test uses an electric field applied across a slab of gel-like material. Hemoglobins migrate through this gel at various rates and to specific locations, depending on their size, shape, and electrical charge. Isoelectric focusing and high-performance liquid chromatography (HPLC) use similar principles to separate hemoglobins and can be used instead of or in various combinations with hemoglobin electrophoresis to determine the types and quantities of hemoglobin present. Hemoglobin electrophoresis results are usually within the normal range for all types of alpha thalassemia. However, hemoglobin A2 levels and sometimes hemoglobin F levels are elevated when beta thalassemia disease or trait is present. Hemoglobin electrophoresis can also detect structurally abnormal hemoglobins that may be co-inherited with a thalassemia trait to cause thalassemia disease (i.e., hemoglobin E) or other types of hemoglobin disease (i.e., sickle hemoglobin). Sometimes DNA testing is needed in addition to the above screening tests. This can be performed to help confirm the diagnosis and establish the exact genetic type of thalassemia.
Diagnosis of thalassemia can occur under various circumstances and at various ages. Several states offer thalassemia screening as part of the usual battery of blood tests done for newborns. This allows for early identification and treatment. Thalassemia can be identified before birth through the use of prenatal diagnosis. Chorionic villus sampling (CVS) can be offered as early as 10 weeks of pregnancy and involves removing a sample of the placenta made by the baby and testing the cells. CVS carries a risk of causing a miscarriage that is between 0.5%-1%. Amniocentesis is generally offered between 15 and 22 weeks of pregnancy, but can sometimes be offered earlier. Two to three tablespoons of the fluid surrounding the baby is removed. This fluid contains fetal cells that can be tested. The risk of miscarriage associated with amniocentesis ranges from 0.33-0.5%. Pregnant woman and couples may choose prenatal testing in order to prepare for the birth of a baby that may have thalassemia. Alternately, knowing the diagnosis during pregnancy allows for the option of pregnancy termination. Preimplantation genetic diagnosis (PGD) is a relatively new technique that involves in-vitro fertilization followed by genetic testing of one cell from each developing embryo. Only the embryos unaffected by sickle cell disease are transferred back into the uterus. PGD is currently available on a research basis only and is relatively expensive.
Individuals with beta thalassemia major receive regular blood transfusions, usually on a monthly basis. This helps prevent severe anemia and allows for more normal growth and development. Transfusion therapy does have limitations, however. Individuals can develop reactions to certain proteins in the blood—called a transfusion reaction. This can make locating appropriately matched donor blood more difficult. Although blood supplies in the United States are very safe, particularly relative to the past and to other areas of the world, there remains an increased risk of exposure to such blood-borne infections as hepatitis. Additionally, the body is not able to get rid of the excess iron that accompanies each transfusion. An additional medication called desferoxamine is administered, usually five nights per week over a period of several hours, using an automatic pump that can be used during sleep or taken anywhere the person goes. This medication is able to bind to the excess iron, which can then be eliminated through urine. If desferoxamine is not used regularly or is unavailable, iron overload can develop and cause tissue damage and organ damage and failure. The heart, liver, and endocrine organs are particularly vulnerable. Desferoxamine itself may rarely produce allergic or toxic side effects, including hearing damage. Signs of desferoxamine toxicity are screened for and generally develop in individuals who overuse the medication when body iron levels are sufficiently low. Overall, however, transfusion and desferoxamine therapy have increased the life expectancy of individuals with the most severe types of beta thalassemia major to the 4th or 5th decade. This can be expected to improve with time and increased developments in treatment, as well as for those with more mild forms of the disease.
New treatments offer additional options for some individuals with beta thalassemia major. There are various medications that target the production of red blood cells (i.e. erythropoeitin) or fetal hemoglobin (i.e. hydroxyurea and butyrate). Their effectiveness in ameliorating the severity of beta thalassemia is currently being investigated. Another promising new treatment is bone marrow transplantation, in which the bone marrow of an affected individual is replaced with the bone marrow of an unaffected donor. If successful, this treatment can provide a cure. However, there is an approximately 10-15% chance the procedure could be unsuccessful (i.e. the thalassemia returns); result in complications (i.e. graft-versus-host disease); or result in death. The risk for specific individuals depends on current health status, age, and other factors. Because of the risks involved and the fact that beta thalassemia is a treatable condition, transplant physicians require a brother or sister donor who has an identically matched tissue type, called HLA type. HLA type refers to the unique set of proteins present on each individual's cells, which allows the immune system to recognize "self" from "foreign." HLA type is genetically determined, so there is a 25% chance for two siblings to be a match. Transplant physicians and researchers are also investigating ways to improve the safety and effectiveness of bone marrow transplantation. Using newborn sibling umbilical cord blood—the blood from the placenta that is otherwise discarded after birth but contains cells that can go on to make bone marrow—seems to provide a safer and perhaps more effective source of donor cells. Donors and recipients may not have to be perfect HLA matches for a successful transplant using cord blood cells. Trials are also underway to determine the effectiveness of "partial transplants," in which a safer transplant procedure is used to replace only a percentage of the affected individual's bone marrow. Other possible treatments on the horizon may include gene therapy techniques aimed at increasing the amount of normal hemoglobin the body is able to make.
