Mechanism and kinetics of astrophysically relevant gas-phase stereoinversion in glutamic acid: A computational study

Molecular Astrophysics 18 (2020) 100061

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Research Paper

Mechanism and kinetics of astrophysically relevant gas-phase stereoinversion in glutamic acid: A computational study Namrata Rani, Vikas

T

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Quantum Chemistry Group, Department of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India

ARTICLE INFO

ABSTRACT

Keywords: Astrochemistry Amino acid Stereoinversion Reaction pathways GRRM

Enantiomeric excess of amino acids observed in the meteoritic samples of carbonaceous chondrites has incited many researchers to search for an extra-terrestrial origin of life on prebiotic Earth. However, in a non-catalytic environment, only racemic amino acids are synthesized. This computational quantum-mechanical study explores non-catalytic mechanistic pathways for stereoinversion in proteinogenic L-glutamic acid, which may be observable under gas-phase conditions of interstellar medium (ISM). The multi-step stereoinversion pathways proposed in this study are traced through a global reaction route mapping (GRRM) strategy utilizing densityfunctional and coupled-cluster theories. Notably, a few of the pathways are observed to proceed through simultaneous intramolecular hydrogen atom and proton transfer as well as through a proton-coupled electron transfer mechanism. The intermediates explored along the stereoinversion pathways resemble ammonium ylide and imine, the key ingredients in Strecker synthesis of amino acids. The thermodynamic and kinetic analysis of the stereoinversion pathways in different temperature regions of ISM are also carried out, predicting the streoinversion to proceed over any dissociation of intermediates and conformers of glutamic acid along the pathways. However, initial step of the pathways involves an unsurmountable energy barrier though the key step responsible for stereoinversion has a very low energy barrier and is predicted to proceeds with significant rates. The work suggests the possibility of observing stereoinversion of glutamic acid in the warmer regions of ISM.

1. Introduction Astrochemical exploration of complex organic molecules in outer space is an ever-increasing venture not only to find exotic molecules but also to answer the cosmic origin of life on early Earth (Pasek, 2015; Ehrenfreund et al., 2002). In particular, the search for basic unit of proteins, the proteinogenic amino acids, in the interstellar medium (ISM) is of keen interest among astrophysicists and astrochemists alike (Brack, 2019; Cobb and Pudritz, 2014). In fact, the continuous investigations on the chemical composition of carbonaceous chondrites (meteorites rich in carbon content) substantiate the speculation of amino acids formation under extra-terrestrial conditions (Elsila et al., 2016; Burton et al., 2012; Pizzarello and Shock, 2010; Burton et al., 2015). Our present study investigates the astrophysically relevant gasphase stereoinversion in the glutamic acid, one of the important nonessential proteinogenic α-amino acids, which is also the most abundant excitatory neurotransmitter in the nervous system of all vertebrates (Meldrum, 2000). Note that glutamic acid is not yet detected in the ISM but there exists a substantial speculation of its presence based on the

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composition analysis of meteorites, namely, the widely studied Murchison and Murray as well as Tagish-lake meteorites (Burton et al., 2015; Kminek and Botta, 2002; Pizzarello and Cronin, 2000; Koga and Naraoka, 2017; Lawless et al., 1971). The amino acids detected in meteorites have been comprehensively reviewed by several researchers (Sephton, 2002; Botta and Bada, 2002). Besides this, the advancements in the state of the art laboratory experiments imitating the tenuous atmosphere of ISM, are also confirming the probable synthesis of complex organic matter under extra-terrestrial environment (Zhen, 2019; Fulvio et al., 2017; Wiesenfeld et al., 2018). For example, glutamic acid has also been reported to be synthesised in studies based on Miller-Urey's experiment (Koga and Naraoka, 2017; Takano et al., 2007; Furukawa et al., 2015). A probable mechanism for the synthesis of glutamic acid in the ISM can be proposed via Strecker synthesis, as schematically presented in Fig. 1 (which can be more appropriately envisaged when occurring on ice analogous in the condensed phase). As depicted in step (1), it involves an important carbonyl precursor (I) which can result from the molecules already detected in the ISM like acetic acid, methylene radical and methyl formate (Mehringer et al., 1997; Churchwell and

Corresponding author. E-mail address: [email protected] (Vikas).

https://doi.org/10.1016/j.molap.2019.100061 Received 18 May 2019; Received in revised form 18 December 2019; Accepted 18 December 2019 Available online 24 December 2019 2405-6758/ © 2019 Elsevier B.V. All rights reserved.

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Fig. 1. A probable mechanistic route (occurring on ice analogues) leading to the formation of glutamic acid from interstellar molecular species.

Winnewisser, 1975; Hollis et al., 1995). This precursor further undergoes ammonia addition to form corresponding imine, which upon collision with HCN and subsequent hydrolysis, can finally result in glutamic acid following the Strecker pathway (step 2) (Koga and Naraoka, 2017; Bada, 2013). However, the aforementioned mechanism will results in the formation of both the enantiomers (a racemic product of glutamic acid). This cannot provide answer to the enantiomeric preference of amino acids, towards laevorotatory (L) form, present in the living organisms, which is a topical query of biogenesis on pre-biotic earth (Davankov, 2018). The extra-terrestrial origin of such biohomochirality has been propelled by the quantitative analysis of meteoritic compositions (Burton et al., 2015; Pizzarello and Cronin, 2000; Pizzarello, 2016; Burton et al., 2012), revealing the presence of L-enantiomer in meteorites (Famiano et al., 2019; Burton, 2018). Glutamic acid has also been reported to be present abundantly in its L-enantiomeric form in the meteoritic samples analysed so far (Elsila et al., 2016; Koga and Naraoka, 2017; Burton, 2018; Pizzarello, 2016; Glavin et al., 2012; Myrgorodska et al., 2015). Moreover, glutamic acid exhibits an anomalous property of conglomeration whereby it crystallizes into one particular enatio-pure form (the conglomerates) from the racemic mixture. This process has been well analysed and applied to explore the origin of bio-homochirality in a study by Viedma (2001). To provide further stereochemical insights into the extraterrestrial origin of enantiomeric excess of amino acids, our research group, through quantum-mechanical computations, has been exploring gasphase stereoinversion pathways in various molecular species under the conditions akin to ISM (Kaur and Vikas, 2015; Kaur and Vikas, 2015; Kaur and Rani, 2018; Rani and Vikas, 2018). Recently, we have explored mechanism and kinetics of such pathways for amino acids, serine and aspartic acid, each having one chiral centre, and also in threonine, an amino acid with two chiral centres (Kaur and Vikas, 2015; Kaur et al., 2018; Rani and Vikas, 2018). These studies suggested that the gas-phase stereoinversion of amino acids proceed through multi-

