Reaction Routes for Experimentally Observed Intermediates in the

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Reaction Routes for Experimentally Observed Intermediates in the Prebiotic Formation of Nucleobases under High Temperature Conditions Yassin Aweis Jeilani, Brooke Ross, Nasrin Aweis, Chelesa Fearce, Huynh Minh Hung, and Minh Tho Nguyen J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b11466 • Publication Date (Web): 23 Feb 2018 Downloaded from http://pubs.acs.org on February 24, 2018

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The Journal of Physical Chemistry

Reaction Routes for Experimentally Observed Intermediates in the Prebiotic Formation of Nucleobases under High Temperature Conditions Yassin A. Jeilani,1,2* Brooke Ross,1 Nasrin Aweis,1 Chelesa Fearce,1 Huynh Minh Hung3 and Minh Tho Nguyen3,* 1

Department of Chemistry and Biochemistry, Spelman College, 350 Spelman Lane, S.W., Box 1134, Atlanta, GA 30314 2

Department of Chemistry, College of Science, University of Hail, Hail, Saudi Arabia

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Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium

*) Corresponding Authors: YJ: [email protected] (404-270-5746); MTN: [email protected] ((32)–16–327-361)

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Abstract The prebiotic synthesis of nucleobases is of particular interest, given the experimental evidence that indicated formation of the nucleobases under abiotic conditions on the Early Earth under high temperature conditions. Biomolecules have been formed under meteoritic impact scenarios that lead to high-temperature and the generation of high-energy. Free radical pathways for the formation of biomolecules are appropriate under these conditions. Density functional theory computations were used to study the free radical routes for the formation of nucleobases at the UB3LYP/6-311G(d,p) level. We have found that both 5-aminoimidazole-4-carboxamide (AICA) and 5-formylaminoimidazole-4-carboxamide (fAICA) are formed first from formamide then the nucleobases are formed. Calculated results show the radical reaction routes of AICA as a precursor for guanine. Both hypoxanthine and xanthine are formed from radical pathways of fAICA. In addition, generation of imino-AICA and imino-fAICA has been shown for the first time to be needed for the production of adenine, purine, and isoguanine. Formation of hypoxanthine and adenine/purine from fAICA and imino-fAICA, respectively, is consistent with experiments performed nearly seven decades ago.

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1. Introduction Prebiotic chemistry is an exciting, yet challenging, field of science because of the lack of sufficient evidence on the conditions on the Early Earth that led to the formation of biomolecules. Indeed, simulation experiments have been often reported to mimic those conditions.1,2 It is hypothesized that Early Earth was exposed to the solar irradiation which would have provided enough energy to initiate chemical reactions.3,

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In addition, simulation

experiments showed that biomolecules including nucleobases can be formed in hydrothermal pores and meteoritic impacts on Early Earth.1 These studies have been critical in predicting the conditions that may have led to the abiotic formation of the first biomolecules. The prebiotic scenarios that led to the chemical reactions on Early Earth for the buildup of biomolecules are essential in understanding the type of reactions that may have led to the accumulation of biomolecules.5 Formation of nucleobases has been reported under meteoritic impact conditions. This impact scenario lead to high temperature that induce the initial formation of free radicals.6 Simulation experiments on high-energy impact scenario on Earth showed the formation of small radicals such as •CN from formamide. These reactive radicals react with formamide to form intermediates that lead to the formation of nucleobases. The proposed pathways in the current study are appropriate for the formation of the nucleobases under such high-temperature conditions. The bottom-up approach on the origin of biomolecules is to understand the reaction pathways that led to the buildup of complex molecules starting from simple precursors such as formamide. Recently, free radical pathways have been proposed as plausible mechanisms for formation of a mixture of nucleobases.7-10 Alternative scenario for the origin of biomolecules is that the biomolecules may have been formed extraterrestrially11 then delivered upon meteoritic

