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Abstract

Enantiomeric excesses of l-amino acids have been detected in meteorites; however, their molecular mechanism and prebiotic syntheses are still a matter of debate. To elucidate the origin of homochirality, alanine and the chiral precursors formed in prebiotic processes were investigated with regard to their stabilities among their isomers by employing the minimum energy principle, namely, the abundancy of a molecule in the interstellar medium is directly correlated to the stability among isomers. To facilitate the search for possible isomers, we developed a new isomer search algorithm, the random connection method, and performed a thorough search for all the stable isomers within a given chemical formula. We found that alanine and most of its precursors are located at higher energy by more than 5.7 kcal mol⁻¹, with respect to the most stable isomer that consists of a linear-chain structure, whereas only the 2-aminopropanenitrile is the most stable isomer among all others possible. The inherent stability of the α-amino nitrile suggests that the 2-aminopropanenitrile is the dominant contribution in the formation of the common enantiomeric excess over α-amino acids.

1. Introduction

Amino acids are the fundamental building blocks of proteins, and only 19 kinds of them with the l-form of the molecular chirality and an achiral one glycine are exploited by all known living organisms on Earth. Although it is still unclear why l-amino acids are selected, a large enantiomeric excess of l-amino acids was found in carbonaceous meteorites, such as the Murchison meteorite. This discovery suggests an extraterrestrial origin of l-amino acids (Elsila et al., 2016; Glavin et al., 2020). In the Murchison meteorite, a wide variety of organic compounds, including insoluble and soluble organic ones, have been identified (Koga and Naraoka, 2017).

For the amino acid component, the meteoritic amino acids possess α, β, γ, and δ amino structures that present the carbon moiety C₂–C₉. The most abundant amino acid in the Murchison meteorite is glycine (∼3 ppm), whereas other relatively abundant amino acids are alanine, β-alanine, and isovaline, all detected at a concentration of ∼1.7 ppm. The diverse composition of the meteoritic amino acids suggests a prebiotic synthesis of amino acids in the meteorites' parent body and/or the interstellar medium (ISM).

The Rosetta mission was able to detect, via mass spectrometry, the presence of volatile glycine and precursor molecules in the coma of comet 67P/Churyumov-Gerasimenko in 2014 (Altwegg et al., 2016; Grady et al., 2018). However, mass spectrometry cannot quantitatively distinguish between structural isomers in the same molecular weight. Therefore, the mechanisms of the chemical evolution of glycine and amino acids still remain unsolved.

The proposed formation pathways for the amino acids are summarized in Fig. 1. The Strecker synthesis in the parent body of meteorites is a typical mechanism (Elsila et al., 2016). The Strecker mechanism has long been postulated for the formation of α-amino acids by the hydrocyanation of imines (RCH = NH) and a subsequent hydrolyzation via the formations of amino nitriles (Fig. 1). Similar to the Strecker mechanism, the cyanohydrin reaction can explain the formation of α-hydroxy acids, also detected in the Murchison meteorite, and they are distributed similarly to the α-amino acids.

FIG. 1.

Proposed formation pathways for α-amino acids and α-hydroxy acids. Intermediate compounds of nitrile (pink), aldehyde (green), carbonylic acid (blue), and amide (yellow) are framed in different colors for the sake of clarity. Hydroxyl compounds are framed by the dashed lines in the corresponding colors. The chiral centers are indicated by an asterisk (*).

Another proposed mechanism worthy of attention is the reaction between the imine and carbomyl anion to form an amide intermediate (Koga and Naraoka, 2017). This scheme is consistent with the formations of a variety of meteoritic amino acids, soluble organic compounds, and alkylated pyridines present in the Murchison meteorite.

An alternative reaction pathway for the synthesis of amino acids is a radical coupling mechanism on grain surfaces in the ISM. Radical species are formed upon interstellar ultraviolet (UV) photolysis and cosmic rays irradiation, and their reaction barriers are low enough to proceed in the cold molecular cloud (T ∼ 10K). The suggested radical coupling mechanisms for the glycine formation can be realized according to three different paths (Garrod, 2013; Singh et al., 2013; Sato et al., 2018); $\begin{matrix} C H_{2} N H_{2} + C H O \to N H_{2} C H_{2} C H O \\ N H_{2} C H_{2} C H O + 2 O H \to N H_{2} C H_{2} C O O H + H_{2} O, \end{matrix}$ (1)

C H_{2} N H_{2} + C O O H \to N H_{2} C H_{2} C O O H,

(2)

N H_{2} + C H_{2} C O O H \to N H_{2} C H_{2} C O O H .

(3)

According to the chemical kinetic simulation in star-forming regions (Garrod, 2013), the dominant reaction processes are (1), (2), and (3) in the low (40K < T < 55K), middle (55K < T < 75K), and high (75K < T < 120K) temperature ranges, respectively. The simulation has demonstrated that the production of glycinal (NH₂CH₂CHO) is a key event for the glycine formation. For the formation of other amino acids, the radical coupling reactions of the type NH₂CHCN + R → NH₂CHRCN have been suggested. These reactions proceed through the formation of aminoacetonitrile (NH₂CH₂CN).

Based on these α-amino acid formation mechanisms, the origin of the molecular chirality can be traced back to their nitrile, aldehyde, and amino compounds with chiral centers, as highlighted in Fig. 1 by the color frames. Even though the generation of amino acids requires these multistep reactions, it is still unclear which formation pathways are dominant compared with other molecular formation reaction channels. If the radical coupling reactions are dominant in these chemical reactions, the molecular mechanism of homochirality is expected to be directly related to the formation processes.

The minimum energy principle (MEP) has been used to predict the presence of interstellar molecules in ISM (Lattelais et al., 2009, 2010). This principle is very efficient for many interstellar molecules with a small number of atoms (from two to six), although a few exceptional cases exist (Fourré et al., 2016, 2020). The MEP assumes that the most abundant molecule/isomer in ISM corresponds to the most stable one.

Although the number of isomers dramatically increase with the number of atoms, we enacted, in the present study, a computational effort in a comprehensive way to evaluate the stability of alanine and chiral alanine precursors within the MEP. The stability of related chiral molecules, namely, α-hydroxy compounds, as well as glycine, were also investigated to compare and test the present theoretical procedure. We implemented a new algorithm to generate isomers for a given chemical composition, and we refer to this approach as the random connection (RC) method.