step pathways, and is predicted to be less feasible in the cold dense molecular clouds though it can occur in the warmer regions of ISM during stellar evolution (Kaur et al., 2018; Rani and Vikas, 2018; Rani and Vikas, 2019). In the present study, we perform quantum-mechanical computations to explore the mechanism and kinetics of probable gas-phase stereoinversion pathways for L-glutamic acid. Note that such gas phase studies are quite relevant due to negligible particle density in the ISM (Ferrière, 2001). The thermochemical and kinetic analysis of explored pathways is further performed in different temperature regions of ISM to reveal a suitable region for observing such stereoinversion. This is further augmented by exploring various dissociation channels (DCs) for L-glutamic acid and intermediates along the stereoinversion pathways. The methodology adopting for tracing various reaction pathways is described in the next section. 2. Methodology In order to trace a complete stereoinversion pathway, an achiral species (with point-group symmetry Cs) is generally searched on the potential energy surface (PES) of the chiral molecular species. The gasphase chiral inversion, passing through an achiral species, can proceed through possible migrations of constituent groups around the chiral centre as depicted in Fig. 2 for glutamic acid. The migration of –H (at chiral carbon) to –NH2 and –COOH groups is more likely to result in stereoinversion, which may proceed through species like ammonium ylides and imines (see later) whereas its shift to –CH2CH2COOH is chemically not conducive due to more likelihood of dissociation to propionic acid. The migration of –NH2 on to –COOH is chemically reversible as in the case of aspartic acid and alanine (Kaur et al., 2018; Ohno and Maeda, 2006), whereas its shift to –CH2CH2COOH is structurally not allowed due to a long side chain and may result in NH2CH2CH2COOH. Similarly, the shift of –COOH (at chiral carbon) onto –H, −NH2, –CH2CH2COOH as well as shift of –NH2 2

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five equilibrium structures located were found to be neither the conformers of glutamic acid nor having appropriate geometry/symmetry for stereoinversion to proceed. This indicated that the stereoinversion pathways are energetically high-lying. To trace these, a further GRRM search was performed by following the five largest ADDs (LADD=5 option in GRRM). It resulted into 158 equilibrium structures and 105 transition structures (after completion of 22 cycles of GRRM search). But again, the located species were found to be irrelevant for tracing a stereoinversion pathway, affirming the presence of energetically high barrier along the stereoinversion pathways. Therefore, an intuitive guess is used to trace various species as can be envisaged along the probable stereoinversion pathways that may result from the suitably oriented conformers for following the possible migrations depicted in Fig. 2. The important transition states are located using two-point scaled hypersphere search method (2PSHS) in GRRM, accompanied by the intrinsic reaction coordinate (IRC) calculations at the DFT/B3LYP/ 6–31 G level of theory. The geometries of various species along the proposed stereoinversion pathways (discussed later) are further refined at a higher level of DFT, namely, M06-2X/aug-cc-pVTZ employing a meta-hybrid Minnesota family M06-2X double-exchange functional (Zhao and Truhlar, 2008) and a correlation consistent triple-zeta, aug-cc-pVTZ, basis set augmented with diffuse functions on an ultrafine grid (Dunning, 1989; Kendall et al., 1992). Note that all the geometry optimizations were followed by vibrational frequency calculations to calculate the zero-point energy (ZPE) correction and to confirm the nature of located stationary point either as an intermediate EQ with all real frequencies or as a first order saddle point corresponding to a TS associated with a single imaginary frequency. The energy refinement of various species were also performed with more reliable coupled-cluster calculations at DF-CCSD(T)/cc-pVTZ//M06-2X/aug-cc-pVTZ level utilizing a computationally economical density fitting (DF) method (City, 1977; Deprince and Sherrill, 2013). Besides this, the effect of dispersion corrections was also estimated at the B3LYP-D3(BJ)/cc-pVTZ level using Grimme's empirical dispersion (D3) and Becke-Jhonson damping (Grimme et al., 2011). However, we did not observed any significant departure in the relative energy profiles at different level of the theory even employing the dispersion corrected functionals of DFT (see the results discussed later). The global minimum conformer of L-glutamic acid in the present study is identified as EQ0# depicted in Fig. 3. Notably, the gas-phase conformational studies of glutamic acid have also been previously studied computationally by Meng and Lin (2011), and experimentally through rotational spectroscopy by Pen et al. (2012). Both these studies has reported EQ0# as the minimum energy conformer. Apart from the global conformer, Fig. 4 depicts important conformers of L-glutamic

Fig. 2. The migrations around the chiral centre leading to stereoinversion in glutamic acid. The probable stereoinversion paths are shown in green whereas the improbable ones in the red (see discussion in the text).(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

to –H are also unlikely to take place. The shift of –CH2CH2COOH on to –NH2 and –COOH though unexpected but do leads to stereoinversion, however, through pathways involving quite high-energy barrier (see later). Thus, there are four likely shifts out of the total twelve possible migrations that may result in stereoinversion as depicted in Fig. 2. A search for various equilibrium structure species (EQs) and transition states (TSs) resulting from the aforementioned migrations, leading to an achiral species, along the stereoinversion pathways on the PES of glutamic acid, was performed computationally by employing a global reaction route mapping(GRRM)41–43strategy while utilizing density-functional theory (DFT) (Parr and Yang, 1989; Koch and Holthausen, 2000). The GRRM traces a reaction pathway through an anharmonic downward distortion following (ADDf) approach (for details see Refs. (Maeda and Ohno, 2004; Maeda and Ohno, 2005; Maeda et al., 2013)).We have successfully employed GRRM for mapping reaction pathways in diverse chemical systems (Kaur and Vikas, 2016; Kaur and Vikas, 2017; Kaur and Vikas, 2017; Kaur and Vikas, 2018; Vikas et al., 2017). Initially, for the present work, a preliminary search was carried out using ‘First Only’ option in GRRM at the level of DFT/B3LYP/6–31+G(d,p) employing a Becke-three-parameterized Lee-Yang-Parr (B3LYP) (Becke, 1993; Lee et al., 1988) exchange-correlation functional of DFT and 6–31+G(d,p) Gaussian basis set with diffuse and polarization functions (Krishnan et al., 1980). In the ‘First Only’ option, only energetically low lying stereochemical pathways are traced around the input structure of L-glutamic acid. In the present case, it resulted into 14 equilibrium structures (EQs) and 12 transition states (TSs). Out of the 14 equilibrium structures, 9 were identified as rotational conformers of glutamic acid, all of which have been provided in Figure S1 of supporting information (SI). The other

