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A light-releasable potentially prebiotic nucleotide activating agent Angelica Mariani, David A. Russell, Thomas Javelle, and John D. Sutherland J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05189 • Publication Date (Web): 02 Jul 2018 Downloaded from http://pubs.acs.org on July 2, 2018

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Journal of the American Chemical Society

A light-releasable potentially prebiotic nucleotide activating agent Angelica Mariani‡, David A. Russell‡, Thomas Javelle, John D. Sutherland* MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.

Supporting Information Placeholder ABSTRACT: Investigations into the chemical origin of

life have recently benefitted from a holistic approach in which possible atmospheric, organic, and inorganic systems chemistries are taken into consideration. In this way, we now report that a selective phosphate activating agent, namely methyl isocyanide, could plausibly have been produced from simple prebiotic feedstocks. We show that methyl isocyanide drives the conversion of nucleoside monophosphates to phosphorimidazolides under potentially prebiotic conditions and in excellent yields for the first time. Importantly, this chemistry allows for repeated re-activation cycles, a property long sought in non-enzymatic oligomerization studies. Further, as the isocyanide is released upon irradiation, the possibility of spatially and temporally controlled activation chemistry is thus raised.

From the pioneering works of Orgel1,2 and Ferris,2,3 through to the most recent breakthroughts of Szostak and co-workers,4,5 nucleoside 5′ -phosphorimidazolides have been used as long-lived activated nucleotides for the non-enzymatic oligomerization and templated copying of RNA. Yet, a prebiotically plausible synthesis of such species remains elusive.6,7 Isocyanides are known phosphate activating agents8 and we have previously described how they could have been involved in a fleeting prebiotic activation of nucleoside monophosphates by Passerini-type chemistry.9 This chemistry requires both isocyanides and aldehydes, and while the latter species arise from the photoredox pathways that lead from HCN to amino acids, lipids, and ribonucleotides10,11 a prebiotic pathway to the former remains to be found. Herein, following along systems chemistry lines, we describe a potentially prebiotic synthesis of methyl isocyanide 1 and demonstrate its use in the in situ formation of 5′ -

phosphorimidazolides via interrupted chemistry in a four component system.

Passerini

Incubation of adenosine 5′ -monophosphate (AMP) with imidazole 2 (Im), acetaldehyde 3 and methyl isocyanide (pH 6) resulted in the formation of adenosine 5′ -phosphorimidazolide (ImpA) in 54% yield after only 30 min (Figure 1, Table S1 and Figure S1a). The reaction could also be performed with other prebiotically relevant aldehydes, such as formaldehyde or glycolaldehyde (41 and 48% yields of ImpA were obtained after 30 min, respectively, data not shown). Screening the reaction with acetaldehyde over a pH range revealed a pH optimum of 6.5 (yield: 71%, Figure 1d and Table S1), presumably reflective of the simultaneous requirements of having imidazole as its free base (pKa of imidazolium ≈ 7.0), dianionic AMP (pKa of AMP monoanion ≈ 6.5), and sufficient acid to protonate acetaldehyde.12 Mechanistically, we speculate that the transient imidoyl phosphate 4 (undetectable by NMR spectroscopy), generated from the reaction of AMP with the nitrilium ion 5, is attacked by imidazole at phosphorus, with the consequent formation of the phosphorimidazolide (Figure 1a). Following its initial formation, and in the absence of a primer-template complex (when polymerization can be expected),4,5 ImpA is progressively hydrolyzed to AMP and thence formation of AMP pyrophosphate (AppA, Figure 2a,b). It is interesting to note that although these outcomes are reflective of the known reactivity of ImpA under these conditions, a connection between 5′ ,5′ -pyrophosphate ribodinucleotides and modern cofactors has been previously suggested.13,14 The other canonical mononucleotides, GMP, CMP, and UMP, displayed analogous behaviors, with ImpN yields ranging from 69 to 75% (Table S1 and Figure S2). Importantly, no modifications occurred to any of the nucleobases, revealing isocyanides to be selective phosphate activating agents.9,15 The requirement for

1 ACS Paragon Plus Environment

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Mg2+ in ribonucleotide polymerization prompted us to investigate the effect of this additive on the synthesis of ImpA. Mg2+ catalysis, as expected, enhanced the

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rate of both ImpA hydrolysis and AppA production (Figure 2b), but did not affect the initial yield of imidazolide (Table S1).