Hemoglobin H disease is a relatively mild form of thalassemia that may go unrecognized. It is not generally considered a condition that will reduce one's life expectancy. Education is an important part of managing the health of an individual with hemoglobin H disease. It is important to be able to recognize the signs of severe anemia that require medical attention. It is also important to be aware of the medications, chemicals, and other exposures to avoid due to the theoretical risk they pose of causing a severe anemia event. When severe anemia occurs, it is treated with blood transfusion therapy. For individuals with hemoglobin H disease, this is rarely required. For those with the hemoglobin H/Constant Spring form of the disease, the need for transfusions may be intermittent or ongoing, perhaps on a monthly basis and requiring desferoxamine treatment. Individuals with this more severe form of the disease may also have an increased chance of requiring removal of an enlarged and/or overactive spleen.
Anemia — A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values. Common symptoms include paleness, fatigue, and shortness of breath.
Bilirubin — A yellow pigment that is the end result of hemoglobin breakdown. This pigment is metabolized in the liver and excreted from the body through the bile. Bloodstream levels are normally low; however, extensive red cell destruction leads to excessive bilirubin formation and jaundice.
Bone marrow — A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones. Bone marrow is the site of blood cell generation.
Bone marrow transplantation — A medical procedure used to treat some diseases that arise from defective blood cell formation in the bone marrow. Healthy bone marrow is extracted from a donor to replace the marrow in an ailing individual. Proteins on the surface of bone marrow cells must be identical or very closely matched between a donor and the recipient.
Desferoxamine — The primary drug used in iron chelation therapy. It aids in counteracting the life-threatening buildup of iron in the body associated with long-term blood transfusions.
Globin — One of the component protein molecules found in hemoglobin. Normal adult hemoglobin has a pair each of alpha-globin and beta-globin molecules.
Heme — The iron-containing molecule in hemoglobin that serves as the site for oxygen binding.
Hemoglobin — Protein-iron compound in the blood that carries oxygen to the cells and carries carbon dioxide away from the cells.
Hemoglobin A — Normal adult hemoglobin that contains a heme molecule, two alpha-globin molecules, and two beta-globin molecules.
Hemoglobin electrophoresis — A laboratory test that separates molecules based on their size, shape, or electrical charge.
Hepatomegaly — An abnormally large liver.
HLA type — Refers to the unique set of proteins called human leukocyte antigens. These proteins are present on each individual's cell and allow the immune system to recognize 'self' from 'foreign'. HLA type is particularly important in organ and tissue transplantation.
Hydroxyurea — A drug that has been shown to induce production of fetal hemoglobin. Fetal hemoglobin has a pair of gamma-globin molecules in place of the typical beta-globins of adult hemoglobin. Higher-than-normal levels of fetal hemoglobin can ameliorate some of the symptoms of thalassemia.
Iron overload — A side effect of frequent blood transfusions in which the body accumulates abnormally high levels of iron. Iron deposits can form in organs, particularly the heart, and cause life-threatening damage.
Jaundice — Yellowing of the skin or eyes due to excess of bilirubin in the blood.
Mutation — A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.
Placenta — The organ responsible for oxygen and nutrition exchange between a pregnant mother and her developing baby.
Red blood cell — Hemoglobin-containing blood cells that transport oxygen from the lungs to tissues. In the tissues, the red blood cells exchange their oxygen for carbon dioxide, which is brought back to the lungs to be exhaled.
Screening — Process through which carriers of a trait may be identified within a population.
Splenomegaly — Enlargement of the spleen.
Because alpha thalassemia major is most often a condition that is fatal in the prenatal or newborn period, treatment has previously been focused on identifying affected pregnancies in order to provide appropriate management to reduce potential maternal complications. Pregnancy termination provides one form of management. Increased prenatal surveillance and early treatment of maternal complications is an approach that is appropriate for mothers who wish to continue their pregnancy with the knowledge that the baby will most likely not survive. In recent years, there have been a handful of infants with this condition who have survived long-term. Most of these infants received experimental treatment including transfusions before birth, early delivery, and even bone marrow transplantation before birth, although the latter procedure has not yet been successful. For those infants that survive to delivery, there seems to be an increased risk of developmental problems and physical effects, particularly heart and genital malformations. Otherwise, their medical outlook is similar to a child with beta thalassemia major, with the important exception that ongoing, life-long blood transfusions begin right at birth.