Fig. 3. Optimized structure of geometrically equivalent enantiomers (with C1 point group symmetry) of global minimum EQ0# at DFT/M06-2X/aug-cc-pVTZ level of theory. The bond lengths (in Å) and bond angles (in degrees) are depicted separately on the two enantiomers only for the sake of clarity, but these are exactly the same in the two enantiomers. 3

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Fig. 4. Conformations of L-glutamic acid relevant to stereoinversion (depicted with respective hydrogen bonding interactions). The nomenclature specified in parenthesis is taken from the literature (Refs. (Meng and Lin, 2011; Pen et al., 2012)) for the already known conformers.

acid from which the stereoinversion pathways are likely to proceed as can be decided following the orientation of various substituents around the chiral centre and type of hydrogen bonding interactions present in the conformers. In the literature, amino acid conformations are broadly categorised into three categories based on the hydrogen bonding interactions present in them: (I) HNeH—O = C (syn-O = CeO-H), (II) HNeH—OH (syn-O = CeO-H), (III) H2N—OH (anti-O = CeO-H) (Pen et al., 2012; Sanz and Alonso, 2010; Alonso et al., 2009). For glutamic acid, syn conformers are likely to be relevant for stereoinversion as can be inferred from Fig. 4. The pathways interconverting these conformers were further traced by locating the transition states (depicted in SI Figure S2) using 2PSHS and IRC calculations. Besides this, the dissociation channels (DCs), depicted in SI Figure S3, were also intuitively traced for the relevant conformers and intermediates along the proposed stereoinversion pathways similar to that explored in the case of glycine, aspartic acid and threonine (Kaur et al., 2018; Rani and Vikas, 2018; Maeda et al., 2018). The energetics of various species along the conformational inter-conversion as well as stereoinversion pathways are provided in Tables 1 and 2 and SI Table S1. Besides this, the four probable stereoinversion pathways, Path 1–4, proposed in this work are depicted in Figs. 5–8 whereas the corresponding relative potential energy profile and Gibbs free-energy profile for the most probable pathway is depicted in Figs. 9 and 10, respectively. It is to be noted that the relative potential energy profile (in Fig. 9) and Gibbs free-energy profile (in Fig. 10) follow the same energetics trends. Further, to have an extensive mechanistic details, the charges on migrating atoms (as listed in Table 3) were analysed through natural bond orbital (NBO) (Weinhold, 2012) analysis of stationary points along the pathways, at the level of M06-2X/aug-cc-pVTZ theory. The surface plots of HOMO corresponding to the optimized geometry of species involved in pathways were also examined as depicted in Figure S4. Besides these, the Gibbs free-energy analysis of the stereoinversion pathways was further performed at different temperatures

corresponding to various temperature-zones of ISM (as listed in Table 4). However, the initial energy-barrier along the pathways proposed for stereoinversion is observed to be quite high (see later) but significant quantum tunnelling is expected because of hydrogen atom/ proton transfer along a few of the pathways. Therefore, the kinetics analysis (provided in Table 5 and SI Figure S5) was carried out by calculating the unimolecular rate constants of each step along the proposed pathways using conventional transition state theory (CTST) but including the quantum mechanical tunnelling through Eckart and Wigner tunnelling potentials (as has been adopted in our previous studies) (Johnston and Heicklen, 1962; Weigner, 1932). The thermokinetic analysis is performed using Kinetic and Statistical Help Program (KISTHELP) (Canneaux et al., 2014), whereas all the quantum-mechanical computations were performed using G09 quantum mechanical software package (Frisch et al., 2009), except for DF-coupled cluster calculations for which PSI-4 code is utilized (Parrish et al., 2017). Based on the thermo-kinetic analysis of the pathways, their relative feasibility in different regions of ISM is discussed in the next section. 3. Results and discussions Glutamic acid with substituents -H, -NH2, -COOH and an acidic side chain –CH2CH2COOH around the asymmetric (carbon) centre exhibits point chirality and C1 point group symmetry. For stereoinversion to occur, one of the necessary requirements is to interrupt the chirality by migrating one of the substituent on to the other as introduced in the previous section through Fig. 2. As introduced before, there are twelve possible migrations that can occur in case of amino acid with one chiral centre, three for each substituent on to the other. The chiral inversion can take place provided such migrations result in an intermediate which is achiral (with Cs point group symmetry) as has been observed in the case of alanine (Ohno and Maeda, 2006). However, even if the resulting intermediate retains the chirality either due to point chirality, 4

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via P1TS0-1, which was confirmed through NBO charge analysis in Table 3. The (positive) charge on the migrating –H(18) increases from 0.200 to 0.493e in the involved transition state P1TS0-1 whereas the (negative) charge on the acceptor N(1) atom decreases from −0.851 to −0.67e in the resulting intermediate P1EQ1 while there is an increase in the negative charge on the chiral centre C(2) through which it departs. This migration of the proton is further confirmed by comparing the HOMO of P1EQ0 and P1EQ1 depicted in Figure S4. The increased electron density on C(2) and decreased one on N(1) while moving from EQ0 to EQ1 can be distinctly observed. However, the initial step along Path 1 is endothermic with an activation energy barrier of 67.01 kcal/mol as evident from the relative energies depicted in Table 1. The resulting ammonium-ylide type intermediate P1EQ1 still possess the point chirality due to the presence of lone pair of electrons as the fourth substituent on C(2). However, this chiral intermediate can flip over to its counterpart of opposite chirality through an energy barrier of only 4.85 kcal/mol via an achiral transition state located between (S)-P1EQ1 and (R)-P1EQ1 (as depicted in Fig. 5). Moreover, no dissociation pathway leading from the species (along Path 1) into ammonia and other fragments could be located as these may be energetically even more higher lying than the initial barrier for the setereoinversion, though such DCs were explored in the case of aspartic acid (Kaur and Rani, 2018) through P1EQ1 type intermediate. Hence, the migration of –H (as a proton) at chiral carbon to –NH2 provides a pathway for the stereoinversion of glutamic acid. However, the initial step still involves a high-energy barrier, therefore, the role of quantum tunnelling becomes significant (as explored through kinetic analysis discussed later).

