Unveiling five naked structures of tartaric acid

Astrochemistry Unveiling Five Naked Structures of Tartaric Acid Elena R. Alonso, Iker Len, Lucie Kolesnikov, Santiago Mata, and Jose Luis Alonso* Abstract: The unbiased, naked structures of tartaric acid, one of the most important organic compounds existing in nature and a candidate to be present in the interstellar medium, has been revealed in this work for the first time. Solid samples of its naturally occurring (R,R) enantiomer have been vaporized by laser ablation, expanded in a supersonic jet, and characterized by Fourier transform microwave spectroscopy. In the isolation conditions of the jet, we have discovered up to five different structures stabilized by intramolecular hydrogen-bond networks dominated by OH···O=C and OH···O motifs extended along the entire molecule. These five forms, two with an extended (trans) disposition of the carbon chain and three with a bent (gauche) disposition, can serve as a basis to represent the shape of tartaric acid. This work also reports the first set of spectroscopy data that can be used to detect tartaric acid in the interstellar medium. In 1848, Louis Pasteur unequivocally established the existence of molecular chirality with the tartaric acid (TA) molecule.[1] Previously, Biot discovered that (2R,3R) tartaric acid in aqueous solution was optically active and that racemictartaric acid was inactive.[2] It led Pasteur to study the morphology of several crystals of (2R,3R)-tartaric acid (( + )-TA) and of rare paratartaric acid (PTA) and their optical behavior in solution, establishing that the (2R,3R)- and (2S,3S)-tartrates are isometric and related one to another as non-superposable mirror images.[3] For all the above, TA is one of the most important organic compounds in stereochemistry history.[4] The naturally occurring form of tartaric acid corresponds to the stereoisomer (R,R) (see Figure 1), obtained from fermenting grape juice in the wine-making process. TA is widely used in the pharmaceutical industry as an excipient and buffering agent and in foods and beverages as an acidulant, among other applications.[5] In the chemistry field, it is used as a chiral building block[6] to produce chiral ligands for metal-catalyzed reactions[7] and provide new organocatalysts.[8] In astrochemistry, TA is a potential molecule to be present in the interstellar medium (ISM). It has already been found in the Murchison meteorite.[9] AstrophyFigure 1. Configurational map of (R,R) tartaric acid based on Newman projections taking into account all its degrees of freedom. [*] Dr. E. R. Alonso Instituto Biofisika (UPV/EHU, CSIC) University of the Basque Country 48940 Leioa (Spain) and Departamento de Qumica Fsica, Facultad de Ciencia y Tecnologa, Universidad del Pas Vasco Barrio Sarriena s/n, 48940 Leioa (Spain) Dr. I. Len, S. Mata, Prof. J. L. Alonso Grupo de Espectroscopia Molecular (GEM), Edificio Quifima, rea de Qumica-Fsica, Laboratorios de Espectroscopia y Bioespectroscopia, Parque Cientfico UVa, Unidad Asociada CSIC Universidad de Valladolid, 47011 Valladolid (Spain) E-mail: [email protected]va.es Dr. L. Kolesnikov Department of Analytical Chemistry University of Chemistry and Technology Technick 5, 16628 Prague 6 (Czech Republic) Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.202105718.  2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made. A ngewandte Chemi e Communications How to cite: Angew. Chem. Int. Ed. 2021,60, 17410–17414 International Edition: doi.org/10.1002/anie.202105718 German Edition: doi.org/10.1002/ange.202105718 17410  2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH Angew. Chem. Int. Ed. 2021,60, 17410 –17414 sics need to draw on high-resolution rotational studies, the same wavelengths of the surveys captured by radio telescopes, to detect a molecule in the ISM.[10] Over 200 molecules have already been detected, including important precursors for biomolecular building blocks.[11] The identification of chiral molecules in the interstellar medium is a remarkable fact that could shed light on the origin of the enantiomeric excess. Up to now, propylene oxide is the only chiral molecule observed in the ISM.[12] The identification of any other chiral molecule, i.e., TA, would be a considerable breakthrough.[13] Owing to its vital importance, the naturally occurring form of TA, the enantiomer (R,R), has been the subject of several structural studies in condensed phases. The crystal structure was explored using X-ray and neutron diffraction methods, displaying a unique configuration corresponding to a structure with a trans (T) disposition of its carbon chain.[14,15] More recently, THz vibrational spectroscopy has been employed, showing a more accurate crystal packaging arrangement of this T configuration.