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impact on early Earth. The radical pathways are also feasible for the formation of the nucleobases under these extraterrestrial conditions that promote the formation of free radicals. Hydrogen cyanide (HCN) is a primary prebiotic precursor that led to the formation of secondary precursors such as formamide (upon hydration).12-14 Wide range of biomolecules including nucleobases are formed from formamide.15-17 Intermediates have been identified and experimentally explored in these reactions. Formation of 5-aminoimidazole-4-carboxamide (AICA) and 5-formylaminoimidazole-4-carboxamide (fAICA) was reported in the reactions of formamide in the presence of montmorillonites.18 Both fAICA and AICA were found as intermediates in the isoguanine pathway.18 Zubay and coworkers reported that hypoxanthine is formed from AICA and ammonium formate that serves as a source of the formyl group.19 Barks et al. reported on formation of nucleobases from either heated or UV irradiated reactions of formamide solutions.20 They found that reactions of UV irradiated formamide spiked with AICA led to greater yield of hypoxanthine. This experiment suggested that AICA is a precursor toward the synthesis of hypoxanthine from formamide. This is consistent with the observations reported by Zubay and coworkers.18 Ferus et al. used high energy laser pulses to simulate extraterrestrial-body impact on early Earth that may have led to nucleobases from formamide.6 They proposed 4-amino-1H-imidazole-5-carbonitrile (AICN) as an intermediate toward both adenine and guanine. According Shaw, AICA leads to both guanine and xanthine as proposed in Scheme 1.21 He also reported that imino-AICA leads to imino-fAICA then to adenine (Scheme 1). Hypoxanthine is formed when AICA is heated in formamide at 185 °C.21 The proposed framework in Scheme 1 is consistent with these studies. There are distinct precursors along the

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pathways that lead to the various nucleobases. Further studies of the step-by-step mechanisms are currently needed to confirm these experimental observations. The reactive free radicals are appropriate for the bottom-up approach for the synthesis of biomolecules under high temperature conditions. We have reported earlier on possible generation of multiple nucleobases starting from formamide or acetylene through free radical pathways.7-9, 22-24

These radical reactions proceed with relatively low energy barriers. The energy barriers

range from barrierless upto 35 kcal/mol.23 In some cases, the barriers can reach as high as 45 kcal/mol.

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Ferus et al demonstrated that both cyanide and formamide radicals are involved in

these reations.6 This group also found the presence of these nucleobases from formamide using high energy and CN radicals.25 Free radical pathways that proceed through experimentally known intermediates have not yet been reported. In this context, we set out to focus on reaction pathways giving rise to nucleobases through experimentally observed intermediates. The pathways were constructed by computations using density functional theory. From calculated results showing radical reaction profiles with relatively low energy barriers, we propose mechanisms that lead first to the formation of both 5-amino- 4-imidazole carboxamide (AICA) and 5-formylaminoimidazole-4-carboxamide (fAICA), and from the latter to a few nucleobases including guanine, isoguanine, adenine, purine, xanthine and isoxanthin. These findings also provide a further support for the abiotic formation of isoguanine that we previously reported.22 Overall, the present theoretical study confirms the existence of some key intermediates that have been previously observed in experiments.

2. Computational Methods

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All electronic structure calculations using density functional theory (DFT) were performed with the aid of the GAUSSIAN 09 suite of programs.26 The popular hybrid B3LYP functional,27,

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in conjunction with the 6-311G(d,p) basis set29 was used for all calculations.

Harmonic vibrational frequency calculations were carried out at the same level in order to confirm the nature of stationary points and to obtain zero-point vibrational energies (ZPE). Each transition structure was characterized by having one imaginary vibrational frequency for the normal mode corresponding to the correct reaction coordinate. Our recent theoretical studies8, 23 pointed out that the B3LYP functional is suitable for investigating reaction pathways involving formamide. The use of this DFT method, in the unrestricted formalism (UB3LYP), allows us to avoid the severe spin-contamination usually encountered in the UHF and UMP2 computations for open-shell radicals, in particular for the radical CN. A uniform scaling factor of 0.967 was used for the ZPE values when calculating the relative energies of the structures considered. Computational

resources

provided

by

XSEDE30

available

at

the

Gridchem

(http://www.gridchem.org) were used to perform quantum chemical calculations.31, 32

3. Results and Discussions There is sufficient experimental evidence that both AICA and fAICA are involved in the pathways leading to nucleobases from formamide. The main focus of the present computations concerns these pathways with both AICA and fAICA as precursors for the nucleobases. We explored the pathways for the formation of nucleobases through these experimentally observed intermediates. For the first time, we show that AICA and fAICA are indeed precursors for nucleobases. One of the first relevant facts revealed by our computations is that both AICA and fAICA are precursors to hypoxanthine, guanine, and xanthine. On the other hand, the imino-