Table 1 ZPE corrected relative electronic energy (in kcal/mol) of various stationary points located along the proposed stereoinversion pathways of L-glutamic acid. The energy values are relative to that of global minimum EQ0# at the specified levels of theory.*. Stationary Point

Point Group

M06-2X/aug-ccpVTZ (ZPE)

DF-CCSD(T)/cc-pVTZ// M06-2X/aug-cc-pVTZ +(ZPE)

Stereoinversion Pathways Path 1 EQ0a C1 2.05 (−0.11) 2.32 P1 TS0-1 C1 65.59 (−4.02) 69.32 P1 EQ1 C1 40.46 (−0.44) 44.11 P1 TS Cs 45.15 (−0.47) 48.96 Path 2 EQ0b C1 0.46 (−0.18) 0.59 P2 TS0-1 C1 51.71 (−3.44) 55.95 P2 EQ1 C1 19.77 (−0.65) 20.88 P2 TS Cs 30.45 (−1.24) 31.34 Path 3 P3 TS0-1 C1 99.66 (−2.85) 103.06 P3 EQ1 C1 39.08 (−0.30) 42.08 P3 TS Cs 42.68 (−0.43) 46.96 Path 4 EQ0c C1 1.11 (−0.03) 1.37 P4 TS0-1 C1 54.97 (−2.53) 58.24 P4 EQ1 C1 19.33 (−1.10) 19.30 P4 TS1-1c C1 23.05 (−1.05) 23.06 P4 EQ1c C1 18.54 (−1.02) 18.66 P4 TS Cs 21.23 (−1.16) 21.59 Transition states for conformational inter-conversions TS#b C1 2.66 (−0.11) 2.66 TSad C1 5.58 (−1.17) 7.22 TSbc C1 5.58 (−0.10) 5.80 C1 7.17 (0.05) 7.26 TSbd TScd C1 3.43 (0.10) 3.48

3.2. Migration of –H (at chiral centre) to –COOH Such type of migration has also been reported to invert the chirality in other amino acids as predicted in the previous studies (Kaur et al., 2018; Rani and Vikas, 2018; Ohno and Maeda, 2006), and is also proposed to be a probable pathway, Path 2, depicted in Fig. 6 for the stereoinversion in glutamic acid. The movement of –H from the chiral carbon to –COOH is chemically allowed and structurally feasible but through EQ0b conformer of glutamic acid. As analysed in Table 3, the H (18) in EQ0b moves to the carbonyl carbon as an hydrogen atom, since there is decrease in the positive charge on migrating H(18) and acceptor C(3) from 0.21 to 0.12e and 0.81 to 0.46e, respectively. There is also an increase in the positive charge (from −0.13 to 0.33e) on the chiral centre C(2), through which –H departs as an atom. This transfer of hydrogen as an atom also results in the increase of negative charge on carbonyl oxygen O(4), due to which the –H(13) atom on the –NH2 group gets in close proximity with this negatively charged oxygen in the involved transition state P2TS0-1 as evident in Fig. 6. However, along Path 2, there is not only a hydrogen-atom transfer but also a simultaneous proton transfer occurs resulting in an imine type intermediate. The latter involves the transfer of –H(13) from –NH2 to O(4), as indicated by an increased positive charge on –H(13) from 0.37 to 0.45e in

⁎ The total energy including ZPE of EQ0# at M06-2x/aug-cc-pVTZ (ZPE) level is −551.49576 (0.153544) a.u., and at DF-CCSD(T)/cc-pVTZ level is −550.66834 a.u. (1 a.u.=627.51 kcal/mol). The ZPE values at M06-2x/aug-ccpVTZ are used for DF-CCSD(T)//DFT calculations. For calculations using other methods employed, see SI Table S1.

axial chirality or helical chirality, an achiral transition state (with Cs point group) can still be located which connects the previous intermediate with its counterpart of opposite chirality as has been predicted in the case of aspartic acid (Kaur et al., 2018), as well as in the present study on glutamic acid (see later). But note that all the twelve migrations for stereoinversion are not possible either chemically or sterically or may result in dissociation as discussed for different cases below. 3.1. Migration of –H (at chiral centre) to –NH2 The conformer EQ0a of glutamic acid is properly oriented for the migration of –H to be feasible on to –NH2 as depicted along stereoinversion pathway, Path 1, in Fig. 5. This migration is chemically feasible since the lone pair on nitrogen can accept the H atom as a proton

Table 2 Same as Table 1 but for the dissociation channels (DCs), also see SI Figure S3 depicting various DCs. Stationary Point

M06-2x/aug-cc-pVTZ (ZPE)

DF-CCSD(T)/cc-pVTZ +(ZPE)

Stationary Point

M06-2x/aug-cc-pVTZ (ZPE)

DF-CCSD(T)/cc-pVTZ +(ZPE)

DC1

87.48 73.23 53.57 47.44 82.95 23.87 71.58 44.43 96.86 21.44

84.67 71.69 55.08 48.08 84.59 22.36 72.23 44.91 101.95 22.63

DC6

52.41 (−2.59) 8.43 (−0.56) 42.67 (0.07) 18.10 (−0.03) 65.07 (−1.73) 10.01 (−2.19) 104.55 (−7.28) 20.13 (−7.02)

52.22 8.50 46.05 20.33 67.37 12.31 105.80 21.63

TS DC1 DC2 TS DC2 DC3 TS DC3 DC4 TS DC4 DC5 TS DC5

(−5.16) (−4.13) (−2.68) (−2.61) (−6.59) (−5.21) (−4.57) (−2.65) (−5.46) (−6.80)

TS DC6 DC7 TS0-1 DC7 EQ1 DC7 TS1 DC7 DC8 TS DC8

5

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Fig. 5. Stereoinversion pathway, Path 1, initiating from conformer (S)-EQ0a. The values in parenthesis are ZPE corrected relative energies (in kcal/mol) w.r.t. global conformer EQ0# at M06-2X/aug-cc-pVTZ level of theory. The atomic distances shown are in angstroms.