Figure 1. Synthesis of ImpA and spiking experiments. a, Suggested mechanism for the methyl isocyanidemediated synthesis of ImpA. 1H (left, magnification showing the H-C(1′ ) region) and 31P (right) NMR spectra confirming the formation of b, ImpA (100 mM AMP, 400 mM 1, 100 mM 2, 400 mM 3, pH 6.5, 3.5 h) and c, AppA (100 mM AMP, 400 mM 1, 100 mM 2, 400 mM 3, 20 mM Mg2+, pH 6.5, 72 h; 5-fold dilution before spiking), by spiking with authentic samples (top). d, Plot of the maximum % yield of ImpA vs. pH of the reaction. (Green: AMP, blue: ImpA, orange: AppA). A desirable feature in prebiotic nucleotide activation chemistry is the possibility of repeatedly activating the spent monomers that derive from imidazolide hydrolysis to allow for further rounds of polymerization.15 Although it was beyond the scope of this study to investigate polymerization, we sought to establish repeated activation chemistry. Importantly, adding methyl isocyanide in aliquots, followed by intervals in which hydrolysis and pyrophosphate formation served as a proxy for polymerization in a more complex system, resulted in cycles of AMP activation, in which every fresh portion of the activating agent triggered the regeneration of ImpA with comparable efficiency (Figure 2c). Recently, Szostak and co-workers4,16 have reported the superiority of nucleoside 5′ -phosphoro-2-aminoimidazolides (2NH2ImpN) in the non-enzymatic copying of oligoribonucleotides, as a result of more efficient formation of a transient imidazolium bridged dinucleotide. In our system, activation of AMP with methyl isocyanide and acetaldehyde in

the presence of 2-aminoimidazole 6 resulted in its conversion to the corresponding 2NH2ImpA at an optimum pH of 7 (Table S1 and Figures S1b and S3). Further optimization resulted in improvements to the production of both ImpA and 2NH2ImpA, with 89 and 76% yields obtained, respectively (Table S1). For this selective phosphate activation chemistry to have occurred on the primordial Earth, a prebiotic syn-


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CO2 + N2 + H2O lightning+ meteorites impact

CO + CN + NO HCN x6

FeII

dissolution

6H+ N2

[Fe(CN)6]47

hn , 2H+

CN-

CN+ H2O

[Fe(CN)5N2]311

12

Figure 2. Synthesis and recycling of ImpA. a, 31P NMR spectra showing ImpA formation and prod-

ucts thereof (100 mM AMP, pH 6.5; reaction times as labeled on each spectrum). b, Plot of % ImpA and AppA (from a) vs. time and effect of Mg2+. c, Plot of % ImpA and AppA vs. time for the (re)cycling of (spent) AMP, by iterative cycles of activation. (Green: AMP, blue: ImpA, orange: AppA). thesis of methyl isocyanide would have been required. We thus considered its possible formation as a result of metallo-organic chemistry.10,17,18 Iron, as the most abundant transition metal on Earth, probably played a fundamental role in the emergence of life’s building blocks.19 Upon exposure to a primordial atmosphere containing HCN, CO, and NO., iron would have formed stable homoleptic complexes such as [Fe(CN)6]4− (ferrocyanide 7, Figure 3),20 but also mixed ligand complexes with ligands isoelectronic with cyanide of the form [Fe(CN)5L]n−, where L = CO (n = 3) or NO (n = 2).19 Continuing a study initiated by Beck,19,21 we investigated the chemistry of the nitrosyl complex [Fe(CN)5NO]2− (nitroprusside, 8), known, inter alia, to mediate the diazotization of amines.21,22 To determine whether nitroprusside could plausibly have formed under prebiotic conditions on Earth, we considered its possible formation from ferrocyanide and the nitrogen oxides NO., NO2− (nitrite), and NO3− (nitrate). Lightning and meteorite impacts in the N2-rich primordial atmosphere would have produced NO. (nitric oxide, Figure 3), which could have been directly absorbed into ferrocyanide containing pools, producing nitroprusside in situ. Alternatively, NO2− and NO3− could have accumulated in solution following disproportionation of NO..23