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AICA and imino-fAICA, derived from AICA and fAICA, respectively, are demonstrated to be precursors for purine, adenine, and isoguanine (Scheme 1). This is the first evidence suggesting that the imino-analogs of AICA and fAICA, instead of AICA and fAICA, are the precursors for purine, adenine, and isoguanine. Scheme 1 summarizes our findings. From formamide, the intermediate 5 (glycinamide derivative) is formed first. Hudson et al.33 has previously suggested that the glycine derivative is a critical intermediate for the synthesis of purines. Scheme 1 shows that the glycinamide backbone in 5 does form the scaffold for the purine ring in the same orientation as the backbone of the purine formed in the biosynthetic pathways as suggested by Hudson et al.33

3.1 Reaction pathways to AICA and fAICA Despite the importance of both AICA and fAICA as intermediates for the synthesis of nucleobases from formamide, the relevant pathways involving them have not been explored. Therefore, we first consider the formation of AICA and fAICA in constructing the energy profiles using quantum chemical computations. The reaction is started by •CN radical attack on formamide to give the radical 2 (Scheme 2) as previously reported.7 Figures 1-3 summarize the energy profiles of the elementary steps for this route. The first step is exoenergetic and has small energy barrier of 1.8 kcal/mol. Cyanoformamide (3) is formed by the loss of •H from 2. Formation of 3 from formamide and •CN radicals is consistent with previous report by Ferus et al.25 Next is the formation of the intermediate 5 from 3. An exoenergetic addition of •H (∆Gr = -27.6 kcal/mol) to 3 requires relatively small energy barrier of 4.4 kcal/mol. The resulting radical 4 abstracts an H from NH3 to give the radical molecule complex 5-NH2. Loss of NH2 radical from this complex leads to 5.

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We find that the addition of one hydrogen radical to formamide at the oxygen atom is slightly exoenergetic (∆Gr = -9.7 kcal/mol) with an energy barrier of 8.5 kcal/mol. Barrierless addition of this formamide radical to 5 gives 6a. Figure 1 shows that the formation of 6a from formamide (1) proceeds with a net release of 48 kcal/mol. The nucleobases are formed from two pathways starting from 5 (Scheme 2). Ammonia (NH3) provides 6a with the hydrogen needed to form the neutral molecule 7a with an energy barrier of 8.3 kcal/mol (Figure 2). Next is the conversion of the OH group in 7a to carbonyl group in two steps. This is accomplished by a hydrogen abstraction from 7a to give 8a with a small energy barrier of less than 1 kcal/mol. Loss of •H from 8a has an energy barrier of 18.0 kcal/mol, and completes the formation of the carbonyl group in 9a. Addition of formamidine radical to 9a gives 10a with a barrier of 16.2 kcal/mol. The radical 10a has all atoms needed for the formation of AICA. The radical center in 10a is located at the oxygen atom that needs to be converted to OH group. Hydrogen abstraction (10a → 11a) with an energy barrier of 3.5 kcal/mol leads to the formation of the OH group in 11a that allows elimination of this OH group (11a → 12a) with a small energy barrier of 3.5 kcal/mol. This OH group is then eliminated as H2O in one step (12a → 13a). This elimination requires 27.4 kcal/mol (Figure 3). The cyclization step (13a → 14a) has an energy barrier of 17.8 kcal/mol, and it is followed by 1,2-hydrogen rearrangement (14a → 15a) to give the radical 15a. Elimination of •NH2 group from 15a requires 21.9 kcal/mol and leads to the formation of AICA in complex with •NH2 (Scheme 1). Then fAICA is formed from AICA in three steps (Figure 3). The reaction starts with hydrogen abstraction from AICA that proceeds with a small barrier of 2.9 kcal/mol (AICA-NH2 → 16a). This is followed by addition of one formamide molecule to 16a followed by elimination of •NH2 to give fAICA. These two steps (16a → 17a and 17a → fAICA) have energy barriers

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of 29.6 and 37.5 kcal/mol, respectively. This completes the formation of fAICA as an intermediate for the nucleobases.