the transition state P2TS0-1, and to 0.50e in the gem‑diol imine type intermediate (S)-P2EQ1. Furthermore, due to the migration of proton from N(1), the negative charge should increase on it but there is a decrease in the negative charge from −0.84 to −0.67e. This anomaly can be explained through the HOMO of P2TS0-1 (depicted in Figure S4) which clearly indicates a synchronous movement of electron density from N(1) to C(2) along with the proton transfer revealing an intramolecular proton coupled electron transfer (PCET) mechanism operative albeit seems to be further coupled with the hydrogen-atom transfer. However, as evident in Fig. 9(b), the initial step along Path 2 is also associated with high-energy barrier of 55.37 kcal/mol leading to an axially chiral intermediate (S)-P2EQ1. The latter though can be inverted to its enantiomer via an achiral transition state P2TS having a plane of symmetry as shown in Fig. 6. Note that this inversion step involves relatively much lower energy-barrier of 10.46 kcal/mol, compared to the dissociation of intermediate (S)-P2EQ1 (into water molecule via DC1 depicted in SI Figure S3) which requires an energy of 64.81 kcal/mol, as evident in Table 2. Therefore, stereoinversion of glutamic acid through Path 2, is more likely to occur than the dissociation.

3.3. Migration of –H (at chiral centre) to –CH2 CH2COOH Such migration is predicted to be feasible for stereoinversion in aspartic acid in the previous study (Kaur and Rani, 2018). Though it is chemically and sterically allowed in the case of glutamic acid but it leads to dissociation into CH3CH2COOH, as explored via a dissociation channel, DC2 depicted in SI Figure S3. This may be due to a longer side chain in glutamic acid compared to that in the aspartic acid. 3.4. Migration of –CH2CH2COOH on to –NH2 The transfer of side chain of amino acid on to –NH2 has been anticipated to lead to stereoinversion in other amino acids (Kaur et al., 2018; Rani and Vikas, 2018; Ohno and Maeda, 2006), though it was predicted to be less probable due to a very high energy barrier but still it is being investigated in the present study mainly because of exotic chemistry expected in the ISM as depicted along stereoinversion pathway, Path 3, in Fig. 7. The shift of –CH2CH2COOH can occur from EQ0b conformer which was also involved along stereoinversion pathway, Path 2, discussed 6

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Fig. 6. Same as Fig. 5 but for stereoinversion pathway, Path 2, initiating from conformer (S)-EQ0b.

previously. The lone pair of electrons on the nitrogen is the attacking site that causes this shift to be chemically viable as also evident from the HOMO of involved transition state P3TS0-1 (as in SI Figure S4) and connecting intermediates in Fig. 7. However, as evident from Table 1, the initial step involves a very high activation energy barrier of 102.47 kcal/mol for the formation of transition state (S)-P3TS0-1. This results in an ammonium ylide type intermediate (S)-P3EQ1 with positive charge on N(1) and negative on C(2) as predicted using NBO charge analysis in Table 3. The negative charge on C(2) is further stabilised through resonance with carbonyl oxygen O(4). Overall, the point chirality in conformer EQ0b is transformed into axial chirality in (S)-P3EQ1, which is finally inverted to (R)-P3EQ1 via Cs point group symmetrized transition state P3TS3 connecting the two enantiomers but with a small energy barrier of only 4.87 kcal/mol. Moreover, no DC could be located which is due to involvement of even more high energy barrier for the dissociation of species along Path 3, therefore, stereoinversion along this pathway is likely to be a more probable event than the dissociation.

3.5. Migration of –CH2CH2COOH on to –COOH The –CH2CH2COOH can also migrate to carbonyl carbon of –COOH group after crossing an energy barrier of 56.86 kcal/mol via transition state (S)-P4TS0-1 as shown along stereoinversion pathway, Path 4, in Fig. 8 as well as in Table 1. This pathway initiates from conformer EQ0c, which has the proper orientation of substituents around achiral centre to allow such migration. As evident in SI Figure S4, this migration causes shift of electron density towards carbonyl oxygen O(4) as can be seen while comparing the HOMO of P4TS0-1 and EQ0c. This causes the transfer of proton from –NH2 to O(4) while simultaneously shifting the electron density from N(1) to C(2) and C(5), via PCET mechanism, similar to that observed along Path 2. This is further evident from the overlapped electron density of N(1), C(2) and C(3) in HOMO of P4EQ1 (Figure S4) as well as indicated by the NBO charge analysis in Table 3. As evident in Fig. 8, the initial step along Path 4 results in a vicinaldiol imine type intermediate (S)-P4EQ1, which exhibits an axial

7

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Fig. 7. Same as Fig. 5 but for stereoinversion pathway, Path 3, initiating from conformer (S)-EQ0b.

chirality. In the case of serine and aspartic acid (Kaur and Vikas, 2015a; Kaur et al., 2018, such pathways at similar stage also could not result in any achiral stationary point through which chiral inversion can take place. In the present case too, no direct channel could be located to invert (S)-P4EQ1. However, as evident along Path 4 in Table 1, a conformational change in (S)-P4EQ1 to helically chiral (S)-P4EQ1c takes place which only involves a small energy barrier of 3.76 kcal/mol. This helically chiral intermediate can invert into its enantiomer (R)-P4EQ1c via transition state P4TS4 requiring only 2.93 kcal/mol of energy. So, overall this migration is predicted to be feasible for stereoinversion similar to that has been predicted in the case of alanine (Ohno and Maeda, 2006). In addition to the stereoinversion pathway, a dissociation pathway DC2 (depicted in SI Figure S3) is located for (S)-P4EQ1 with an energy requirement of 35.79 kcal/mol which is much higher than the that required for its stereoinversion. The dissociation of the starting conformer EQ0c is also traced which leads to CO and H2O (as depicted through DC3 in SI Figure S3), but it is also predicted to have a very high energy barrier of 83.22 kcal/mol as listed in Table 2. Thus, stereoinversion along Path 4 is also likely to proceeds over the dissociation.