As discussed above, the prognosis for individuals with the most serious types of thalassemia has improved drastically in the last several years following recent medical advances in transfusion, chemo-, and transplantation therapy. Advances continue and promise to improve the life expectancy and quality of life further for affected individuals.
"First Known Heart Attack Associated With Beta-thalassemia Major Reported." Heart Disease Weekly February 22, 2004: 10.
"Novel Alpha-thalassemia Mutations Identified." Hematology Week January 26, 2004: 19.
Children's Blood Foundation. 333 East 38th St., Room 830, New York, NY 10016-2745. (212) 297-4336. cfg@nyh.med.cornell.edu.
Cooley's Anemia Foundation, Inc. 129-09 26th Ave. #203, Flushing, NY 11354. (800) 522-7222 or (718) 321-2873. http://www.thalassemia.org.
March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. http://www.modimes.org.
National Heart, Lung, and Blood Institute. PO Box 30105, Bethseda, MD 20824-0105. (301) 592-8573. nhlbiinfo@rover.nhlbi.nih.gov. http://www.nhlbi.nih.gov.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www.rarediseases.org.
Bojanowski J. "Alpha Thalassemia Major: The Possibility of Long-Term Survival." Pamphlet from the Northern California Comprehensive Thalassemia Center. (1999).
Children's Hospital Oakland, Northern California Comprehensive Thalassemia Center website. http://www.thalassemia.com.
Cooley's Anemia Foundation, Inc. website. http://www.thalassemia.org/gohome.html.
Joint Center for Sickle Cell and Thalassemic Disorders website. http://cancer.mgh.harvard.edu/medOnc/sickle.htm.
[thal″ah-se´me-ah]
a heterogeneous group of hereditary hemolytic anemias marked by a decreased rate of synthesis of one or more hemoglobin polypeptide chains, classified according to the chain involved (α, β, δ); the two major categories are α- and β-thalassemia.
α-thalassemia (alpha-thalassemia) that caused by diminished synthesis of alpha chains of hemoglobin. The homozygous form is incompatible with life, the stillborn infant displaying severe hydrops fetalis. The heterozygous form may be asymptomatic or marked by mild anemia.
β-thalassemia (beta-thalassemia) that caused by diminished synthesis of beta chains of hemoglobin. The homozygous form is called t. major and the heterozygous form is called t. minor.
thalassemia ma´jor the homozygous form of β-thalassemia, in which hemoglobin A is completely absent; it appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia; hepatosplenomegaly; skeletal deformation; mongoloid facies; and cardiac enlargement.
thalassemia mi´nor the heterozygous form of β-thalassemia; it is usually asymptomatic, but there may be mild anemia.
sickle cell–thalassemia a hereditary anemia involving simultaneous heterozygosity for hemoglobin S and thalassemia.
thal·as·se·mi·a
, thalassanemia (thal'ă-sē'mē-ă, thă-las-ă-nē'mē-ă),
Any of a group of inherited disorders of hemoglobin metabolism in which there is impaired synthesis of one or more of the polypeptide chains of globin; several genetic types exist, and the corresponding clinical picture may vary from barely detectable hematologic abnormality to severe and fatal anemia.
[G. thalassa, the sea, + haima, blood]
/thal·as·se·mia/ (thal″ah-se´me-ah) a heterogeneous group of hereditary hemolytic anemias marked by a decreased rate of synthesis of one or more hemoglobin polypeptide chains, classified according to the chain involved (α, β, δ); the two major categories are α- and β-thalassemia.
α-thalassemia that caused by diminished synthesis of alpha chains of hemoglobin. The homozygous form is incompatible with life, the stillborn infant displaying severe hydrops fetalis. The heterozygous form may be asymptomatic or marked by mild anemia.
β-thalassemia that caused by diminished synthesis of beta chains of hemoglobin. The homozygous form is called t. major and the heterozygous form is called t. minor.
thalassemia ma´jor the homozygous form of β, in which hemoglobin A is completely absent; it appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia, hepatosplenomegaly, skeletal deformation, mongoloid facies, and cardiac enlargement.
thalassemia mi´nor the heterozygous form of β, usually asymptomatic, although there is sometimes mild anemia.
(thăl′ə-sē′mē-ə)
An inherited form of anemia occurring chiefly among people of Mediterranean descent, caused by faulty synthesis of part of the hemoglobin molecule. Also called Mediterranean anemia.
thal′as·se′mic adj.