hn

CH3NC 1

[Fe(CN)6]47 low pH

[Fe(CN)5NO]28 H2PO2CH3NH2 HCN sponge Ni 9

[Fe(CN)5CNCH3]3CN-

NO3-

NO2-

[Fe(CN)6]47

[Fe(CN)5N2CH3]210

H2 O

Figure 3. Schematic representation of the systems chemistry network producing methyl isocyanide (1).21 High-energy atmospheric chemistry generates HCN (via CN.), CO and NO.. NO. undergoes various disproportionation reactions upon dissolution,23 providing NO2− and NO3−. HCN is stored in solution as 7, which reacts with NO2− (or NO3−) to provide 8.37 HCN is also a source of CH3NH2 9, which is diazotized by 8. Alkylation of 7 by 10 gives 12 and 11. Irradiation of 12 in the presence of CN− releases 1 and returns 7; reaction of 11 with CN− returns 7, releasing N2. Combining literature reports that nitroprusside24 can be formed from NO2− and [Fe(CN)5H2O]3−, and that the latter can be produced by photoaquation of ferrocyanide,25-27 we found that irradiating a mixture of ferrocyanide and NO2− in the pH range 7-9.8 with 365 nm light afforded nitroprusside as the only new FeII complex detectable by 13C NMR spectroscopy (Figure S4a). Importantly, irradiation of the same mixture with 254 nm light also afforded nitroprusside, albeit less efficiently, suggesting that broad band irradiation from the young sun could have supported the formation of this complex. We next investigated the reactions of nitroprusside with methylamine 9, which would have been delivered to the primordial Earth in comets.28 Alternatively, hydrogenation of HCN to methylamine would have been expected to occur in a geochemical scenario in which iron-nickel meteorites containing schreibersite (Fe,Ni)3P underwent corrosion in HCN-containing pools. In an anoxic environment, corrosion of schreibersite has been shown to give soluble FeII, H2PO2− (hypophosphite), HPO32− (phosphite) and HPO42− (phosphate), while the bulk iron-nickel alloy matrix gives insoluble porous nickel (sponge nickel) or nickel-enriched alloy.29,30