[16] In solution, vibrational circular dichroism (VCD),[17,18] NMR,[19] and vibrational Raman optical activity (ROA)[20,21] show the same T (trans) configuration determined in its crystal structure and stabilized by two intramolecular hydrogen bondings between each OH and C=O group attached to the same chiral carbon. We find it surprising that despite three absolute configurations of the carbon chain are possible, one “trans” (T) and two “gauche” (G+,G ) (see Figure 1), only the “trans” form has been observed. Even when diffraction and spectroscopic methods are feasible, their structural description is biased by crystal packing forces and solvent effects, wiping out the conformational variety of TA; they do not reflect its raw structure. TA contains four hydroxyl groups that can act as proton donors or acceptors, while the two carbonyl groups act as proton acceptors. Even a relatively small molecule, such as TA, is expected to exist in many conformations due to its torsional flexibility based on the seven internal torsions (see Figure 1). From looking at the different torsion angles, we can bring forward different starting configurations shown in Figure 1. The notation used to label each configuration includes the T, G+, and Glabels to denote the main carbon chains configuration, based on the atorsion angles value. The following two subscripts: s or a, indicate the “syn”or “anti” arrangement of the hydroxyl group attached to each chiral carbon (C*) concerning its adjacent C=O group of the carboxylic group. Thus, we can anticipate the formation of intricate networks of intramolecular hydrogen bonds that can potentially stabilize many structures and presumably play an important role in the numerous properties developed by this essential molecule. Its conformational analysis requires an experimental study under isolated conditions to disentangle the intramolecular hydrogen bonding puzzle between these adjacent groups. In this context, high-resolution rotational spectroscopy emerges as a unique spectroscopic method that does entirely remove unwanted environmental interference. However, it requires sufficient partial pressure of the analyte in the gas phase. Unfortunately, TA is solid with a high melting point (174 8 C) and thermal instability. It cannot be transferred intact into the vapor phase by conventional heating procedures, so unperturbed condition studies have not yet been possible. Despite its essential role, no structural data have been reported for the unbiased tartaric acid. The dicarboxylic succinic acid has been studied by rotational spectroscopy and a gauche conformer observed.[22] A comprehensive structural study of (R,R) TA has been carried out using rotational spectroscopy coupled to a laser ablation system to fill this structural information gap on this relevant molecule. This strategy allowed us to unveil the natural and dominating conformations that compose TAs structural landscape, avoiding the vaporization issues. This experimental approach has proven ideal for exploring the architecture of numerous solid biomolecules of amino acids,[23] nucleosides,[24] sugars,[25] and dipeptides,[26] among others, constituting a definitive tool in the conformational analysis. The experiments were performed with the LA-CPFTMW (laser ablation chirped pulse Fourier transform microwave) spectrometer built at the University of Valladolid.[29,30] The broadband rotational spectrum in the 6– 12 GHz frequency range is shown in Figure 2. Previous to its analysis, lines corresponding to known photofragment species and water clusters were identified and removed, and we proceeded to the conformational identification. At first sight, the spectrum is dominated by strong mc-type R-branch progressions of J+11, J ! J0, J,J+12, J ! J1, J and J+12, J1 ! J1, J1(J=1 to 4) belonging to a dominant species, labeled as rotamer I in Figure 1a. After an iterative process of measuring and fitting[27] rotational transitions, a set of experimental rotational constants for rotamer I was obtained using a semirigid rotor Hamiltonian.[28] They are collected in the first column of Table 1. To ascertain the TA conformer responsible for the intensely observed spectrum of rotamer I, we have to compare the above derived spectroscopic constants with those calculated by ab initio and DFT computational methods (Supporting Information, Tables S6 and S7) complementing previous computational works.