3.2 Formation of hypoxanthine, xanthine, and guanine. It is particularly important in considering the subsequent pathways from fAICA to understand which nucleobases can be formed from this precursor. Scheme 1 shows that the pathway from fAICA leads to hypoxanthine and xanthine. Figure 4 schematically displays the calculated energy profiles that illustrate the route from fAICA to hypoxanthine (22). In the first step, the radical derivative 18 of fAICA is formed by hydrogen abstraction using •NH2 (Scheme 3) with an energy barrier of 2.5 kcal/mol. This is followed by a cyclization step to form the sixmembered ring of the nucleobases with an energy barrier of 17.9 kcal/mol (Figure 4). Again, hydrogen abstraction from NH3 leads to the radical molecule complex 20. Note that both hydrogen abstraction steps, fAICA → 18 and 19 → 20 have small barriers of 2.5 and 0.7 kcal/mol, respectively. One more exoenergetic hydrogen abstraction 20 → 21 also proceeds with a small energy barrier (Figure 4). Loss of OH radical from 21 gives the hypoxanthine complex 22-OH. This is followed by a dissociation of this complex to form hypoxanthine 22. In addition, loss of one hydrogen radical from the intermediate 19 leads to xanthine 22. This confirms that structurally related nucleobases are formed from one reaction route. AICA is also a precursor of guanine (Scheme 1). The pathway to guanine starts from the radical 16a that is derived from AICA. Figure 5 shows the energy profile for this pathway. To form guanine (29) from AICA, it requires one additional carbon to complete the atoms needed for the formation of the six-membered ring in the nucleobase. This is accomplished by the addition of formamidine to the radical 16a to give 23. This addition proceeds with an energy

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barrier of 25.2 kcal/mol. Loss of •NH2 from 23 has a barrier of 11.6 kcal/mol to give the neutral molecule 24 (Figure 5). Next step is the formation of the six-membered ring in guanine. The first step is the hydrogen abstraction step 24 → 25 that proceeds with a small energy barrier of 2.4 kcal/mol and it is followed by cyclization step. The small barrier for the hydrogen abstraction is comparable to the previous hydrogen abstraction steps (fAICA → 18 and 19 → 20). In addition, these hydrogen abstraction steps are slightly exoenergetic (Figures 4 and 5). The energy barrier of 17.8 kcal/mol for the cyclization step (25 → 26) is comparable to the cyclization step of 18 → 19 (17.9 kcal/mol). Another hydrogen abstraction (26 → 27) that is slightly exoenergetic with a small energy barrier leads to the formation of the amino group in guanine (Figure 5). The abstraction of one hydrogen atom from 27 leads to the formation of the highly stable 28 and proceeds without an energy barrier at the B3LYP/6-311G(d,p) level. The final step to guanine 29 from the radical 28 has the highest energy barrier of 29.4 kcal/mol along this pathway. This completes the number of nucleobases formed from AICA and fAICA.

3.3 Formation of imino-AICA and imino-fAICA Formation of purine nucleobases (purine and adenine) has often been proposed starting from AICA and fAICA. However, the step-by-step pathways to purines from AICA have not been reported yet. The first pathways leading to the purines from the imino-analog of AICA are proposed (Scheme 1). In addition, these free radical pathways proceed with relatively low-energy barriers. The pathways leading to the imino analogs of AICA and fAICA are closely related to those for the formation of both AICA and fAICA (Schemes 2 and 4). The pathways start with an exoenergetic addition of hydrogen radical to 5. This addition is almost barrierless with a net release of 49.1 kcal/mol to form 6b (Figure 6). Addition of

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formamidine to the radical 6b (Scheme 4) gives 7b with an energy barrier of 21.6 kcal/mol (Figure 6). This energy barrier is comparable to the energy barrier of 25.2 kcal/mol for the similar addition of formamidine to 15a. This is followed by the loss of •H from 7b (Schemes 4) to give 8b. The energy barrier (17.5 kcal/mol) for this loss of •H from 7b is comparable to the loss of •H from 8a (18.0 kcal/mol). Hydrogen abstraction 9b has a small energy barrier of 2.4 kcal/mol (Figure 7) and leads to 10b. This is consistent with previous steps of hydrogen abstractions that proceed with relatively low energy barriers (e.g., fAICA → 18, 19 → 20, and 24 → 25). The barrier for the loss of water from 11b to give 12b is 27.5 kcal/mol. Next step is the cyclization 12b → 13b to form the five-membered ring that is found in the nucleobases (Figure 7). To form the imino analog of AICA (imino-AICA), the loss of one •NH2 group form 13b is required. This loss is accomplished in two steps. The first step is the hydrogen rearrangement step 13b → 14b (Scheme 4). The energy barrier (15.7 kcal/mol) for this hydrogen rearrangement is comparable to the step 14a → 15a with an energy barrier of 16.1 kcal/mol. Loss of •NH2 from 14b is associated with an energy barrier of 21.8 kcal/mol leading to the formation of imino-AICA. This is followed by the production of imino-fAICA in three steps. Hydrogen abstraction from imino-AICA leads to 15b that is exoenergetic with small energy barrier of 1.4 kcal/mol (Figure 7). This is followed by an endoenergetic addition of formamide to 15b giving 16b. Loss of •NH2 from 16b completes the formation of imino-fAICA.