3.5.1. Dissociation channels (DCs) In addition to the DCs discussed along the aforementioned pathways, five more dissociation pathways were traced out from the global conformer EQ0# as summarized in SI Figure S3. All these dissociation channels are analysed to involve even higher activation barrier than the initiation step along stereoinversion Path1, Path 2 and Path 4 except for the case of DC6 and DC7 as analysed in Table 2 and SI Figure S3. However, these dissociations take place from the global conformer EQ0#, not directly involved along the stereoinversion pathways proposed to initiate rather from its rotational conformers. The later can result with much ease from the conformational interconversion as evident from the potential energy profiles in Fig. 9(a). The stereoinversion pathways are likely to be even more probable over the dissociation under the gas-phase conditions of ISM, which in fact has too low particle density to allow a collision event for dissociation to proceed. 3.5.2. Thermo-kinetic analysis To assess the thermodynamic feasibility, the relative energy change and Gibbs free-energy change (ΔG) along the conformational pathways and four stereoinversion pathways (Path 1–4) explored in this work, is 8

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Fig. 8. Same as Fig. 5, but for stereoinversion pathway, Path 4, initiating from conformer (S)-EQ0c.

analysed in Figs. 9 and 10 as well as in Table 4 under various temperature zones of ISM. The latter has region of cold dense molecular clouds at temperature of 10–50 K, diffuse molecular clouds at 50–100 K, hot core and corino of protostars at 100–300 K, and regions with even higher temperature up to 1000 K is associated with innerprotoplanetary discs around young stars. The regions with temperature

more than 1000 K are photon-dominated regions (PDR), and with even higher temperature up to 107 K constitute hot ionized (HII) regions (Hollenbach, 1999; Yamamoto, 2017). Though the conformational barrier between various conformers of glutamic acid is quite low, but none of the proposed stereoinversion pathway (including the most probable Path 2) is thermodynamically feasible in any region of the 9

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Fig. 9. Relative potential energy profiles of pathways for (a) interconversion between various conformers of L-glutamic acid depicted in Fig. 4 (for the geometries of located transition-states, see SI Figure S2), (b) the most probable stereoinversion path 2 depicted in Fig. 6, at the ZPE corrected DF-CCSD(T)/cc-pVTZ//DFT/M06-2X/ aug-cc-pVTZ level of theory. The energies are relative to the energy of global conformer EQ0#.

ISM, mainly due to high initial barrier (along the first step). However, the key step leading to chiral inversion involves a free-energy change of only 2–5 kcal/mol, particularly in the low temperature regions. Thermodynamically, a non-catalytic stereoinversion in glutamic acid seems to be an unlikely event, however, as analysed in the previous sections, the proposed stereoinversion pathways proceed through hydrogen atom and proton transfer. Therefore, the role of quantum-mechanical tunnelling can be anticipated. As analysed through the unimolecular rate coefficients in Table 5 and SI Figure S5 as well as tunnelling transmission coefficient listed in Table 5, significant quantum tunnelling is predicted, particularly, at low temperatures and along those steps of pathways where hydrogen-atom and protontransfer is involved. But the rate coefficient of initial step along the pathways, despite significant tunnelling, is still too low for the stereoinversion pathway to initiate, particularly in the low-temperature regions, due to very high initial barrier. Therefore, even the quantum tunnelling in lower temperature zones is unable to drive the reaction at moderate rate. However, at temperatures near 500 K and above, the rates are sufficient to support the stereoinversion in glutamic acid. For example, along Path 2, the initial step proceeds with a rate of ca.10-10s-1 at temperature of 500 K, which though seems to be quite insignificant but it is still quite relevant on the time-scale of most of the astrochemical events. Note that except for the initial step along the proposed

multi-step stereoinversion pathways, the rest of the reaction proceed with high rates (see SI Figure S5). In particular, for the stereoinversion step involving achiral transition state species, the rate constants, for example along most probable Path 2, are more than 104 s-1 − at temperatures above 200 K as evident in Table 5 and Figure S5. Further note that as already discussed in the previous section, the dissociation of most of the species involved along the proposed pathways require more energy, as can be seen from dissociation channels listed in Table 2 and those depicted in SI Figure S3. Moreover, as evident from Table 5 and SI Figure S5, the key chiral inversion event is kinetically favourable with very high rates along all the pathways, irrespective of the ISM region in which it may occur, where the dissociation of intermediates along the pathways is a less probable event as analysed previously. Further, comparing the rate coefficients of the slowest (initial step) along all the pathways, the stereoinversion along Path 2 is kinetically more favourable with overall order as: Path 2 >Path 1>Path 4>Path 3. The above analysis suggests that the very low temperature regions of ISM corresponding to cold dense neutral medium are kinetically not favoured (for stereoinversion) and the higher temperature of protoplanetary disks are thermodynamically not feasible for stereoinversion in glutamic acid. Even more high temperatures, >1000 K, correspond to photo-dissociation region and mainly consists of strong photon flux 10

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Fig. 10. Relative Gibbs free energy profiles at 298.15 K for (a) interconversion between various conformers of L-glutamic acid (depicted in Fig. 4) (b) the most probable stereoinversion path 2 depicted in Fig. 6, at the DFT/M06-2X/aug-cc-pVTZ level of theory. The energies are relative to the energy of global conformer EQ0#.

as the most appropriate region for stereoinversion to be observed in glutamic acid. Such temperature region is associated with hot molecular cores or corinos of low-mass protostars which are formed during the earliest stages of star formation due to gravitational collapse of dense molecular clouds and hence, are comparatively warmer than molecular clouds (Yamamoto, 2017; Garrod and Widicus Weaver, 2013). Moreover, the hot cores of protostars are already known for terrestrial type chemistry prevailing in them. Complex organic molecules from alcohols, aldehydes, nitriles, acids, amides to esters have previously been reported to be present in this region, which in fact is being extensively searched for key prebiotic species (Yamamoto, 2017; Garrod and Widicus Weaver, 2013; Herbst and Herbst, 2017). Finally, note that the gas-phase intra-molecular stereochemical pathways (revealed by the present study) proceeds through achiral transition state species that resemble ammonium ylides and imines, the key ingredients in Strecker synthesis of amino acids. As depicted in Fig. 1, similar achiral species would also form during the synthesis of an amino acid on the ice analogues but through inter-molecular processes. Therefore, the corresponding condensed phase inter-molecular stereoinversion pathways are also likely to proceeds through such prochiral transition state species. These species upon subsequent attack by other species, for example, by HCN (from equally probable re and si face) will

Table 3 Natural atomic charges (in the units of electronic charge, e) deduced from NBO calculations at M06-2X/aug-cc-pVTZ level of theory, at the key atomic sites in relevant stationary points along the proposed stereoinversion pathways. The significant values are depicted in bold. Stationary Point

N (1)

C (2)

C (3)

O (4)

C (5)

H (13)

H (18)