The validity of this method was carefully assessed for glycine, whose isomers and isomerization channels were recently explored by Ohno et al. (2021) using their scaled hypersphere search-anharmonic downward distortion following the (SHS-ADDF) method. The group of Fourré et al. (2016, 2020) developed and benchmarked a software tool that was able to determine all possible isomers of a given composition.

Their approach uses a one-to-one correspondence between atoms with bonds and a weighted graph with vertexes within the graph theory framework. A thorough inspection of a specified vertex in a graph allows for extraction of all the possible isomers identified as unique graphs. Such a procedure is well suited for small-size molecules if the number of conformational degrees of freedoms are negligible. However, for larger molecules, the counting of all the possible graphs implies the risk of including unrealistic structures and connections, thus, requiring a more careful handling of the conformational degrees of freedom.

For this reason, our RC method represents a viable way to overcome these difficulties by introducing random samplings for both bond connections and initial atomic geometries and introducing a universal molecular force field that does not require adjustment according to the molecules that are targeted. The detailed computational procedure is described in Section 2. The advantages and disadvantages of our RC method compared with the previous approach by Fourré et al. (2016, 2020) are summarized in the Supporting Information (Supplementary Table S1).

In Section 3, the results of stable isomers for seven molecules, specifically glycine (A), alanine (B), alaninamide (C), 2-aminopropanal (D), 2-aminopropanenitrile (E), lactic acid (F), and lactonitrile (G), are presented. Their molecular structures are sketched in Fig. 2, and we can observe that C–E are the chiral precursors of B, whereas G is a unique chiral precursor of α-hydroxy acid F. These compounds are all strictly related to the promising prebiotic syntheses of B and F. Discussions concerning the origin of homochirality and limitation of the present theoretical approach, in the context of the results obtained here, are given in Sections 3.8 and 3.9. Finally, in Section 4, we summarized discussions as a conclusion.

FIG. 2.

Molecular structures investigated in the present study (A–G). The chiral centers are indicated by an asterisk (*).

2. Methods

The computational procedures of the RC method are detailed in this section. The overall flowchart is sketched in Fig. 3 and can be summarized as follows:

FIG. 3.

Schematic flowchart of the RC method proposed and implemented in the present work. By repeating the procedures 2–4, a number of isomers in different conformations are generated. RC = random connection.

A target molecule is initially identified. The number of atoms and their chemical types are then counted by virtually eliminating all their covalent bonds. For example, the molecule shown in Fig. 3 contains (1) one oxygen atom with two covalent bonds, (2) one carbon atom with four covalent bonds, (3) one nitrogen atom with three covalent bonds, and (4) five hydrogen atoms with one covalent bond. This virtual splitting allows for the identification of all the main building blocks of related isomers.

To construct new isomers, the isolated atoms are redistributed uniformly in a cubic box of 10 Å side length. Despite looking a bit arbitrary, this procedure is necessary to sample different conformers. The atoms are then newly bond-connected to other atoms with unconnected bonds. Initially, heavy atoms are connected. The bond-connections are randomly selected from all the available possibilities. Then, unconnected bonds are saturated with hydrogen atoms. By this procedure, the bonds are drawn to form a single molecule saturating the number of covalent bonds of each atom, avoiding spurious formation of separate molecules. If the atom types are not unique, all the possible atom-type-sets are searched separately. For instance, the O atom in a carboxylic acid has two possibilities, either the double-bonded carbonyl oxygen ( = O) or the single-bonded hydroxyl/ether oxygen (-O-).

After the molecule has the complete information of bond connection, the molecular geometry is optimized at a force field level. Our specific force field consists of a harmonic and a van der Waals component, accounting for the bonding (E _R) and nonbonding (E _vdW) interactions, respectively

\begin{matrix} E = E_{R} + E_{v d W} \\ E_{R} = \sum_{i j} \frac{1}{2} k_{i j} {(r - r_{i j})}^{2} \\ E_{v d W} = \sum_{k l} D_{k l} \{- 2 {(r_{k l} ∕ r)}^{6} + {(r_{k l} ∕ r)}^{12}\} \end{matrix}

The indices i, j run over all the bonded atom pairs, and the indices k, l run over the nonbonded atom pairs. This force field is a simplified form of the universal force field (UFF) (Rappe et al., 1992). The other terms of the original UFF, that is, bond angle bending (E _q), dihedral angle torsion (E _q), and electrostatic terms (E _el), are not considered in the present study, because an exploratory rough optimization is needed in this stage. Further and more accurate optimizations within electronic structure calculations are carried out in the next optimization step, where the bond information is not valid under the calculation. All the parameters used in the present study (r _ij, D _ij) are reported in the supporting information (Supplementary Table S2).

The accurate structural optimization within higher-level theoretical approaches is performed at this step. We stress the fact that, in practical applications of this protocol, steps 2–4 should be carried out many times for sampling. It is not always granted that the former step succeeds in the generation of new bond-connections and different conformations of the isomer. It is recommended to carefully check the sets of the generated molecular structures before performing higher-level theoretical calculations, which is the most time-consuming. In our case, we adapted a procedure that makes use of two different levels of electronic structure calculation. In a first instance, we used a density functional theory (DFT) approach at the theoretical levels of B3LYP/6-31G and B3LYP/6-311++G(d,p). The DFT can properly reproduce the stable molecular structures and has been shown to be a viable way to be applicable to a high number of samplings. Zero-point vibrational energy (ZPE) corrections were evaluated at the B3LYP/6-311++G(d,p) theoretical level by performing frequency calculations. In the RC method, random samplings were performed for both connections and geometries. If the number of samplings is insufficient, a complete search for isomers is not pursued. Duplications that resulted in an identical molecule were used to check whether the sampling was sufficient. We found that 1000 samplings were sufficient to generate stable isomers for the present molecules (A-G). On a second instance, for the stable isomers, a more accurate ab initio method, CCSD(T)/cc-pVTZ, was used for a more accurate energy evaluation. The ZPE corrections for the CCSD(T) were obtained from the B3LYP/6-311++G(d,p) calculations.