3.4 Formation of purines The most important aspect of the free radical mechanisms is the formation of multiple nucleobases in a network of pathways that share the same precursors (Scheme 1). This is consistent with experimental observation for the formation of multiple nucleobases as well as

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intermediates.20, 34, 35 Scheme 5 shows the pathways leading to adenine, purine, and isoguanine. This pathway starts with an exoenergetic abstraction of hydrogen from imino-fAICA (iminofAICA → 30) that is associated with a net release of 17.6 kcal/mol. The six-membered ring of the nucleobases is then formed in the next step to give 31. This step has the highest energy barrier of 36.4 kcal/mol along this pathway (Figure 8). Starting from 31, hydrogen 1,3-rearrangement proceeds with an energy barrier of 16.1 kcal/mol to give 32. The radical center in 32 is at nitrogen that is alpha to the hydroxyl group. This allows the elimination of the OH group leading to the formation of the radical molecule complex 33-OH. This elimination of OH proceeds with an energy barrier of 19.8 kcal/mol. The complex 33-OH gives 33 that is a precursor for both adenine and purine. Note that 33 has all heavy atoms (C and N) needed for the formation of both nucleobases. Adenine is formed in two hydrogen abstraction steps. The first step is hydrogen abstraction by •NH2 that is followed by a second hydrogen abstraction from NH3 to give adenine. The first hydrogen abstraction step (33 → 34) is barrierless and highly exoenergetic with a net release of 35.2 kcal/mol. The second hydrogen abstraction (34 → Adenine) has a small energy barrier of 6.6 kcal/mol (Figure 8). Formation of purine from 33 is associated with a net release of 22 kcal/mol (Figure 9). The main strategy in this pathway is the conversion of the exocyclic NH in 33 to NH2 group followed by its elimination (Scheme 5). This is accomplished by the addition of two hydrogens across the exocyclic double bond in the first two steps. The first addition of •H (33 → 35) is highly exoenergetic with the release of 45.9 kcal/mol and has an energy barrier of 9.0 kcal/mol (Figure 9). The second hydrogen abstraction (35 → 36) has a high-energy barrier of 39.1 kcal/mol. The energy released from the first step (33 → 35) is available to overcome the barrier needed for the second step (35 → 36).

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For the elimination of NH2 group to take place, the strategy is to generative a reactive radical center by removing hydrogen atom from 36. This is accomplished by using •NH2 to remove hydrogen from the neutral molecule 36. Figure 9 shows that this hydrogen abstraction is highly exoenergetic with the release of 32.2. kcal/mol (36 → 37). Purine is finally formed by the elimination of •NH2 from 37 with an energy barrier of 18 kcal/mol. In addition to the purines, we find that 31 (Scheme 5) has the skeleton of heavy atoms needed for the formation of isoguanine. This pathway involves three steps with small energy barriers (within 1.8 – 4.3 kcal/mol range, Figure 10) and a net release of 16.2 kcal/mol. The first step is the exoenergetic formation of the carbonyl group (31 → 38) and has a small barrier of 4.3 kcal/mol. The next step is the formation of the NH2 group of isoguanine. Hydrogen abstraction from 38 leads to the resonance stabilized radical 39. This hydrogen abstraction proceeds with small energy barrier of 4.0 kcal/mol. Ammonia provides the hydrogen needed to complete the formation of isoguanine (Scheme 5). This last step is slightly exoenergetic and has a small energy barrier of 1.8 kcal/mol (Figure 10).

3.5 Comparing B3LYP results with M06 data To account for dispersion interactions, we repeated the computations at M062x/6311G(d,p) level of theory.36 We performed these calculations for the formation of hypoxanthine from fAICA. We find that the M062x results (both the activation energies (∆E±) and reaction energies (∆E)) are comparable to the B3LYP data (Table 1). We also tested the effect of basis sets on the computations. We find that the results using Def2TZVPP37 are comparable with the 6-311G(d,p) data. As expected, these results suggested that dispersion interactions do not have significant effects on the energetics of these pathways. Next, we performed the computations in

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water using polarizable continuum model (PCM). Water was selected as solvent because water is appropriate for prebiotic reactions. The results from these calculations were comparable with those in the gas phase with the exception of two steps (18 → 19 and 19 → 20). Table 1 shows that step 18 → 19 is exoenergetic in water (∆E = -16.0 kcal/mol) but endoenergetic in the gas phase (∆E = 11.4 kcal/mol). On the other hand, step 19 → 20 is endoenergetic in water (∆E =23.1 kcal/mol) and slightly exoenergetic in the gas phase (∆E =-4.4 kcal/mol). In addition, the step 19 → 20 has larger energy barrier in water (∆E± = 23.1 kcal/mol). These results suggest that the pathways may still proceed to the formation of the nucleobases in the presence of water. However, it is known that the amount of the nucleobases formed is significantly reduced in the presence of water. There is currently a need to further understand the effect of water on the pathways.