EQ0a P1 TS0-1 P1 EQ1 EQ0b P2 TS0-1 P2 EQ1 P3 TS0-1 P3 EQ1 P3 TS EQ0c P4 TS0-1 P4 EQ1

−0.851 −0.853 −0.665 −0.837 −0.720 −0.671 −0.837 −0.753 −0.547 −0.837 −0.707 −0.652

−0.127 −0.276 −0.239 −0.132 0.328 0.305 −0.132 −0.317 −0.435 −0.134 0.190 0.122

0.822 0.726 0.684 0.807 0.460 0.368 0.807 0.684 0.672 0.804 0.572 0.494

−0.605 −0.663 −0.715 −0.609 −0.812 −0.740 −0.609 −0.739 −0.796 −0.616 −0.849 −0.754

−0.389 −0.417 −0.419 −0.385 −0.460 −0.479 −0.385 −0.073 −0.184 −0.381 −0.409 −0.412

0.359 0.401 0.392 0.366 0.447 0.501 0.366 0.426 0.469 0.366 0.445 0.500

0.200 0.493 0.397 0.211 0.119 0.155 0.211 0.214 0.217 0.222 0.218 0.171

emitted from the high-mass stars which can ionize most of the neutral molecules. (Hollenbach, 1999) Considering the thermal and kinetic analysis together, a temperature region of 100–300 K can be proposed 11

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Table 4 Gibbs free-energy change (ΔG, in kcal/mol), at DFT/M06-2X/aug-cc-pVTZ level of theory, along various steps of the proposed stereoinversion pathways of L-glutamic acid depicted in Figs. 5–8, at different temperature zones of ISM. The free-energy change is analysed up to the achiral stationary point necessary for the stereoinversion. T (K) PATH 1 (S)-EQ0a → (S)-P1TS0−1 (S)-P1TS0−1→ (S)- P1EQ1 (S)- P1EQ1 → P1TS(achiral) ΔG(Path 1) PATH 2 (S)-EQ0b → (S)-P2TS0−1 (S)-P2TS0−1→ (S)- P2EQ1 (S)- P2EQ1 → P2TS(achiral) ΔG(Path 2) PATH 3 (S)-EQ0b → (S)-P3TS0−1 (S)-P3TS0−1→ (S)- P3EQ1 (S)- P3EQ1 → P3TS(achiral) ΔG(Path 3) PATH 4 (S)-EQ0c → (S)-P4TS0−1 (S)-P4TS0−1→ (S)- P4EQ1 (S)- P4EQ1 → P4(S)- P4TS1-1c (S)-P4TS1-1c→ (S)- P4EQ1c (S)- P4EQ1c → P4TS(achiral) ΔG(Path 4)

10

50

100

298.15

500

1000

4000

8000

63.54 −25.13 4.69 43.10

63.53 −25.21 4.81 43.13

63.50 −25.37 5.07 43.20

63.26 −26.07 6.40 43.59

62.90 −26.80 8.04 44.14

61.99 −28.62 12.75 46.12

60.34 −43.21 47.99 65.12

64.68 −69.16 102.30 97.82

51.25 −31.93 10.67 29.99

51.25 −31.93 10.69 30.01

51.30 −31.97 10.74 30.07

51.68 −32.30 11.04 30.42

52.15 −32.76 11.52 30.92

53.53 −34.19 13.21 32.55

65.74 −47.30 29.95 48.39

88.45 −71.31 59.63 76.76

99.21 −60.59 3.60 42.22

99.21 −60.59 3.59 42.21

99.24 −60.63 3.56 42.17

99.47 −60.85 3.60 42.22

99.69 −61.03 3.83 42.49

100.24 −61.38 4.96 43.83

108.19 −68.13 18.88 58.94

125.69 −84.19 44.94 86.44

53.86 −35.63 3.71 −4.51 2.68 20.12

53.88 −35.63 3.75 −4.51 2.69 20.17

53.96 −35.66 3.84 −4.56 2.73 20.32

54.51 −35.93 4.61 −5.13 3.19 21.25

55.05 −36.32 5.72 −6.04 3.93 22.35

56.44 −37.61 9.11 −8.89 6.33 25.40

69.41 −51.13 36.39 −32.88 27.60 49.40

93.64 −76.31 80.13 −72.23 63.37 88.60

finally result in racemic amino acids. Therefore, the corresponding condensed-phase inter-molecular stereoinversion pathways are unlikely to contribute towards enantiomeric excess. On the other hand, if the synthesized amino acids on ice-analogues are desorbed, then the only gas-phase pathways available for stereoinversion would be through intra-molecular processes because of ultra-low particle density in the ISM. In such a case, any contribution towards enantiomeric excess would depend upon which enantiomer is being preferentially desorbed, however, such phenomenon is yet unknown. Nevertheless, it is likely that during the synthesis of amino acids (in the condensed phase), the desorption from ice analogues may result in

intermediate isomeric species explored along the proposed stereoinversion pathways. In such a case, gas-phase stereoinversion would be quite fast process because the initial high barrier is avoided. For example, this may happen due to some photochemical reactions that generally may involve excited state potential energy surfaces (which though are computationally more difficult to explore). On the contrary, in the condensed phase, the stereoinversion of amino acid is energetically less favoured because in order to invert, it has to pass through achiral transition state species, which can only be reached after the loss of H2O and HCN molecules, as can be envisaged from Fig. 1. Note that even in the gas phase, loss of H2O would require ca. 87 kcal/

Table 5 Rate coefficients (k, in sec−1) and tunnelling transmission coefficient (χ), for each elementary steps (1, 2, 3 etc.), along the proposed stereoinversion pathways depicted in Figs. 5–8, at the DFT/M06-2X/aug-cc-pVTZ Level of Theory. T (K) Path 1 (S)- EQ0a → (S)-