All the electronic structure calculations were performed using the Gaussian16 program package (Frisch et al., 2016). Molecular structures shown in the figures were drawn using the visual molecular dynamics program (Humphrey et al., 1996).

3. Results and Analysis

3.1. Glycine isomers (C₂H₅NO₂, A)

Glycine is the simplest amino acid and is a fundamental constituent of the main chain of proteins. Moreover, glycine can be synthesized in the laboratory and has been found in meteorites. Theoretical studies have been performed to inspect the formation and molecular properties of glycine, with special attention to conformers and isomers. This makes glycine the best reference molecule with which to check the validity of our RC method. Ohno et al. (2021) showed that there are two isomers that are lower in energy, and hence more stable, than glycine by using their SHS-ADDF method.

The most stable isomer was identified as CH₃NHCOOCH (N-methylcarbamic acid, A1) with four conformations, and the second stable isomer was CH₃OCONH₂ (methyl carbamate, A2) with one conformer, more stable than glycine (A3). Glycine has two low-lying conformers (10.0, 10.7 kcal mol⁻¹), and NH₂COCH₂OH (glycolamide, A4) with two conformers (10.3, 10.9 kcal mol⁻¹) turned out to be energetically stable and comparable to the glycine isomers.

The RC method allowed for reproduction of the reported results, and three stable conformers of glycine were obtained (Table 1 and Fig. 4). These results suggest that glycine is not the most stable isomer in C₂H₅NO₂, and its energy is higher by 10.0 kcal mol⁻¹ relative to the most stable isomer. The formation of the C_α carbon, -NH-C_α-CO-, requires higher energy compared with the formation of the direct carbonyl-amino groups linkage, that is, the peptide bond (-NH-CO-). All these stable isomers contain the carbonyl group (-C = O-), and the other unsaturated bonds of the ethylene group (C = C) and imine group (C = N) are not relatively stable. NH₂CH₂OCHO (aminomethyl formate, A5) is the next stable isomer with respect to A4.

FIG. 4.

Stable isomers of the glycine composition (C₂H₅NO₂). Most stable conformers for each isomer (A1–A5) are shown. Glycine is A3. Here and in the following figures, a standard color code is used: gray for C, blue for N, red for O, and white for H. Molecular structures for all the stable conformational isomers (A1–A5) are shown in the supporting information (Supplementary Figure S1).

Table 1.

Relative Energies (ΔE) and Number of Stable Conformations (N _conf.) in Isomers in Glycine Composition (C₂H₅NO₂) as Obtained by the Random Connection Method

Isomer	ΔE, kcal mol⁻¹ ^a	N_conf. ^b	Molecule
A1	0 (0), 1.3 (1.4), 7.7 (6.7), 8.8 (8.0)	4 (4)	CH₃NHCOOH, N-methylcarbamic acid
A2	4.6 (4.7), 12.8 (12.0)	1 (1)	CH₃OCONH₂, methyl carbamate
A3	10.0 (8.4), 10.7 (9.4), 11.5 (10.1)	0 (0)	H₂NCH₂COOH, glycine
A4	10.3 (10.5), 10.9 (11.7)	0 (0)	H₂NCOCH₂OH, glycolamide
A5	18.0 (16.9)	0 (0)	NH₂CH₂OCHO, aminomethyl formate

ZPE corrected relative energies (ΔE) with respect to the most stable isomer at the theoretical level B3LYP//6-311++G(d,p). Relative energies computed at the CCSD(T)/cc-pVTZ level are shown in parentheses.

Number of stable conformations with respect to the most stable conformation of glycine (A3), whose ΔE is italics. Values in parentheses are the results obtained at the CCSD(T)/cc-pVTZ level.

ZPE = zero-point vibrational energy.

3.2. Alanine isomers (C₃H₇NO₂, B)

Given the reliability of the RC method in generating the stable isomers of glycine, we used this approach to search for alanine isomers (C₃H₇NO₂). After 1000 samplings, we obtained 4 isomers that were more stable than alanine: N-ethylcarbamic acid (CH₃CH₂NHCOOH, B1), ethylcarbamate (NH₂COOCH₂CH₃, urethane, B2), N-dimethylcarbamic acid [(CH₃)₂NCOOH, B3], and 2-hydroxypropanamide [NH₂COCH(OH)CH₃, B4]. The molecular structures are shown in Fig. 5, and their relative energies are summarized in Table 2.

FIG. 5.

Stable isomers of the alanine composition (C₃H₇NO₂). Most stable conformers for each isomer (B1–B11) are shown. Alanine is labeled as B5. All the chiral centers are indicated by an asterisk (*). Molecular structures for all the stable conformational isomers (B1–B11) are shown in the supporting information (Supplementary Figure S2).

Table 2.

Relative Energies (ΔE) and Number of Stable Conformations (N _conf.) in Isomers in Alanine Composition (C₃H₇NO₂) as Obtained by the Random Connection Method

Isomer^a	ΔE, kcal mol⁻¹ ^b	N_conf. ^c	Molecule
B1	0 (0), 1.4 (1.4), 7.5 (6.5), 9.1 (8.1)	4 (4)	CH₃CH₂NHCOOH, N-ethylcarbamic acid
B2	3.5 (3.7), 10.9 (10.6), 12.4 (11.8)	1 (1)	NH₂COOCH₂CH₃, ethylcarbamate
B3	7.5 (7.1), 15.9 (14.4)	1 (1)	(CH₃)₂NCOOH, N-dimethylcarbamic acid
B4^*	8.9 (9.3), 9.1 (8.7), 9.4 (9.5), 9.5 (9.5)	4 (4)	NH₂COCH(OH)CH₃, 2-hydroxypropanamide
B5^*	10.3 (7.9), 10.6 (8.3), 11.4 (9.2), 11.5 (9.0), 12.2 (9.6)	0 (0)	NH₂CH(CH₃)COOH, alanine
B6	10.4 (10.6)	0 (0)	NH₂COCH₂CH₂OH, 3-hydroxypropanamide
B7	10.9 (9.1), 11.1 (9.3), 11.4 (9.6), 11.9 (10.5), 12.9 (11.4)	0 (0)	NH₂CH₂CH₂COOH, 3-aminopropanoic acid (β-alanine)
B8	11.1 (11.9), 12.5 (13.2)	0 (0)	CH₃NHCOOCH₃, methyl methyl carbamate
B9	11.4 (11.9), 11.4 (11.9)	0 (0)	CH₃CONHCH₂OH, N-(hydroxymethyl)acetamide
B10	11.9 (11.4), 12.7 (12.8)	0 (0)	NH₂CH₂OCOCH₃, aminomethyl formate
B11^*	13.6 (13.2)	0 (0)	CHONHCH(OH)CH₃, N-(1-hydroxyethyl)formate

Isomers contain a chiral center are marked by asterisk.