4. Concluding remarks The free radical pathways illustrate that the formamide chemistry provides complete routes for the prebiotic origin of nucleobases. The imidazole precursors (AICA and fAICA) are also present in the metabolic steps leading to purine biosynthesis. When AICA was heated in formamide at 185 °C hypoxanthine was formed.21 Shaw33 experimentally demonstrated that fAICA readily cyclizes to hypoxanthine, and further suggested that all C and N atoms in hypoxanthine originate from fAICA as proposed in the pathways. This experimental observation is consistent with the pathways in Scheme 1. Using montmorillonites, formamide led to the formation of purine, adenine, AICA, and fAICA.18 Formation of both AICA and fAICA together with the purines further support these proposed pathways. AICA also leads to xanthine in the presence of urea. Scheme 3 shows that the radical 16a derived from AICA leads to xanthine and

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guanine. The proposed pathways summarized in Scheme 1 are also consistent with previous suggestion that AICA is a precursor for both hypoxanthine and guanine.20 One of the significant predictions of the proposed pathways in the present study is that imino-AICA and imino-fAICA, instead of AICA and fAICA, are needed to produce purines (adenine and purine). This is equally consistent with the results of previous experiments reported by Shaw that pointed out in 1950 the need of imino-fAICA for the production of the purines.21 Imino-AICA has been shown to give imino-fAICA. Shaw also demonstrated that imino-AICA leads to the formation of isoguanine as predicted in Scheme 5.21 Reflux of concentrated solution of ammonia and HCN led to the formation of the following nucleobases: AICA, amino-AICA, formamide, and formamidine as well as adenine.34 These experimentally identified intermediates also appear in free radical pathways in the current study. Some of the steps along the proposed pathways have relatively large energy barriers (E± = 31 kcal/mol for 16a → 17a, E± = 29 kcal/mol for 28 → 29, E± = 39 kcal/mol for 35 → 36). These barriers suggest the need of a catalyst for these reactions to take place. The free radical mechanisms are appropriate under these high-energy scenarios that are associated with the release of large reaction energies.

Supporting Information. Optimized geometries of all structures considered in this study. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgements YAJ thanks Apple-Thurgood Marshall College Fund and NASA-MIRS program for support. YAJ also thanks United Negro College Fund for 2017-2018 Henry C. McBay Research

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Fellowship award. MTN is indebted to KU Leuven Research Council (GOA program). The authors are grateful to the Gridchem (www.gridchem.org) for allocating computer times. This program used the Extreme Science and Engineering Discovery Environment(XSEDE) facilities that is supported by USA National Science Foundation grant number ACI-105357.

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8. Jeilani, Y. A.; Fearce, C.; Nguyen, M. T. Acetylene as an Essential Building Block for Prebiotic Formation of Pyrimidine Bases on Titan. Phys. Chem. Chem. Phys. 2015, 17, 24294-24303. 9. Jeilani, Y. A.; Orlando, T. M.; Pope, A.; Pirim, C.; Nguyen, M. T. Prebiotic Synthesis of Triazines from Urea: A Theoretical Study of Free Radical Routes to Melamine, Ammeline, Ammelide, and Cyanuric Acid. RSC Advances 2014, 4, 32375-32382. 10. Ferus, M.; Michalčíková, R.; Shestivská, V.; Šponer, J. í.; Šponer, J. E.; Civiš, S. HighEnergy Chemistry of Formamide: A Simpler Way for Nucleobase Formation. J. Phys. Chem. A 2014, 118, 719-736. 11. Hörst, S. M.; Yelle, R. V.; Buch, A.; Carrasco, N.; Cernogora, G.; Dutuit, O.; Quirico, E.; Sciamma-O'Brien, E.; Smith, M. A.; Somogyi, Á. Formation of Amino Acids and Nucleotide Bases in a Titan Atmosphere Simulation Experiment. Astrobiology 2012, 12, 809-817. 12. Miller, S. In Which Organic Compounds Could Have Occurred on the Prebiotic Earth?, Cold Spring Harbor Symposia on Quantitative Biology, Cold Spring Harbor Laboratory Press: 1987; pp 17-27. 13. Sanchez, R.; Ferris, J.; Orgel, L. Conditions for Purine Synthesis: Did Prebiotic Synthesis Occur at Low Temperatures? Science 1966, 153, 72-73. 14. Zahnle, K. J. Photochemistry of Methane and the Formation of Hydrocyanic Acid (HCN) in the Earth's Early Atmosphere. J. Geophys. Res.: Atmos. 1986, 91, 2819-2834. 15. Saladino, R.; Crestini, C.; Pino, S.; Costanzo, G.; Di Mauro, E. Formamide and the Origin of Life. Phys. Life Rev. 2012, 9, 84-104.