As hypophosphite is known to decompose to H2 and phosphite in the presence of Raney Nickel,31 we have recently investigated the hypophosphite-sponge Nickel combination as a plausible prebiotic hydrogenation system in keeping with the general geochemical scenario described above. Accordingly, we found that reduction of HCN with hypophosphite and sponge nickel afforded methylamine as the sole organic product, identified by 1H and 13C NMR spectroscopy (Figure S4b,c). The reaction of methylamine with nitroprusside in the presence of CN− and HPO42− (pH 9.8) proceeded with slow evolution of a gas, presumably N2, indicative of diazotisation chemistry. Analysis of the reaction mixture by 1H and 31P NMR spectroscopy confirmed the presence of products expected from the trapping of [Fe(CN)5N2CH3]2− 10 by the nucleophiles H2O, CN−, and HPO42−, namely CH3OH (methanol), CH3CN (acetonitrile), and CH3OPO32− (methyl phosphate, Figure 4a,b and Figure S5a), respectively, together with an initially unidentified species. Reasoning that ferrocyanide is also produced under the above reaction conditions (by reaction of cyanide with [Fe(CN)5N2]3− 11, Fig. 3, or [Fe(CN)5H2O]3−), and realizing that it could act as a nucleophile in its own right, we tentatively assigned the species as the isocyanide complex [Fe(CN)5CNCH3]3− 12. This assignment was strengthened by repeating the above reaction with ferrocyanide (1 equivalent) present from the outset, which led to an increase in the intensity of the new signal, and unambiguously confirmed by comparison with the 1H NMR spectrum of an authentic standard prepared by addition of methyl isocyanide to a solution of [Fe(CN)5H2O]3− (Figure 4c,e and Figure S6b-d). Although initially concerned by the pH discontinuity between the activation chemistry and methyl isocyanide synthesis, we found that complex 12 could be generated in a pH range between 7-9.8, as the diazotization chemistry still proceeds, albeit more slowly, at neutral pH. Mixed ligand isocyanide complexes are known to undergo isocyanide ligand exchange in coordinating organic solvents upon irradiation at 365 nm.32 Irradiation of an aqueous solution of complex 12 at this wavelength, in the presence of excess CN− provided free methyl isocyanide (yield: 50% after 2 h, Figure S6), clearly identified by its characteristic 1:1:1 triplet at δ 3.16 in the 1H NMR spectrum, and ferrocyanide.33 The remaining materials detectable by 1H NMR spectroscopy were residual complex 12 (41%), and two new complexes, tentatively assigned as cis[Fe(CN)4(CNCH3)2]2− and trans-

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[Fe(CN)4(CNCH3)2]2− (signals unassigned, 9%). Further irradiation did not improve the yield of methyl isocyanide, which we attribute to a photostationary equilibrium having been reached. Next, we sought to link the diazotization chemistry and the photolysis of complex 12, in order to demonstrate that methyl isocyanide could be synthesized in a plausible geochemical setting. Accordingly, a mixture of methylamine, ferrocyanide and nitroprusside, in the presence of CN− and HPO42− (pH 9.8), was allowed to react for 20 h. The mixture of products obtained was then irradiated for 2 h in the presence of excess CN−. Analysis by 1H NMR spectroscopy showed the expected mixture of products, including methyl isocyanide (Figure 4d). Interestingly, the by-product of the imidazolide synthesis described above is 2-hydroxy-Nmethylpropanamide 13, hydrolysis of which would regenerate methylamine and thus feed back into a new cycle for the production of fresh methyl isocyanide. The other product of the hydrolysis would be lactate, a major player in extant and maybe early metabolism. Overall these findings depict a common plausible scenario in which HCN is central not only to the synthesis of protein, lipid and RNA building blocks, but also drives chemical pathways that ultimately lead to nucleotide activation. In this scenario, methyl isocyanide could have been produced in a ferrocyanide and nitroprusside containing environment upon delivery of methylamine. Pools containing different accumulated materials (possibly at different pHs), could have occasionally been linked by streams,34 allowing the methyl isocyanide and nucleotide producing subsystems to mix, thereby enabling nucleotide activation and polymerization chemistry. The lack of high-yielding and prebiotically plausible phosphate activating agents has been a central problem in origin of life research for nearly 60 years, prompting the use of pre-activated nucleotide substrates,4,7 synthetic surrogates of ineffective prebiotic reactants,6,35 or prebiotically questionable syntheses of desirable activating agents.36 Here, for the first time, we describe a prebiotically plausible synthesis of methyl isocyanide, a storable and light-releasable activating agent, and demonstrate its use in the efficient in situ activation of nucleotide monophosphates.


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Journal of the American Chemical Society Angelica Mariani: 0000-0002-2547-4224 David A. Russell: 0000-0002-2182-4178 John D. Sutherland: 0000-0001-7099-4731 Author Contributions

‡These authors contributed equally. Funding Sources

This work was supported by the Medical Research Council (grant no. MC_UP_A024_1009) and a grant from the Simons Foundation (grant no. 290362 to J.D.S.). The authors declare no competing financial interests.

ACKNOWLEDGMENT We thank L. Wu and Z. Liu for authentic standards of ImpA and AppA, and all J.D.S. group members for fruitful discussions.

