Multiple-H-bonded-zwitterionic tetramer structure for L-(+)-2-chlorophenylglycine, as investigated by UV, IR and Raman spectroscopy and electronic structure calculations

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Highlights

  • A multi-H-bonded tetramer DFT model is proposed for L-(+)-2-Chlorophenylglycine.

  • Tetramer is a network of fourteen inter/intra-N−H···O, C−H···O and Cα−H···Cl bonds.

  • Experimental UV, IR and Raman band structures fit computed tetramer properties.

  • UV band structure at 221−194 nm is shown due to dissociated tetramer species.

Abstract

A DFT tetramer model constructed of multi-H-bonds at B3LYP/6-311G(d,p) level has been proposed for L-(+)-2-Chlorophenylglycine. Motivation in part for the tetramer model comes from the observed IR spectra near 3400−2500 cm−1 showing a very broad sub-band structure spread over ∼ 900 cm−1 without distinct sharp bands; secondly, XRD structures of similar molecular solids show multiple H-bonds among monomers. Therefore, the proposed tetramer consists of fourteen H-bonds arising from a network of inter-/intra-molecularly X−H···Y bonds: N−H···O, C−H···O and Cα−H···Cl bonds, all from four monomer species. The strengths and degree of these H-bonds being covalent, ionic or partial have been determined using topological parameters from AIM calculations. Other weaker van der Waals interactions and steric clashes in relation to the N−H···O, C−H···O and Cα−H···Cl bonds have also been evaluated by the method of ‘non-covalent interactions (NCI)’. Further, the charge transfer from the Y lone pair orbital (donor) to the X−H anti-bonding orbital (acceptor) have been explained on the basis of overlapping of orbitals using NBO analysis. Computed stabilization energies for the X−H···Y bonds have shown the inter-molecular N−H···O bonds to be the strongest of the H-bonds. Concentration-dependent UV spectral analysis aided by TD-DFT-based calculations at B3LYP/6-311G(d,p) with SMD model in water has shown that a strong band at 221 nm, among other bands, blue-shifts to 194 nm with a concomitant arrival of a shoulder band at 219 nm. The bands are assigned to the π→π* transition. This observation has been interpreted to be the result of dissociation of the tetrameric species into monomeric species and is supported by the stabilization of computed ground and excited electronic levels. By the same interpretation, three vibronic bands seen at 260−280 nm also have been explained. Computed vibrational modes of the tetramer fit very well with the experimental IR and Raman band features including low frequency Raman modes below 350 cm−1. It has been shown the consistency among the H-bonding descriptors - H···Y bond distance, change in X−H bond length, X−H frequency shifts, electron density, H-bond energy and stabilization energy by graphical correlations.

Introduction

Experimental and computational studies of isolated and inter-acting biological molecular systems as building blocks in general and amino acids in particular have lately evoked interest owing to their structural flexibility and conformational states [1]. Structures of these molecular systems in a condensed state are characterized by a delicate balance of covalent as well as non-covalent interactions. Of the non-covalent interactions (NCI), H-bonding plays a key functional role in determining structures of oligomer species as has been demonstrated in crystal engineering, supramolecular chemistry, self-assembly, molecular recognition and DNA intercalations just to name a few [[2], [3], [4]]. Amino acids are known to exist either in neutral (NE) or zwitterionic (ZW) form depending on the local environment and their associated properties, namely, crystal structure, spectroscopic features and intra- and inter-molecular interactions [[5], [6], [7], [8]]. It is of primary interest to study isolated molecular oligomers in a gas phase to ensure their properties are accurately computed and subsequently to study the influence of inter-molecular interactions in a solvent medium to achieve good agreement with experiment [9,10]. In the present paper we have proposed a DFT-computed tetramer structure built from inter-molecular N−H···O/C−H···O bonds and intra-molecular N−H···O/Cα−H···Cl bonds in water as a solvent medium for L-(+)-2-Chlorophenylglycine. We have found that, out of the four monomeric fragments which make up the tetramer structure, one monomeric fragment is completely H-bonded to all of its neighbors in agreement with XRD structures of Phenylglycine and 2-Fluorophenylglycine [11,12]. As a result, computed structural, vibrational and electronic properties combined with experimental IR, Raman and UV spectral features have all been consistent in providing a satisfactory characterization of the inter-molecular N−H···O/C−H···O bonds and intra-molecular N−H···O/Cα−H···Cl bonds in the tetramer structure.