Number of stable conformations with respect to the most stable conformation of alanine (B5), whose ΔE is italics. Values in parentheses are the results obtained at the CCSD(T)/cc-pVTZ level.

Alanine (B5) is energetically located at 10.3 kcal mol⁻¹ above the most stable molecule, B1. Compared with the isomers of glycine, the stable isomers of alanine can be rationalized in terms of methyl-group substitutions to the glycine isomers. For example, the methyl group substitutions of A1 at the methyl group hydrogen, amide group hydrogen, and carboxyl group hydrogen generate the isomers B1, B3, and B8 [A1 → (B1, B3, B8)].

In an analogous way, other stable isomers of alanine can be realized as follows: A2 → B2, A3 → B5, A4 → (B4, B9), and A5 → B10, where the arrow “→” indicates a methyl group substitution. According to the relation of the methyl group substitution, the higher energy state of alanine (10.3 kcal mol⁻¹) is related to the higher energy state of glycine (10.0 kcal mol⁻¹), because A3 and B5 carry the same α-amino acid structure, and the most stable isomers A1 and B1 share the same molecular framework with a carbamic acid group (-NHCOOH).

It should be mentioned that there are no stable isomers that contain the ethylene group and imine in the stable isomers of alanine. It is also expected that all the monomer forms of the amino acids are characterized by an instability in comparison with the isomers, because the main chain part of the amino acid, NH₂-CH-COOH, is energetically located at a higher value with respect to the methylcarbamic acid part (-CH₂-NH-COOH).

3.3. Alaninamide isomers (C₃H₈N₂O, C)

As alanine is not the most stable isomer in C₃H₈N₂O, we turned our investigation to the alanine derivative, alaninamide. For this system, Fig. 6 and Table 3 show the molecular structures and summarize their relative energies. We found that only the N-ethylurea (C1) is more stable than alanineamide (C2). Indeed, C2 is energetically located 5.7 kcal mol⁻¹ above C1. C1 can assume four stable conformations that differ in the conformation of the amino and ethyl groups.

FIG. 6.

Stable isomers of the alaninamide composition (C₃H₈N₂O). Most stable conformers for each isomer (C1–C8) are are shown. Alanineamide is labeled as C2. All the chiral centers are indicated by an asterisk (*). Molecular structures for all the stable conformational isomers (C1–C8) are shown in the supporting information (Supplementary Figure S3).

Table 3.

Relative Energies (ΔE) and Number of Stable Conformations (N _conf.) for Isomers in Alaninamide Composition (C₃H₈N₂O) as Obtained by the Random Connection Method

Isomer^a	ΔE, kcal mol⁻¹ ^b	N_conf. ^c	Molecule
C1	0 (0), 0.2 (0.5), 1.2 (1.6), 1.6 (1.7)	4 (4)	NH₂CONHCH₂CH₃, N-ethylurea
C2^*	5.7 (4.4), 5.8 (4.7), 7.5 (6.2), 8.4 (6.9), 9.0 (7.6)	0 (0)	NH₂CHCH₃CONH₂, alaninamide
C3	7.1 (6.6), 8.2 (7.4), 8.8 (8.0), 9.5 (9.3)	0 (0)	NH₂CH₂CH₂CONH₂, 3-amino propan amide
C4	7.2 (7.8), 8.1 (9.0), 12.8 (13.2)	0 (0)	CH₃NHCONHCH₃, N,N′-dimethylurea
C5	8.3 (7.8)	0 (0)	(CH₃)₂NCONH2, N,N-dimethylurea
C6	8.9 (8.8), 10.0 (10.3), 12.2 (12.1)	0 (0)	NH₂CH₂NHCOCH₃, N-(aminomethyl) acetamide
C7	11.7 (12.1)	0 (0)	NH₂CH₂CONHCH₃, 2-amino-N-methylacetamide
C8^*	12.2 (11.1)	0 (0)	NH₂CH(CH₃)NHCHO, N-(1-aminoethyl)formamide

Isomers contain a chiral center are marked by asterisk.

Number of stable isomers with respect to the most stable conformation of alanine amide (C2), whose ΔE is italics. Values in parentheses are the results obtained at the CCSD(T)/cc-pVTZ level.

The isomers whose stability is comparable to C2 are 3-amino propan amide (C3), N,N′-dimethylurea (C4), N,N-dimethylurea (C5), and N-(aminomethyl)acetamide (C6). The 2-Amino-N-methylacetamide (C7) and N-(1-aminoethyl)formamide (C8) are still existing isomers; however, they are located at higher relative energies than C2 (11.7, 12.2 kcal mol⁻¹).

C1, C4, and C5 are all urea derivatives. From the viewpoint of group substitution, C1 is an aminated compound of B1 at the carboxyl hydroxy group, and C1 is also related to an aminated compound of B2 at the carboxyl ether group. Similarly, C2 is related to both B5 and B4. The relatively higher stability of C2 compared with B5 (10.3 kcal mol⁻¹) can be explained by the substitution relation of B4 → C2 (5.7 kcal mol⁻¹). Another remarkable feature in the alaninamide isomers (C) is that the β-amino amide (C3) becomes the next stable isomer to the α-amino acid (C2). This feature was observed for the alanine isomers (B7).