[29,30] Table 1 shows the spectroscopic parameters predicted for the six lowenergy conformers in an energy window of 1000 cm1above the global minimum. The comparison allows us to assign the rotamer I unambiguously to the Ts,s conformer. It is predicted as the global minimum and presents a C2-symmetry with a unique non-zero value of electric dipole moment component in the c-axis (see Figure 3) consistent with the observed c-type selection rules. After removing all the lines corresponding to Ts,s conformer, many weaker lines remained unassigned. They should belong to other low-energy conformers of tartaric acid. Following the same procedure, four other rotameric species were assigned, corresponding to G+a,s, Ta,s (II), Ga,s, Gs,s (see Figure 2b and c). All the measured rotational transition frequencies are in the Supporting Information, Tables S1–S5. Finally, different frequency ranges were deeply analyzed to detect the Ta,s (I) conformer, but no lines were found. The absence of spectral signatures attributable to Ta,s(I) conformer could be explained by the low values of dipole moment components (see Table 1). Relative intensity measurements of selected transitions made it possible to evaluate the relative abundance of the observed conformers to be: Tss(~49%), G+as(~38%), Tas(~7%), Gaa(~5%), Gss(~1%). Scale A ngewandte Chemi e Communications 17411Angew. Chem. Int. Ed. 2021,60, 17410 –17414  2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH www.angewandte.org factors ranging from 0.996 to 1.014 bring the MP2 ab initio values of the rotational constants into coincidence with the experimental ones, reflecting the excellent match between theory and experiment. Consequently, the ab initio structures can be taken as a good approximation of the actual structures for the five TA conformers. The estimated relative abundances on the other hand, show small variations with those predicted using the calculated energies. This fact shows the importance of microwave data as a benchmark to improve and develop accurate computational chemistry methods. The structures of the five detected conformers of TA, depicted in Figure 3, can be rationalized in terms of the intramolecular hydrogen bonding networks responsible for their stabilization. The most abundant Ts,s conformer appears over stabilized by two O H···O=C hydrogen bonds between the OH group of each asymmetric carbon (C*) and its vicinal O=Cof the carboxylic group reinforced by two terminal cis-carboxylic interactions keeping a C2-symmetry. Four cooperative intramolecular hydrogen bonds, two OH···OH type and another two OH···O=C type, are responsible for stabilizing the three G+a,s, Ga,a, and Gs,s gauche conformers. Conformer G+a,s stabilizes its structure through a cooperative OH···OH···OH···O=C network extended along the carbon chain and closing a seven-membered cyclic network through an OH···O=C between the two terminals carboxylic groups in a transarrangement. The other C2symmetry conformers Ga,a and Gs,s stabilizes its structure through two cooperative OH···OH···O=C hydrogen-bond networks forming two sixmembered cyclic networks for each of them. The formation of six or seven-membered cyclic networks contributes to the Figure 2. a) Broadband rotational spectrum of (R,R) Tartaric acid from 6 to 12 GHz. The spectrum is dominated by strong (and also weaker) mcR-branch rotational transitions progressions for T,s,s, T,a,s(II), G,a,a and G,s,s and weaker maR-branch rotational transitions progressions for G+,a,s and T,a,s (II). b) A spectrum fragment showing identified transitions of the observed conformers. c) A 20 superzoom showing a weak transition of the G,s,s conformer. Table 1: Experimental spectroscopic parameters for the five observed rotamers of tartaric acid. T,s,s T,a,s (I) G+,a,s T,a,s (II) G,a,a G,s,s Rotamer I[e] Theor.[f] Theor. Rotamer II Theor. Rotamer III Theor. Rotamer IV Theor. Rotamer V Theor. A[a] 2501.57910(86)[g] 2490 2505 2086.53041(96) 2082 2477.6433(23) 2488 1823.17494(81) 1823 1781.89105(74) 1772 B 844.52864(48) 849 843 1078.70088(40) 1080 825.84623(72) 824 1169.0241(10) 1167 1189.31507(75) 1199 C 833.92841(53) 845 819 748.80543(41) 754 796.37217(86) 803 980.81467(94) 995 971.8262(13) 982 DJ0.0441(78) 0.0311(61) 0.0435(83) 0.168(29) 0.197(13) DJK 0.249(28) 0.197(38) – – 0.196(40) ma– 0.0 0.8 obs. 1.6 obs. 3.7 – 0.0 – 0.0 mb– 0.0 0.2 obs. 2.6 – 0.4 – 0.0 – 0.0 mcobs. 2.5 0.0 – 0.0 obs. 1.8 obs. 2.6 obs. 3.7 N[b] 29–51241615 s[c] 6.0 – 7.7 8.9 6.6 2.5 DEZPE – 0 556 762 960 906 873 DG[d] – 0 697 1203 1169 1301 1345 [a] A, B, and C represent the rotational constants (in MHz); DJ,D JK represent the determined centrifugal distortion constants (in kHz); ma,mb, and mcare the electric dipole moment components (in D). [b] Number of fitted transitions. [c] RMS deviation of the fit in kHz. [d] Relative energies (in cm1) with respect to the global minimum, taking into account the zero-point energy (ZPE). Gibbs energies (in cm1) calculated at 298 K. [e] Experimentally determined rotational and centrifugal constants. [f] Theoretically predicted rotational constants at the MP2 level. [g] Standard error in parentheses in the last digit units. A ngewandte Chemi e Communications 17412 www.angewandte.org  2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH Angew. Chem. Int. Ed. 2021,60, 17410 –17414 over-stabilization of the gauche conformers compared to the less abundant Ta,s(II) conformer. Three cooperatives OH···OH···OH···O=C hydrogen bonds extended along the carbon chain, stabilize this last observed conformer. With the hydrogen bonding interactions verified by the NCIPLOT program,[31–33] where the reduced gradient of the electronic density is 3D represented, there is a more detailed view of the places involved in the intramolecular interactions (Supporting Information, Figure S1). As mentioned above, TA is found only in the trans configuration in condensed phases, both in the crystal and solution.