REFERENCES 1.

2.

3.

4.

Figure 4. Prebiotic synthesis of methyl isocyanide (1). a, Schematic representation of the synthesis of 1 via 12. b, 1H NMR spectrum showing the synthesis of 12 without added 7 (20 h). c, as b with 7 present from the start (20 h). d, 1H NMR spectrum showing the mixture of products obtained following photolysis of prebiotically synthesized 12 (2 h of irradiation). e, 1H NMR spectrum of synthetically prepared 12. (Green: CH3NH2/CH3NH3+, blue: [Fe(CN)5CNCH3]3−, orange: CNCH3).

5.

6.

7.

8.

9.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. Materials, methods, compound characterization, supplementary Figures and Tables (PDF).

10.

11.

AUTHOR INFORMATION Corresponding Author

J.D.S. [email protected]. ORCID

12.

13.

Weimann, B. J.; Lohrmann, R.; Orgel, L. E.; SchneiderBernloehr, H.; Sulston, J. E. Template-directed synthesis with adenosine-5'-phosphorimidazolide. Science 1968, 161, 387. Ferris, J. P.; Hill Jr, A. R.; Liu, R.; Orgel, L. E. Synthesis of long prebiotic oligomers on mineral surfaces. Nature 1996, 381, 59-61. Ferris, J. P.; Ertem, G. Oligomerization of ribonucleotides on montmorillonite: reaction of the 5′ -phosphorimidazolide of adenosine. Science 1992, 257, 1387-1389. Li, L.; Prywes N.; Tam C. P.; O'Flaherty D. K.; Lelyveld V. S.; Izgu E. C.; Pal A.; Szostak J. W. Enhanced nonenzymatic RNA copying with 2-aminoimidazole activated nucleotides. J. Am. Chem. Soc. 2017, 139, 1810-1813. Zhang, W.; Tam, C. P.; Zhou L.; Oh S. S.; Wang J; Szostak J. W. Structural rationale for the enhanced catalysis of nonenzymatic RNA primer extension by a downstream oligonucleotide. J. Am. Chem. Soc. 2018, 140, 2829-2840. Joyce, G. F.; Orgel, L. E. in The RNA World (eds Gesteland, R. F., Cech, T. R. & Atkins, J. F.) 23–56 (Cold Spring Harbor Laboratory Press, 2006). Lohrmann, R. Formation of nucleoside 5'-phosphoramidates under potentially prebiological conditions. J. Mol. Evol. 1977, 10, 137-154. Mizuno, Y.; Kobayashi, J. New phosphorylation procedure. Activation of phosphates with cyclohexyl isocyanide. J. Chem. Soc. Chem. Commun. 1974, 997-998. Mullen, L. B.; Sutherland, J. D. Simultaneous nucleotide activation and synthesis of amino acid amides by a potentially prebiotic multi-component reaction. Angew. Chem. Int. Ed. 2007, 46, 8063-8066. Patel, B. H.; Percivalle, C.; Ritson, D. J.; Duffy, C. D.; Sutherland, J. D. Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Nat. Chem. 2015, 7, 301-307. Ritson, D. J.; Sutherland, J. D. Synthesis of aldehydic ribonucleotide and amino acid precursors by photoredox chemistry. Angew. Chem. Int. Ed. 2013, 52, 5845-5847. Sutherland, J. D.; Mullen, L. B.; Buchet. F. F. Potentially prebiotic Passerini-type reactions of phosphates. Synlett 2008, 14, 2161-2163. Yarus, M. Darwinian behaviour in a cold, sporadically fed pool of ribonucleotides. Astrobiology 2012, 12, 870-883.



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27.