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16. Saladino, R.; Ciambecchini, U.; Crestini, C.; Costanzo, G.; Negri, R.; Di Mauro, E. One‐Pot TiO2‐Catalyzed Synthesis of Nucleic Bases and Acyclonucleosides from Formamide: Implications for the Origin of Life. ChemBioChem 2003, 4, 514-521. 17. Saladino, R.; Crestini, C.; Costanzo, G.; Negri, R.; Di Mauro, E. A Possible Prebiotic Synthesis of Purine, Adenine, Cytosine, And 4 (3H)-Pyrimidinone from Formamide: Implications for the Origin Of Life. Bioorg. Med. Chem. 2001, 9, 1249-1253. 18. Saladino, R.; Crestini, C.; Ciambecchini, U.; Ciciriello, F.; Costanzo, G.; Di Mauro, E. Synthesis and Degradation of Nucleobases and Nucleic Acids by Formamide in the Presence of Montmorillonites. ChemBioChem 2004, 5, 1558-1566. 19. Z ubay, G.; Mui, T. Prebiotic Synthesis of Nucleotides. Origins Life Evol. Biospheres 2001, 31, 87-102. 20. Barks, H. L.; Buckley, R.; Grieves, G. A.; Di Mauro, E.; Hud, N. V.; Orlando, T. M. Guanine, Adenine, and Hypoxanthine Production in UV‐Irradiated Formamide Solutions: Relaxation of the Requirements for Prebiotic Purine Nucleobase Formation. ChemBioChem 2010, 11, 1240-1243. 21. Shaw, E. A New Synthesis of the Purines Adenine, Hypoxanthine, Xanthine, and Isoguanine. J. Biol. Chem. 1950, 185, 439-448. 22. Jeilani, Y. A.; Nguyen, H. T.; Cardelino, B. H.; Nguyen, M. T. Free Radical Pathways for the Prebiotic Formation of Xanthine and Isoguanine from Formamide. Chem. Phys. Lett. 2014, 598, 58-64. 23. Jeilani, Y. A.; Williams, P. N.; Walton, S.; Nguyen, M. T. Unified Reaction Pathways for the Prebiotic Formation of RNA and DNA Nucleobases. Phys. Chem. Chem. Phys. 2016, 18, 20177-20188.

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32. Dooley, R.; Milfeld, K.; Guiang, C.; Pamidighantam, S.; Allen, G. From Proposal to Production:

Lessons

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Cyberinfrastructure. J. Grid Computing 2006, 4, 195-208. 33. Hudson, J. S.; Eberle, J. F.; Vachhani, R. H.; Rogers, L. C.; Wade, J. H.; Krishnamurthy, R.; Springsteen, G. A Unified Mechanism for Abiotic Adenine and Purine Synthesis in Formamide. Angew. Chem., Int. Ed. 2012, 51, 5134-5137. 34. Saladino, R.; Botta, G.; Delfino, M.; Di Mauro, E. Meteorites as Catalysts for Prebiotic Chemistry. Chem. - Eur. J. 2013, 19, 16916-16922. 35. Saladino, R.; Crestini, C.; Ciciriello, F.; Costanzo, G.; Di Mauro, E. Formamide Chemistry and the Origin of Informational Polymers. Chem. Biodiversity 2007, 4, 694-720. 36. Zhaoa, Y.; Donald G.; Truhlar, D. G. A new Local Density Functional for Main-Group Thermochemistry, Transition Metal Bonding, Thermochemical Kinetics, and Noncovalent Interactions. J. Chem. Phys. 2006, 125, 194101–194118. 37. Weigend, F. Accurate Coulomb-Fitting Basis Sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8, 1057-1065