3.4. 2-Aminopropanal isomers (C₃H₇NO, D)

In the ensemble of systems that have the C₃H₇NO composition, we found that there are eight isomers more stable than 2-aminopropanal (D9) (Fig. 7). These stable isomers are propanamide (D1), N-methylacetamide (D2), N-ethylformamide (D3), propanimidic acid (D4), N,N-dimethylformamide (D5), 1-aminopropan-2-one (D6), N-methylethanimidic acid (D7), and ethylmethanimidic acid (D8). At variance with these eight stable structures, D9 is higher in energy than the most stable isomer D1 by 23.9 kcal mol⁻¹ (Table 4).

FIG. 7.

Stable isomers of the 2-aminopropanal composition (C₃H₇NO). Most stable conformers for each isomer (D1–D12) are shown. 2-Aminopropanal is labeled as D9. All the chiral centers are indicated by an asterisk (*). Molecular structures for all the stable conformational isomers (D1–D12) are shown in the supporting information (Supplementary Figure S4).

Table 4.

Relative Energies (ΔE) and Number of Stable Conformations (N _conf.) for Isomers in 2-Aminopropanal Composition (C₃H₇NO) as Obtained by the Random Connection Method

Isomer^a	ΔE, kcal mol⁻¹ ^b	N_conf. ^c	Molecule
D1	0 (0), 1.0 (1.2)	2 (2)	NH₂COCH₂CH₃, propanamide
D2	4.2 (5.1), 6.8 (7.5), 6.8 (7.5)	3 (3)	CH₃NHCOCH₃, N-methylacetamide
D3	8.8 (9.3), 9.6 (10.4)	2 (2)	CH₃CH₂NHCHO, N-ethylformamide
D4	13.2 (10.5), 16.6 (13.6), 16.8 (13.9), 17.4 (14.6)	4 (4)	HN = C(OH)CH₂CH₃, propanimidic acid
D5	14.3 (14.5)	1 (1)	(CH₃)₂NCHO, N,N-dimethylformamide
D6	17.9 (17.0), 18.7 (18.0), 19.9 (19.1), 20.8 (19.9)	4 (4)	NH₂CH₂COCH₃, 1-aminopropan-2-one
D7	19.0 (17.6), 21.5 (19.6)	2 (2)	CH₃NC(CH₃)OH, N-methylethanimidic acid
D8	23.7 (22.0), 25.9 (23.5), 26.0 (24.4), 27.0 (25.2), 27.8 (25.9)	1 (0)	CH₃CH₂N = CHOH, ethylmethanimidic acid
D9^*	23.9 (21.7), 23.9 (21.7), 24.6 (22.9), 24.9 (22.6), 24.9 (22.9), 25.1 (23.0)	0 (0)	NH₂CH(CH₃)CHO, 2-aminopropanal
D10	24.7 (22.6)	0 (0)	CH₃C = NHOCH₃, methyl ethanimidate
D11	25.2 (23.4), 25.9 (24.1), 26.1 (24.7), 26.3 (24.8), 26.8 (25.4), 26.9 (25.5), 27.0 (25.8), 27.2 (25.8), 27.2 (26.1)	0 (0)	NH₂CH₂CH₂CHO, 3-aminopropanal
D12	32.7 (31.7)	0 (0)	CH₃N = CHOCH₃, methyl methylmethanimidate

Isomers contain a chiral center are marked by asterisk.

Number of stable isomers with respect to the most stable conformation of 2-aminopropanal (D9), whose ΔE is italics. Values in parentheses are the results obtained at the CCSD(T)/cc-pVTZ level.

The number of conformations of the stable isomers is 2, 3, 2, 4, 1, 4, 2, and 1 for all the systems from D1 to D8 in this order. The stable isomers of D1, D2, D3, and D5 are all amide compounds, and various chemical species can be present, not only with the carbonyl group (C = O) but also with the hydroxyl group (D4) and with the ether group (D10) in the energy range around the value of D9. Concerning the nitrogen compound, the imine group (C = N) also confers a relative stability to the compounds D4, D7, D8, and D10 next to the amide compounds.

Other stable isomers above D10 are 3-aminopropanal (D11) and methyl methylmethanimidate (D12). For the group substitution, the analogy with alanine can be seen by replacing a hydroxy group with a hydrogen atom. By substitution at the carboxy group, the following correspondence can be inferred: B1 → D3, B3 → D5, B5 → D9, and B7 → D11. Similarly, by substitution at the hydrocarbon, the correspondence becomes B4 → D1, B6 → D1, and B9 → D2. The latter substitution contributes toward stabilizing the isomers.

Another correspondence worthy of note is the tautomerization of amide (-NH-CO-) into imidic acid [-N = C(OH)-]. The analogies that arise in this case are D1 → D4, D2 → D7, and D3 → D8. Due to the relative abundance of more stable isomers, 2-aminopropanal (D9) cannot be regarded as a stable isomer for the C₃H₇NO composition.

3.5. 2-Aminopropanenitrile isomers (C₃H₆N₂, E)

As a further step in our investigation, we focused on the isomers of amid nitril, NH₂CH(CH₃)CN. We found that the most stable form is 2-aminopropanenitrile (E1) (Fig. 8). The second stable isomer is 3-aminopropanenitrile (E2), and the relative energy with respect to E1 is only 0.1 kcal mol⁻¹ (Table 5). The energy difference becomes 0.9 kcal mol⁻¹ at the more accurate theoretical level, CCSD(T)/cc-pVTZ (Table 5). Other stable isomers are propanimidamide (E3), ethylcyanamide (E4), imidazoline (dihydro imidazole, E5), N-ethylmethanimidamide (E6), propane-1,2-diimine (E7), and (methylamino)acetonitrile (E8), and they are also comparable in stability to E1, having relative energies of 3.5, 4.1, 5.3, 6.3, 7.3, and 7.9 kcal mol⁻¹, respectively.

FIG. 8.

Stable isomers of the 2-aminopropanenitrile composition (C₃H₆N₂). Most stable conformers for each isomer (E1–E8) are shown. 2Aaminopropanenitrile is labeled as E1. All the chiral centers are indicated by an asterisk (*). Molecular structures for all the stable conformational isomers (E1–E8) are shown in the supporting information (Supplementary Figure S5).

Table 5.