Majerfeld, I.; Puthenvedu, D.; Yarus, M. Cross-backbone templating; ribodinucleotides made on poly(C). RNA 2016, 22, 397-407. Szostak, J. W. The eightfold path to non-enzymatic RNA replication. J. Systems Chem. 2012, 3, 2. Fahrenbach, A. C.; Giurgiu C.; Tam C. P.; Li L.; Hongo Y.; Aono M.; Szostak J. W. Common and potentially prebiotic origin for precursors of nucleotide synthesis and activation. J. Am. Chem. Soc. 2017, 139, 8780-8783. Sutherland, J. D. The origin of life – out of the blue. Angew. Chem. Int. Ed. 2016, 55, 104-121. Powner, M. W.; Sutherland, J. D. Prebiotic chemistry: a new modus operandi. Phil. Trans. R. Soc. B 2011, 366, 2870-2877. Beck, M. Prebiotic coordination chemistry: the potential role of transition-metal complexes in the chemical evolution. NASA TM-75381, 1979, originally published in Kemiai Közlemenyek 1978, 50, 223-240. Keefe, A. D.; Miller, S. L. Was ferrocyanide a prebiotic reagent? Orig. Life Evol. Biosph. 1996, 26, 111-129. Dózsa, L.; Kormos, V.; Beck, M. T. Kinetics of the reaction of pentacyanonitrosylferrate(II) with aliphatic amines. Inorg. Chim. Acta 1984, 82, 69-74. Maltz, H.; Grant, M. A.; Navaroli, M. C. Reaction of nitroprusside with amines. J. Org. Chem. 1971, 36, 363-364. Mancinelli, R. L.; McKay, C. The evolution of nitrogen cycling. Origins Life Evol. Biosph. 1988, 18, 311-325. Swinehart, J. H.; Rock, P. A. The equilibrium and kinetic properties of the aqueous hydroxide-nitroprusside system. Inorg. Chem. 1966, 5, 573-576. Stein, G. Photochemistry of the ferrocyanide ion in aqueous solution: hydrated electron formation and aquation. Israel J. Chem. 1970, 8, 691-697. Shirom, M.; Stein, G. Excited state chemistry of the ferrocyanide ion in aqueous solution. II. Photoaquation. J. Chem. Phys. 1971, 55, 3379-3382. Gáspár, V.; Beck, M. T. Kinetics of the photoaquation of hexacyanoferrate(II) ion. Polyhedron 1983, 2, 387-391.

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28. Aponte, J. C.; Elsila, J. E.; Glavin, D. P.; Milam, S. N.; Charnley, S. B.; Dworkin, J. P. Pathways to meteoritic glycine and methylamine. ACS Earth Space Chem. 2017, 1, 3-13. 29. Pasek, M. A.; Harnmeijer, J. P.; Buick, R.; Gull, M.; Atlas, A. Evidence for reactive reduced phosphorus species in the early Archean ocean. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 10089-10094. 30. Tackett, S. L.; Mayer Jr, W. M.; Pany, F. G.; Moore, C. B. Electrolytic dissolution of iron meteorites. Science 1966, 153, 877-880. 31. Backeberg, O. G.; Staskun, B. A novel reduction of nitriles to aldehydes. J. Chem. Soc. 1962, 3961-3963. 32. Costanzo, L. L.; Giuffrida, S.; De Guidi, G.; Condorelli, G. Photochemical and thermal behaviour of isocyanide complexes. V*. Photolysis of Fe(CNCH3)4(CN)2 in acetonitrile. J. Organomet. Chem. 1986, 315, 73-77. 33. The full wavelength dependence of this ligand exchange reaction has not been studied, but, as expected, the release of free methyl isocyanide did not occur upon irradiation at 254 nm. 34. Ritson, D. J.; Battilocchio, C.; Ley, S. V.; Sutherland, J. D. Mimicking the surface and prebiotic chemistry of early Earth using flow chemistry. Nat. Commun. 2018, 9, 1821. 35. Jauker, M.; Griesser, H; Richert, C. Copying of RNA sequences without pre-activation. Angew. Chem. Int. Ed. 2015, 54, 14559-14563. 36. During the preparation of this manuscript, a report on the purportedly prebiotic synthesis of nucleoside 5'- phosphorimidazolides from 1 M sodium cyanide and 1 M sodium hypochlorite (bleach) was published: Yi, R.; Hongo, Y.; Fahrenbach, A. C. Synthesis of imidazole-activated ribonucleotides using cyanogen chloride. Chem Commun. 2018, 54, 511-514. 37. Butler, A. R.; Glidewell, C.; Hyde, A. R.; McGinnis, J. Nitrogen-15 and carbon-13 NMR study of Roussin salts and esters and of pentacyanoferrate complexes. Inorg. Chem. 1985, 24, 2931-2934.