[thal′əsē′mē·ə]
Etymology: Gk, thalassa, sea, a + haima, without blood
production and hemolytic anemia characterized by microcytic, hypochromic red blood cells. Thalassemia is caused by inherited deficiency of alpha- or beta-globin synthesis. See also hemochromatosis, hemosiderosis.
Beta thalassemia, clinical thalassemia, Cooley's anemia, Mediterranean anemia, thalassemia major Hematology A group of genetic diseases by underproduction of hemoglobin due to mutations in the beta globin gene, which is more common in Mediterraneans Heredity Parents are carriers–heterozygotes; one in 4 children is homozygous for the mutation and thus has full-blown disease Clinical See Anemia. Cf Sickle cell anemia.
α-thalassemia
Hemoglobin Barts Hematology An inherited condition caused by a defect in the synthesis of the Hb α chain; Hb Barts hemoglobinopathy is characterized by the presence of 4 gamma chains; it is more common in southeast Asians; the most severe form of alpha thalassemia causes stillbirth due to hydrops fetalis Heredity Parents are carriers–heterozygotes; one in 4 children is homozygous for the mutation and thus has full-blown disease Clinical Pallor, fatiguability, FTT, fever, infections, diarrhea Management Transfusions
Thalassemia major Hematology A hemoglobinopathy caused by a defect in the synthesis of Hb β chain Clinical Pallor, fatigability, FTT, fever due to infections, diarrhea, bone deformities, hepatosplenomegaly Management Transfusions, but iron overload can damage the heart, liver, and endocrine systems, ergo iron chelation–early use of deferiprone, deferoxamine ↓ transfusion-related iron overload and may protect against DM, cardiac disease, early death
δ-thalassemia
Hematology A condition characterized by a defect of Hb A2–α2δ2; because Hb A2 comprises only 3% of the circulating Hb, even its complete absence; δ-thalassemia has little clinical or hematologic impact
γ-thalassemia
Hematology A condition characterized by a defect of gamma–γ Hb chains found in Hb F–α2γ2; because Hb F is present primarily in the fetus and newborns, it is rarely seen outside of the neonatal period, but may cause transient neonatal hemolytic anemia.
, thalassanemia (thal'ă-sē'mē-ă, -ă-să-nē'mē-ă)
Any of a group of inherited disorders of hemoglobin metabolism in which there is impaired synthesis of one or more of the polypeptide chains of globin; several genetic types exist, and the corresponding clinical picture may vary from barely detectable hematologic abnormality to severe and fatal anemia. People of Mediterranean, extraction are more often affected than others by this type of anemia.
Synonym(s): thalassaemia, thalassanaemia.
Any of a group of inherited disorders of hemoglobin metabolism with impaired synthesis of one or more polypeptide chains of globin; several genetic types exist.
<a href="https://medical-dictionary.thefreedictionary.com/Thalassaemia+minor">thalassemia</a>
Barts hemoglobin
beta hemoglobinopathy
beta-delta thalassemia
beta-thalassaemia
Bite Cell
black gallstone
I know of a couple, totally unrelated and unbeknownst to them, who are silent carriers of Thalassaemia minor.
Pakistan: Genetic factor: All in the genes
But, unfortunately, when one person with thalassaemia minor carrier happens to marry another with the same diagnosis, there is a strong possibility that their child would be thalassaemia major, as happened in the case of Taneja.
' My life depends upon a monthly blood transfusion '
0] thalassaemia demonstrates variable severity, ranging from a condition similar to [beta] thalassaemia minor to something approaching thalassaemia major.
A retrospective review of homozygous haemoglobin E patients
Thal, Alan P.
thalame
thalamencephalic
thalamencephalon
thalamic
thalamic fasciculus
thalamic nucleus
thalamic pain syndrome
thalamic peduncle
thalamic radiation
thalamo-
thalamocoele
thalamocortical
thalamocortical fibers
thalamogeniculate artery
thalamolenticular
thalamoperforating artery
thalamostriate radiation
thalamotuberal artery
Thalassaemia minor
thalassaemiaor Cooley's disease
thalassemic facies
thalasso-
Thalassobacter
Thalassobacter utilis
thalassoplankton
thalassoposia
thalidomide neuropathy
Thalidomider
thallium poisoning
Thalarctos
THALAS
Thalasaemia
Thalassaemia Association of Malaysia
thalassaemia major
Thalassaemias
thalassaemic
thalassanaemia
Thalassemia Action Group
Thalassemia Clinical Research Network
thalassemia syndrome

Answer: Severe anemia that begins even before birth.