Relative Energies (ΔE) and Number of Stable Conformations (N _conf.) for Isomers in 2-Aminopropanenitrile Composition (C₃H₇NO) as Obtained by the Random Connection Method

Isomer^a	ΔE, kcal mol⁻¹ ^b	Molecule
E1^*	0 (0), 1.8 (1.6), 1.9 (1.8)	NH₂CH(CH₃)CN, 2-aminopropanenitrile
E2	0.1 (0.9), 0.2 (0.9), 0.5 (1.4), 0.6 (1.7), 1.5 (2.4)	NH₂CH₂CH₂CN, 3-aminopropanenitrile
E3	3.5 (7.8), 4.2 (8.6), 4.5 (8.8), 4.7 (11.9)	NH₂(CH₂CH)C = NH, propanimidamide
E4	4.1 (6.7), 4.1 (6.8), 4.3 (6.8)	NCNCH₂CH₃, ethylcyanamide
E5	5.3 (6.8)	NCH₂NHCH₂CH_2, imidazoline
E6	6.3 (12.8)	HN = CHNHCH = CH₂, N-ethylmethanimidamide
E7	7.3 (9.7)	HN = CH(CH₃)C = NH, propane-1,2-diimine
E8	7.9 (8.9), 9.5 (10.6)	CH₃NHCH₂CN, (methylamino)acetonitrile

Isomers contain a chiral center are marked by asterisk.

Number of stable conformations with respect to the most stable conformation of 2-aminopropanenitrile (E1), whose ΔE is italics. Values in parentheses are the results obtained at the CCSD(T)/cc-pVTZ level.

Imidazoline (E5) is characterized by a five-membered ring structure, and the molecular framework is different from other isomers. Amide compounds (-CN) confer stability to the isomers E1, E2, and E4, and other isomers that have the imine group (C = N) accompany an unsaturated bond or ring formation. The reason for higher stability of E1 can be ascribed to the fact that the nitril group does not become a linker but acts only as a terminal block and prefers to form a chemical bond with C atom in comparison with N atom of, for example, E4. Hence, in this case the most stable isomer turns out to be α-amid nitrile (E1), followed by β-amid nitrile (E2).

3.6. Lactic acid isomers (C₃H₆O₃, F)

Isomers of lactic acid, 2-hydroxypropanoic acid [HOCH(CH₃)COH], were our next target. We found that only etabonic acid (F1) is more stable than lactic acid (F2) by 3.2 kcal mol⁻¹ (Table 6 and Fig. 9). F1 has four stable conformations energetically lower than F2. The higher energy isomers are 3-hydroxypropanoic acid (F3), hydroxymethyl acetate (F4), and 1-hydroxyethyl formate (F5), which is still located on the energy scale at a value lower than 10 kcal mol⁻¹. Compared with the alanine isomers (B), group substitution from the amide group (-NH-) to the oxygen atom (-O-) shows close correspondence, specifically (B1, B2) → F1, (B4, B5) → F2, (B6, B7) → F3, (B9, B10) → F4, and B11 → F5.

FIG. 9.

Stable isomers of the lactic acid composition (C₃H₆O₃). Most stable conformers for each isomer (F1–F5) are shown. Lactic acid is labeled as F2. All the chiral centers are indicated by an asterisk (*). Molecular structures for all the stable conformational isomers (F1–F5) are shown in the supporting information (Supplementary Figure S6).

Table 6.

Relative Energies (ΔE) and Number of Stable Conformations (N _conf.) for Isomers in Lactic Acid Composition (C₃H₆O₃) as Obtained by the Random Connection Method

Isomer^a	ΔE, kcal mol⁻¹ ^b	N_conf. ^c	Molecule
F1	0 (0), 0.7 (1.2), 1.0 (1.2), 3.2 (3.6), 11.1 (10.8)	4 (3)	CH₃CH₂OCOOH, etabonic acid
F2^*	3.2 (3.2), 5.1 (5.6), 5.2 (5.7)	0 (0)	CH₃CH(OH)COOH, lactic acid
F3	4.0 (4.5), 5.8 (6.8)	0 (0)	CH₂(OH) CH₂COOH, 3-hydroxypropanoic acid
F4	6.4 (7.2)	0 (0)	CH₃COOCH₂OH, hydroxymethyl acetate
F5^*	8.6 (8.7), 11.3 (11.0)	0 (0)	CH₃CH(OH)OCHO, 1-hydroxyethyl formate

Isomers contain a chiral center are marked by asterisk.

Number of stable conformations with respect to the most stable conformation of lactic acid (F2), whose ΔE is italics. Values in parentheses are the results obtained at the CCSD(T)/cc-pVTZ level.

In this substitution, B3 with the secondary carbamate group has no corresponding isomer in the lactic acid isomers (F). From the substitution relation, lactic acid resembles alanine in terms of isomer stability (B1 → F1, B5 → F2). β-Hydroxycarbonate F3 can be found at an energy slightly higher than α-hydroxycarbonate F2. This characteristic is observed also in other alanine compounds (B7, C3, D11, E2).

3.7. Lactonitrile isomers (C₃H₅NO, G)

To complete our study, we sought the isomers of hydroxy nitril, HOCH(CH₃)CN. In this case, we found that two isomers are more stable than 2-hydroxypropanenitrile (G3) (Fig. 10). These isomers are isocyanatoethane (G1) and 3-hydroxypropanenitrile (G2). The isocyanato compound G1 is significantly more stable than the hydroxy nitrile compounds G2 and G3 [ΔE(G2) = 15.5 kcal mol⁻¹ and ΔE(G3) = 16.5 kcal mol⁻¹] (Table 7).

FIG. 10.

Stable isomers of lactonitrile composition (C₃H₅NO). Most stable conformers for each isomer (G1–G6) are shown. Lactonitrile is labeled as G3. All the chiral centers are indicated by an asterisk (*). Molecular structures for all the stable conformational isomers (G1–G6) are shown in the supporting information (Supplementary Figure S7).

Table 7.