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SYNOPSIS TOC

ACS Paragon Plus Environment

7

N

a H+

1

5

1H

AMP

N

H

O

OH

HO

c

+ ImpA

31P

N

N

O N P O O

NH2

O

N

N

N 13 H

4

+ AppA

1H

HO

OH

+ AppA

31P

O

N

N

N

N

OH

H2O

NH2

N N

O

HO

ImpA H 2N

Page 8 of 11

O O P O O

N

N O

HO

OO O P P O O O AppA

O

N

AMP

N

HO

N

N OH

N

NH2 N N

O

OH OH

d 100

ImpA

Yield %

AppA

50

0

-5

-10

-15

0 pH

00

5 δ/ ppm

8.

6.0

50

6.1

7.

δ/ ppm

00

-10

7.

-5

75

0

6.

5 δ/ ppm

50

5.9

6.

6.0

25

ACS Paragon Plus Environment 6.

13 2 b3 +4 ImpA 5 6 7 8 9 10 11 12 13 14 15 16 17 6.1 δ/ ppm 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51

N

O O P O O

00

+

Journal of the American Chemical Society N N 2

6.

O

HO

OH

N

NH2 N

100

b

ImpA

AppA Page 9Journal of 11 of the American Chemical Society

72h

% species

a

15h

50

0 100 % species

1 2 5h 3 4 2.5h 5 6 1.5h 7 8 0.5h 9 10 115 10 δ / ppm 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

ImpA (+Mg2+)

AppA (+Mg2+)

Time (h)

c

20

40

60

80

60

80

50

ACS Paragon Plus Environment 0

-5

-10

-15

0

Time (h)

20

40

Journal of the American Chemical Society CO2 + N2 + H2O lightning+

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1 meteorites 2 impact 3 CO + CN + NO 4 5 HCN 6 x6 7 dissolution FeII 8 9 6H+ 10 NO3[Fe(CN)6]4N2 NO211 7 12 h , 2H+ 13 [Fe(CN)6]414 CNCN7 + H2O 15 low pH 16 [Fe(CN)5N2]317 11 18 [Fe(CN)5NO]219 [Fe(CN)5CNCH3]38 20 H2PO212 21 CH3NH2 HCN sponge Ni 22 9 CN 23 h [Fe(CN)6]4ACS Paragon Plus Environment 24 [Fe(CN)5N2CH3]2H 2O 7 25 CH3NC 10 26 1 27 28 29 30 31 32 33 34 35 36 37 38 39 40

a

[Fe(CN)6]4- (7)

CN

CN-, HPO42-

NC CN 12 CNCH3

2-

NC CN 2- (8) CNPage 11 Journal of[Fe(CN) 11 of the American Chemical Society 5NO] Fe CH NH CH NC + [Fe(CN) ]43

2

9

1 b 2 3 4 CH OPO 5 6 7 c 8 9 10 11 CH OPO 12 13 d14 15 16 CH OPO 17 18 19 20 e21 22 23 24 25 26 27 28 δ / ppm 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 3

3

3

h

+ CH3OH, CH3CN, CH3OPO32-

3

6

1

7

CH3OH CH3CN

23

CH3OH

CH3CN

23

CH3OH CH3CN

23

ACS Paragon Plus Environment 3.25

3.00

2.75

2.50

2.25

A Light-Releasable Potentially Prebiotic ... - ACS Publications

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