[14–19] Strikingly, TAs isolated structures observed in the supersonic expansion of our experiment comprise both trans and gauche forms almost equally populated. This remarkable fact should be explained by looking at the structure and interactions that may take place in the different conformers. In the trans-TA structures (see Figures 3 and S1), the carboxylic groups are not involved in any intramolecular interaction. The opposite is true for the gauche-TA forms; both acidic groups participate in intramolecular hydrogen bonding networks. These observations may indicate that the trans-TA configuration allows the monomers to interact with each other at both ends through a double OH···O=C interaction, allowing a natural extension of the TA units forming a kind of TA intermolecular chain. Additionally, the trans configuration allows the interaction between the chains central hydroxyl groups in a parallel disposition, resulting in strong hydrogen bonds between the TA chains. All this reinforces the existence of the trans forms in condensed phases, which is not possible in the gauche arrangement. In conclusion, the discriminating power obtained combining the high-quality rotational data provided by our LA-CPFTMW technique with those of high-level quantum chemical calculations has enabled disentangling the conformational puzzle of TA. Five naked structures of TA have been unequivocally identified, leading to the first determination Figure 3. Close-up picture of the trans and gauche tridimensional structures of the five observed conformers and non-observed Ta,s(I) conformer of tartaric acid showing the intramolecular hydrogen bonding networks (distances) that stabilize them calculated at MP2 6–311++G(d,p) level. A ngewandte Chemi e Communications 17413Angew. Chem. Int. Ed. 2021,60, 17410 –17414  2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH www.angewandte.org of its conformational landscape. It is precious information since the behavior in solution should fluctuate between the most stable trans structures found in the isolation conditions of the gas phase. The study provides direct and comprehensive information, at the atomic resolution, on the hydrogen bond networks of tartaric acid that exist as a result of OH····OH, and O H····O=C contacts, closing five-, six-, or seven-membered cyclic structures. The detected conformers adapt their molecular shapes to optimize the sequence of intramolecular hydrogen bonds, increasing their strength by cooperativity.[34,35] Last but not least, the experimental set of rotational parameters enable, for the first time, the search of TA in the interstellar medium. Except for propylene oxide, all the complex organic molecules detected in the interstellar medium are achiral. The detection of another chiral molecule is one of the most pursued targets in astrobiology to try to shed light on the quest of chirality in the interstellar medium and the origin of life. In the event that its detection is not possible in the actual surveys from radiotelescopes, with the advances that continuously happen in radioastronomy, this data will still be essential for possible future identifications. Present results show the vital role of chemistry laboratory experiments in the astrophysics field. Acknowledgements The financial fundings from Ministerio de Ciencia e Innovacin (CTQ201676393-P and PID2019-111396GB-I00) and Junta de Castilla y Len (Grants VA077U16 and VA244P20) are gratefully acknowledged. E.R.A. thanks Ministerio de Ciencia e Innovacin for a Juan de la Cierva de formacin grant (FJC2018-037320-I). Conflict of Interest The authors declare no conflict of interest. Keywords: astrochemistry · chiral molecules · laser ablation · rotational spectroscopy · tartaric acid [1] L. Pasteur, Ann. Chim. Phys. 1848,24, 442–459. [2] J.-B. Biot, Mem. Acad. Sci. Inst. Fr. 1817,2, 4– 136. [3] H. D. Flack, Acta Crystallogr. Sect. A 2009,65, 371– 389. [4] J. Gal, Helv. Chim. Acta 2013,96, 1617– 1657. [5] “Tartaric Acid—Chemical Economics Handbook (CEH) jIHS Markit”, can be found under https://ihsmarkit.com/products/ tartaric-acid-chemical-economics-handbook.html. [6] J. Gawronski, K. 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Lpez de la Paz, G. Ellis, M. Prez, J. Perkins, J. JimnezBarbero, C. Vicent, Eur. J. Org. Chem. 2002, 840–855. Manuscript received: April 27, 2021 Accepted manuscript online: June 1, 2021 Version of record online: July 1, 2021 A ngewandte Chemi e Communications 17414 www.angewandte.org  2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH Angew. Chem. Int. Ed. 2021,60, 17410 –17414