Relative Energies (ΔE) and Number of Stable Conformations (N _conf.) for Isomers in Lactonitrile Composition (C₃H₅NO) as Obtained by the Random Connection Method

Isomer^a	ΔE, kcal mol⁻¹ ^b	N_conf. ^c	Molecule
G1	0 (0)	1 (1)	CH₃CH₂-N = C = O, isocyanatoethane
G2	15.5 (9.7), 15.8 (10.4), 16.3 (10.8), 16.6 (11.0), 17.3 (11.6)	3 (1)	NCCH₂CH₂OH, 3-hydroxypropanenitrile
G3^*	16.5 (10.3), 16.8 (10.5), 18.3 (11.8)	0 (0)	CH₃CH(OH)CN, 2-hydroxypropanenitrile
G4	21.3 (15.5)	0 (0)	c-CH₂CH₂NCHO-, 4,5-dihydro-1,3-oxazole
G5	27.9 (23.6), 28.2 (23.7)	0 (0)	CH₃CH₂OCN, ethyl cyanate
G6	28.6 (22.9)	0 (0)	c-CH₂CH = NCH₂O-, 2,5-dihydro-1,3-oxazole

Isomers contain a chiral center are marked by asterisk.

Number of stable conformations with respect to the most stable conformation of lactonitrile (G3), whose ΔE is italics. Values in parentheses are the results obtained at the CCSD(T)/cc-pVTZ level.

Hydroxypropanenitriles (G2, G3) can assume three conformations as a result of the rotation of the hydroxy group. β-Hydroxynitrile G2 is slightly lower in energy than α-hydroxynitrile G3. The five-membered ring isomers of the dihydro-oxazoles (G4, G5) are characterized by higher energies with respect to G3 [ΔE(G4) = 21.3 kcal mol⁻¹ ΔE(G5) = 27.9 kcal mol⁻¹]. Ethyl cyanate (G6) is further located at a higher energy [ΔE(G6) = 28.6 kcal mol⁻¹]. Having assessed the high stability of G1, a correspondence of hydroxy nitrils (G) with amid nitrils (E) can be established by introducing a substitution of an amid (NH₂) to the hydroxy (OH): E1 → G3, E2 → G2, E4 → G6, E5 → G4. As the order of these substitutions is different, the stabilities in the isomers between the amid nitrils (E) and hydroxynitriles (G) differ consistently with this reordering.

3.8. Origin of homochirality

The present results indicate that the thermodynamical stability of amino nitrile is remarkably advantageous, and that amino nitrile is a key chiral molecule in comparison with other precursors and amino acids in the interstellar and circumstellar medium. Recently, the first chiral molecule, propylene oxide, was detected in Sagittarius (Sgr) B2(N) (McGuire et al., 2016). Theoretical investigations carried out by Hori and coworkers suggest that the photolysis of propylene oxide or a cation precursor can induce the homochirality (Hori et al., 2022).

If the enantiomeric excess of chiral isomer generates from photoreactions under circular polarized light (Fukushima et al., 2020), the most stable and longest-living species, aminonitriles, become the best candidates responsible for the enantiomeric excess of amino acids. Therefore, we expect that the 2-aminopropanenitrile (3-aminopropanenitrile) might be a crucial molecule that contributes to the origin of homochirality for all the chiral α-amino acids (β-amino acids). Although 2-aminopropanenitrile has not yet been detected in Sgr B2(N) (Møllendal et al., 2012), observations and analyses for aminonitriles are worth consideration as targets.

On the other hand, aminoacetonitrile, the precursor of glycine, has been detected in Sgr B2 (Belloche et al., 2008). Amino acids are much less stable than nitriles on UV irradiation and cosmic rays in interstellar regions (Bernstein et al., 2004). Previous theoretical studies have shown that the formation of aminoacetonitrile requires the overcoming of a relatively low energy barrier (ΔU = 8–9 kcal mol⁻¹), though the hydrolysis of aminoacetonitrile to glycine is characterized by a higher electronic energy barrier (ΔU = 27-34 kcal mol⁻¹), which cannot proceed at cryogenic temperatures (Woon, 2008; Rimola et al., 2010).

Assuming a typical temperature of T < 100K in the molecular cloud, the energy differences of ΔE = 3.2 and 5.7 kcal mol⁻¹ correspond to the population differences of less than 1.0 × 10⁻⁷ and 3.5 × 10⁻¹³ according to the Boltzmann distribution. It should be noted that abundance in the ISM is not only determined exclusively by thermal stability but also by environmental effects, such as adsorption and reactivity with atomic hydrogen, which can contribute to abundance as well (Fourré et al., 2020). Nonetheless, it becomes clear that a small relative energy difference of even ΔE = 3.2 kcal mol⁻¹ contributes to the relative probability in the ISM.

These reactions are deeply different from ordinary chemical reactions that occur in the laboratory at T = 300K, which can overcome energy barrier up to the values of about ΔE = 20 kcal mol⁻¹ by thermal activation (Shoji et al., 2022).

3.9. Limitation of the present theoretical approach

In the present theoretical investigation, amino acids and their chiral precursors are assumed to be in the gas phase. In the ISM, the dominant molecular formation occurs on the surface of dust and ice, and the processes of adsorption and diffusion of molecules on the surfaces can play a role in the chemical evolution of interstellar molecules (Vidali, 2013; Wakelam et al., 2017; Kayanuma et al., 2017). Indeed, isomers of isocyanic acid (HNCO) have been shown to be characterized by different adsorption energies with an upper limit of 19.4 kcal mol⁻¹ (Lattelais et al., 2015).

Nonetheless, even for the large perturbation on relative energies due to surfaces adsorption, HNCO and HOCN isomers remain the most and the second-most stable isomers, respectively. Thus, this energetic order is not jeopardized by the vicinity of an adsorbing surface. This is consistent with our results, and it is confirmation that the relative energies obtained in the gas phase (MEP) are reliable and represent a reliable predictive quantity for the identification of molecules. Further theoretical investigations on the relative stabilities on icy surfaces will be desirable and represent the target of forthcoming studies.

4. Conclusion

To investigate the stabilities of alanine and the related chiral molecules among their isomers, six chiral molecules formed during prebiotic processes and achiral glycine were targeted in the present theoretical study. The molecular mechanism of the formation of homochirality of amino acids is intimately related to the origin of life on Earth. The molecules of amino acids and their precursors are of a large size compared with molecules detected in ISM, and their conformational isomers as well as their structural isomers should be searched explicitly for their relative stabilities.