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Figure and Schemes Captions Figure 1: Schematic energy profiles illustrating the free radical pathway for the formation of 6a Figure 2: Schematic energy profiles illustrating the free radical pathway for the formation of 12a Figure 3: Schematic energy profiles illustrating the free radical pathway for the formation of AICA and fAICA Figure 4: Schematic energy profiles illustrating the free radical pathway for the formation of hypoxanthine (22) Figure 5: Schematic energy profiles illustrating the free radical pathway for the formation of guanine (29) Figure 6: Schematic energy profiles illustrating the free radical pathway for the formation of 12b Figure 7: Schematic energy profiles illustrating the free radical pathway for the formation of imino-AICA and imino-fAICA Figure 8: Schematic energy profiles illustrating the free radical pathway for the formation of adenine Figure 9: Schematic energy profiles illustrating the free radical pathway for the formation of purine Figure 10: Schematic energy profiles illustrating the free radical pathway for the formation of isoguanine Scheme 1. Structures of procursors for the formation of nucleobases Scheme 2. Formation of fAICA from formamide Scheme 3. Formation of hypoxanthine, xanthine, and guanine Scheme 4. Formation of imino-AICA and imino-fAICA Scheme 5. Formation of adenine, purine, and isoguanine

Table 1. Energies (kcal/mol) for the formation of hypoxanthine (22) at B3LYP, M06, and M062x level of theory

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List of Tables Table 1. Energies (kcal/mol) for the formation of hypoxanthine (22) at B3LYP and M062x level of theory Basis Sets B3LYP Description fAICA → 18 18 → 19 19 → 20 20 → 21 21 → 22-OH 22-OH → 22 n.b. = no barrier

∆E± 2.5 17.9 0.7 2.2 23.1 -

∆E -3.2 11.4 -4.4 -20.9 14.8 11.4

6-311G(d,p) PCMB3LYP (a) ∆E± ∆E 6.2 -0.3 11.4 -16.0 25.0 23.1 2.7 -19.1 21.6 16.2 6.6

M062x ∆E± 5.0 19.1 n.b. 7.1 28.2 -

(a) PCM solvent = Water

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∆E 0.7 8.2 -12.1 -14.9 16.2 11.2

Def2TZVPP M062x ∆E± 7.5 18.3 1.1 6.3 28.0 -

∆E 0.7 7.6 -9.4 -18.2 17.5 8.9

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List of Schemes Scheme 1

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Scheme 2

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Scheme 3

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Scheme 4

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Scheme 5

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List of Figures Figure 1

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Figure 2

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Figure 3

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Figure 4

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Figure 5

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Figure 6

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Figure 7

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Figure 8

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Figure 9

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Figure 10

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TOC for the manuscipt

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Figure 1: Schematic energy profiles illustrating the free radical pathway for the formation of 6a 223x149mm (300 x 300 DPI)



Figure 2: Schematic energy profiles illustrating the free radical pathway for the formation of 12a 245x182mm (300 x 300 DPI)


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Figure 3: Schematic energy profiles illustrating the free radical pathway for the formation of AICA and fAICA 245x144mm (300 x 300 DPI)



Figure 4: Schematic energy profiles illustrating the free radical pathway for the formation of hypoxanthine (22) 237x161mm (300 x 300 DPI)


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Figure 5: Schematic energy profiles illustrating the free radical pathway for the formation of guanine (29) 246x147mm (300 x 300 DPI)



Figure 6: Schematic energy profiles illustrating the free radical pathway for the formation of 12b 247x175mm (300 x 300 DPI)


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Figure 7: Schematic energy profiles illustrating the free radical pathway for the formation of imino-AICA and imino-fAICA 240x146mm (300 x 300 DPI)



Figure 8: Schematic energy profiles illustrating the free radical pathway for the formation of adenine 249x128mm (300 x 300 DPI)


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Figure 9: Schematic energy profiles illustrating the free radical pathway for the formation of purine 187x120mm (300 x 300 DPI)



Figure 10: Schematic energy profiles illustrating the free radical pathway for the formation of isoguanine 182x119mm (300 x 300 DPI)


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Scheme 1. Structures of procursors for the formation of nucleobases 181x102mm (300 x 300 DPI)



Scheme 2. Formation of fAICA from formamide 255x135mm (300 x 300 DPI)


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Scheme 4. Formation of imino-AICA and imino-fAICA 242x110mm (300 x 300 DPI)



Scheme 5. Formation of adenine, purine, and isoguanine 180x143mm (300 x 300 DPI)


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Scheme 3. Formation of hypoxanthine, xanthine, and guanine 184x148mm (300 x 300 DPI)


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