P1

EQ1

Inversion (S)- P1EQ1→ (R)Path 2 (S)- EQ0b → (S)-

EQ1

(S)-

P4

EQ1→ (S)-

P2

EQ1 P3

EQ1

P4

EQ1

P4

EQ1c

Inversion (S)- P4EQ1c → (R)-

⁎

EQ1

P3

Inversion (S)- P3EQ1→ (R)Path 4 (S)- EQ0c → (S)-

EQ1

P2

Inversion (S)- P2EQ1→ (R)Path 3 (S)- EQ0b → (S)-

P1

P4

EQ1c

100

200

298.15

500

1000

4000

8000

χ k1 χ

9.92 × 1030 3.396 × 10−96 1.240

2.292 × 10°8 4.998 × 10−49 1.060

2.474 × 10°2 6.558 × 10−32 1.020

3.160 1.059 × 10−14 1.000

1.290 7.634 × 10−01 1.000

1.010 4.269 × 1010 1.100

1.000 2.851 × 1012 0.950

k2

2.151 × 10°1

2.620 × 10°6

1.291 × 10°8

3.188 × 10°9

3.394 × 1010

2.185 × 1011

2.551 × 1011

χ k1 χ*

8.691 × 10°7 1.403 × 10−92 1.030

3.740 8.976 × 10−44 1.010

1.660 1.363 × 10−25 1.000

1.972 1.663 × 10−10 1.000

1.040 4.348 × 10°1 1.000

1.000 2.141 × 1010 1.000

0.990 6.358 × 1011 1.000

k2

7.196 × 10−12

5.518

5.000 × 10°4

9.618 × 10°7

2.709 × 1010

1.925 × 1012

3.917 × 1012

χ k1 χ

6.875 × 1019 1.875 × 10−185 1.130

6.661 × 10°2 7.674 × 10−94 1.030

3.770 2.892 × 10−60 1.020

1.480 4.128 × 10−31 1.010

1.100 2.824 × 10−09 0.990

1.010 1.031 × 10°8 0.980

0.990 6.103 × 1010 0.890

k2

3.742 × 10°4

5.534 × 10°8

1.448 × 1010

2.226 × 1011

1.717 × 1012

7.560 × 1012

8.790 × 1012

χ k1 χ k2 χ

1.169 × 10°1 2.817 × 10−105 1.090 9.065 × 10°3 1.150

1.490 3.473 × 10−47 1.020 1.168 × 10°8 1.040

1.190 8.286 × 10−28 1.000 2.582 × 10°9 1.020

1.060 9.598 × 10−12 1.030 3.380 × 1010 0.990

1.010 9.749 9.500 × 10−01 2.020 × 1011 1.050

1.020 1.367 × 1010 9.900 × 10−01 8.479 × 1011 1.000

0.920 4.236 × 1011 0.900 9.686 × 1011 1.100

k3

2.581 × 10°6

2.802 × 10°9

2.902 × 1010

1.986 × 1011

9.051 × 1011

2.576 × 1012

3.418 × 1012

tunnelling coefficient for this particular step along Path 2 is calculated using Wigner tunnelling correction (Weigner, 1932). 12

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mol, as indicated by dissociation channels depicted in Figure S3.

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Hollenbach, D.J., 1999. Photodissociation regions in the interstellar medium of galaxies. Rev. Mod. Phys. 71, 173–230. Hollis, J.M., Jewell, P.R., Lovas, F.J., 1995. Confirmation of interstellar methylene. Astrophy. J. 438, 259–264. Iglesias-groth, S., Cataldo, F., Ursini, O., Manchado, A., 2011. Amino acids in comets and meteorites : stability under gamma radiation and preservation of the enantiomeric excess. Mon. Not. R. Astron. Soc. 410, 1447–1453. Johnston, H.S., Heicklen, J., 1962. Tunnelling corrections for unsymmetrical Eckart potential energy barriers. J. Phys. Chem. 66, 532–533. Kaur, G., Vikas, 2015a. Mechanisms for D-L interconversion in serine. Tetrahedron Lett. 56, 142–145. Kaur, R., 2016. Vikas exploring the role of a single water molecule in the tropospheric reaction of glycolaldehyde with an OH radical: a mechanistic and kinetics study. RSC Adv. 6, 29080–29098. Kaur, R., Rani, N., Vikas, 2018. 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4. Conclusion In the present work, four multi-step non-catalytic pathways are computationally revealed for a probable gas-phase stereoinversion in glutamic acid under conditions accessible in interstellar medium. The different pathways traced initiate from various conformers of glutamic acid. A few of the pathways are analysed to proceed through simultaneous intramolecular hydrogen atom and proton transfer. Besides this, a proton-coupled electron transfer mechanism was found to be operative along the pathways. The initiation step along all the pathways involves a very high-energy barrier, however, the key step involving chiral inversion requires only a very low energy barrier and is analysed to proceed with significant rates. Thus, due to very high barrier for the initiation step, the racemization of glutamic acid is a quite slow process, which is in accordance with the recent study on preservation of meteoritic enantiomeric excess of amino acid even upon high energy gamma radiation (Iglesias-groth et al., 2011). The enantiomeric excess observed in the meteoritic carbonaceous chondrites is generally believed to be caused by destruction of one of the enantiomer by circularly polarized light which is an important component of stellar radiations. Such enantiomeric excess, however, can also result or may have been further enhanced through the stereoinversion pathways proposed in the present study. However, this will require that the key intermediates or achiral transition state species along the proposed stereoinversion pathways result either by desorption of species being formed due to inter-molecular processes on the ice analogues (in the condensed phase) or from some photochemical intra-molecular gasphase reactions in the ISM. Credit author statement Both authors contributed equally. Declaration of Competing Interest The authors declare no competing financial interest. Acknowledgments The authors gratefully acknowledge the financial assistance from Science & Engineering Research Board(SERB), India, under as research project (sanction order No. EMR/2016/002074). Namrata Rani thanks University Grants Commission (UGC), New Delhi (India) for providing SRF(NET) fellowship. The authors are also grateful to the Department of Chemistry, Panjab University, Chandigarh, for providing other computational software and resources. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.molap.2019.100061. References Alonso, J.L., Pérez, C., Eugenia Sanz, M., López, J.C., Blanco, S., 2009. Seven conformers of L-Threonine in the gas phase: a LA-MB-FTMW study. Phys. Chem. Chem. Phys. 11, 617–627. Bada, J.L., 2013. New insights into prebiotic chemistry from Stanley Miller’s spark discharge experiments. Chem. Soc. Rev. 42, 2186–2196. Becke, A.D., 1993. A new mixing of Hartree-Fock and local density-functional theories. J. Chem. Phys. 98, 1372–1377. Botta, O., Bada, J.L., 2002. Extraterrestrial organic compounds in meteorites. Surv. Geophys. 23, 411–467. Brack, A., 2019. Chemical biosignatures at the origins. In: Cavalazzi, B., Westall, F. (Eds.), Biosignatures for Astrobiology. Advances in Astrobiology and Biogeophysics. Springer, Cham.

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