The approach originally proposed by Fourré et al. (2016, 2020) has been demonstrated to be efficient for the search for ISM molecules provided that the number of conformers is not too large. Nonetheless, it can fail in finding exhaustively all the relevant conformers and unexpected bonding, especially for larger and complex molecules. To overcome this difficulty, we developed a new isomer search algorithm, referred to as the RC method, by introducing random selections for the degrees of freedoms of bond connection and conformation.

The successful application of the RC method to glycine allowed us to move to the actual target of this study. More precisely, two isomers, N-methylcarbamic acid (A1) and methyl carbamate (A2), could be obtained and their more stable four and one conformers were obtained completely for A1 and A2, respectively. Glycine (A3) remains higher in energy than the most stable isomer by ΔE(A3) = 10.0 kcal mol⁻¹. All the energetics obtained at the B3LYP were refined within the CCSD(T) approach. Relative energies computed at the CCSD(T) level, shown in parentheses in Tables 1–7, turned out to be qualitatively similar to those obtained at the B3LYP//6–311++G(d,p) level. Hence, our analysis was mainly based on the B3LYP/6-311++G(d,p) results. Moreover, CCSD(T) calculations become clearly computationally demanding for larger-sized molecules.

The RC method was applied to chiral molecules, including alanine and alanine precursors. Based on the relationship of the molecular frameworks in different compositions, we found that there are structural similarities between the stable isomers. Among the stable isomers of alanine and alanine precursors (B–E), all the most stable ones—B1, C1, D1—assume a linear chain framework like N-ethylcarbamic acid (B1) with the ethyl group, whereas alanine and the precursors (B5, C2, D9), which have the α-amino acid framework like alanine (B5), are all higher energy isomers by more than 5.7 kcal mol⁻¹. All the structural correlations to the alanine isomers under the group substitutions are summarized in the supporting information (Supplementary Table S3).

The higher energies of α-amino acid and the precursors can be explained by the group substitutions; the main chain part of the amino acid, NH₂-CH-COOH, is higher in energy with respect to the methylcarbamic acid part (-CH₂-NH-COOH).

Analogously, the hydroxy acids and the precursors (F and G) have the same relationship as alanine; however, only the α-hydroxy acid (F2) is energetically as low as 3.2 kcal mol⁻¹. This result suggests that stability among the isomers during the formation of α-hydroxy acid is highest in lactic acid (F2). Another remarkable feature is the fact that the corresponding isomers of the β-amino/hydroxy acid are similarly stable over the precursors (B7, C3, D11, E2, F3, G2) comparable to those of the α-amino/hydroxy acid (B5, C2, D9, E1, F2, G3). This feature can explain the wide variety of amino acids detected in meteorites.

Despite their structural similarities to B5, 2-aminopropanenitrile (E1) is the most stable among the isomers. This unique property of E1 can be ascribed to two different features: On the one hand, the amino and nitrile groups are not stably bonded, and on the other hand, the nitrile group acts as a terminal moiety in the molecular structure. Additional structural correlations between 2-aminopropanenitrile isomers (E) and lactonitrile isomers (G) under the group substitutions are summarized in the supporting information (Supplementary Table S4).

The intrinsic stability of 2-aminopropanenitrile is a convincing piece of evidence on which the origin of homochirality of amino acids can be rationalized. To generate the enantiomeric excesses of l-amino acids, the aminonitrile state is a fundamental element, given that it is the easiest to form and the one characterized by the longest lifetime. As such, it plays a major role in the enantiomeric excess issue. The aminonitrile intermediates are promising candidates to induce the homochirality of amino acids in prebiotic syntheses.

In this respect, this work can stimulate forthcoming theoretical and experimental investigations to consolidate or disprove the outcome of our modeling.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research was supported by JST, PRESTO Grant Number JPMJPR19G6, Japan and JSPS KAKENHI grant numbers 19H00697, 20H05453, 20H05088, and 22H04916. This work used computational resources of (1) Cygnus system through Multidisciplinary Cooperative Research Program in CCS, University of Tsukuba, and (2) supercomputer Fugaku provided by the RIKEN Center for Computational Science (Project ID: hp210115). Mauro Boero thanks the HPC Center at the University of Strasbourg funded by the Equipex Equip@Meso project and the CPER Alsacalcul/Big Data, and the Grand Equipement National de Calcul Intensif (GENCI) under allocation DARI-A0100906092.

Supplementary Material

Supplementary Figure S1

Supplementary Figure S2

Supplementary Figure S3

Supplementary Figure S4

Supplementary Figure S5

Supplementary Figure S6

Supplementary Figure S7

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Abbreviations Used

Associate Editor: Michael C. Storrie-Lombardi

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Supplementary Material

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Comprehensive Search of Stable Isomers of Alanine and Alanine Precursors in Prebiotic Syntheses

Abstract

1. Introduction

2. Methods

3. Results and Analysis

3.1. Glycine isomers (C2H5NO2, A)

3.2. Alanine isomers (C3H7NO2, B)

3.3. Alaninamide isomers (C3H8N2O, C)

3.4. 2-Aminopropanal isomers (C3H7NO, D)

3.5. 2-Aminopropanenitrile isomers (C3H6N2, E)

3.6. Lactic acid isomers (C3H6O3, F)

3.7. Lactonitrile isomers (C3H5NO, G)

3.8. Origin of homochirality

3.9. Limitation of the present theoretical approach

4. Conclusion

Footnotes

Author Disclosure Statement

Funding Information

Supplementary Material

Abbreviations Used

References

Supplementary Material

3.1. Glycine isomers (C₂H₅NO₂, A)

3.2. Alanine isomers (C₃H₇NO₂, B)

3.3. Alaninamide isomers (C₃H₈N₂O, C)

3.4. 2-Aminopropanal isomers (C₃H₇NO, D)

3.5. 2-Aminopropanenitrile isomers (C₃H₆N₂, E)

3.6. Lactic acid isomers (C₃H₆O₃, F)

3.7. Lactonitrile isomers (C₃H₅NO, G)