Phenylglycine is a non-proteinogenic amino acid, widely employed as a substrate in the β-lactam drugs that are semi-synthetic penicillins and cephalosporins. Also, L-Phenylglycine has a pharmacologic and analgesic efficacy profile similar to that of Pregabalin and Gabapentin. Moreover, halogenated phenylglycine derivatives are found to be genotoxic amino acids [[13], [14], [15]]. L-(+)-2-Chlorophenylglycine (2CPG) is a non-proteinogenic amino acid, predominantly having application in the studies of pharmacological activities like its parent, Phenylglycine [16]. It is reasonable to assume a neutral (NE) form in gas phase and zwitterionic (ZW) form in a condensed phase for 2CPG, both of which will be explored in the present study. In the ZW form, the ammonium, −NH3+ moiety is a predominant donor while the carboxylate, −COOsingle bond moiety is the acceptor, resulting in the N−H···O bonding. Without exception, the −NH3+ moiety donates three H-bonds, whereas the −COOsingle bond moiety always accepts between four and six bonds [7] and thus 2CPG is expected to form oligomeric structures bound by N−H···O bonds. In addition, intra-molecular C−H···Cl bond would involve the H-atoms bonded to the α-carbon atom (Cα) as seen in the H-bond geometries of the amino acids [7]. A structural study of DL-Phenylglycine and 2-Fluorophenylglycine have shown their ZW form with all the three H atoms of the ammonium moiety forming H-bonds with the carboxylate O atoms of the three adjacent molecules. L Woloszyn et al have characterized the O−H···O, N−H···O and C−H···O bonds in DL-Phenylglycinium methane sulfonate by XRD, NMR and vibrational studies [15]. Vibrational study of these H-bonds in D-Phenylglycinium perchlorate have also been reported [17]. Though there have been several vibrational studies of amino acids in ZW form, a comprehensive characterization of the multiple N−H···O and C−H···O bonds in a trimer structure in vapor phase and solvated environment appears scarce because of the inadequate treatment of the problem by ignoring the participation of more than one N−H bond from −NH3+ moiety in characterizing N−H-bonded structure [[18], [19], [20], [21]]. Such inadequate treatment is also not in agreement with oligomeric structures such as a tetramer as observed in XRD studies [5,7,22]. To achieve a good agreement between theory and experiment there is a need for modeling oligomeric structures, that is to say, a completely H-bonded tetramer structure as has been shown by us for DL-β-leucine [5]. To date there is no similar study on a completely H-bonded tetramer structure for 2CPG on the basis of combined structural, vibrational and electronic properties.

In this paper, we have shown that while a NE form of 2CPG is a stable conformer in the vapor phase, it is a stable ZW form in a condensed state such as water when computed at the B3LYP/6-311G(d,p)-cum-SCRF-SMD level of calculation. The results have led to a completely H-bonded ZW tetramer with N−H···O, C−H···O and Cα−H···Cl bonds that has been proposed for 2CPG. The topological parameters computed from Atoms in Molecules (AIM) calculations have been used to evaluate the strengths of different H-bonds. Further, these H-bonds including the weaker van der Waals interactions and steric clashes have also been evaluated by the 2D scatter plots and 3D isosurfaces using Noncovalent Interactions (NCI) method. Charge transfers from the Y lone pair orbital (donor) to the X−H anti-bonding orbital (acceptor) upon H-bonding are studied and strengths of H-bonds are analyzed on the basis of stabilization energies from NBO analysis. Solvent-dependent UV band structure at 190−225 nm has been interpreted to be the result of dissociation of tetramer species into monomer species; the region at 260−280 nm has been attributed to the vibronic structure. TD-DFT-based calculations at B3LYP/6-311G(d,p) with SMD model in water have produced these spectral features thereby validating interpretation. These results are also supported by HOMO-LUMO energy analysis. In addition, the computed tetramer vibrational modes are analyzed together with the experimental IR and Raman band features including low frequency Raman modes. Further, the correlations among the change in H···Y bond distance, change in X−H bond length, X−H frequency shifts, electron density, H-bond energy and stabilization energy as H-bonding descriptors have been discussed.

Section snippets

Computational

Ab initio RHF and DFT calculations were carried out using the Gaussian 16 and Gauss View 6.0.16 programs [23,24]. All the calculations were run on a heavy-duty Work Station with Dual Intel Xeon E5-2620V4 processor (20M cache, 8 cores, 2.1 GHz, total cores:16; RAM:32 GB DDR 4 memory). A relaxed potential energy surface (PES) scan was performed on a NE structure in a gas phase for all the torsional angles responsible for the non-rigidity of the molecular structure of 2CPG yielding a single stable

Structural characterization of the tetramer

In the absence of 2CPG structural data to the best of our knowledge, the geometrical parameters of its conformers are compared with the XRD data of its nearest molecular systems, namely, DL-Phenylglycine (PG) and 2-Fluorophenylglycine (2FPG). Both PG and 2FPG crystallize into monoclinic crystal system with P21/c space group with four molecules per unit cell [11,12]. The crystal packing is stabilized by the inter-molecular N−H···O bonds with the participation of all the three ammonium H atoms as

Conclusion

A tetramer model with multi-H-bonds with N−H···O, C−H···O and Cα−H···Cl bonds at B3LYP/6-311G(d,p) level has been proposed for L-(+)-2-Chlorophenylglycine. Observed IR spectra near 3400−2500 cm−1 showing a very broad sub-band structure spread over ∼ 900 cm−1 without distinct sharp bands have been satisfactorily explained by the vibrational properties of the tetramer model. Secondly, XRD structures of similar molecular solids showing multiple H-bonds among monomers are in agreement with the

CRediT authorship contribution statement

Madhuri D. Prabhu: Conceptualization, Formal analysis, Data curation, Writing – original draft. Jayashree Tonannavar: Conceptualization, Investigation, Formal analysis, Data curation. J. Tonannavar: Conceptualization, Investigation, Formal analysis, Data curation, Funding acquisition, Writing – original draft.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

We thank USIC at Karnatak University for FT-IR, Raman and UV-Vis spectrometer facilities under DST-funded PURSE Programme. The Molecular Modeling lab under UPE-FAR-I & DST-PURSE-Phase-II programme at Karnatak University provided for DFT calculations is gratefully acknowledged. This work has been supported by UGC-SAP-CAS-II and DST-PURSE-Phase-II programme. Karnatak University Research Studentship and UGC-Senior Research Fellowship awarded to Ms. Madhuri D. Prabhu are gratefully acknowledged.

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