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Home , Cyanamide, Glycolaldehyde, Tholin

DOI:10.1002/chem.201601999 Full Paper

& Prebiotic Chemistry Prebiotic-LikeCondensationsofCyanamideand : Revisiting Intractable Biotars Nieves Lavado,* Juan CarlosEscamilla, Martín valos, Reyes Babiano,* Pedro Cintas, JosØ Luis JimØnez, and Juan Carlos Palacios[a]

Abstract: We report adetailed investigation into the nature in particularNMR and mass (ESI mode), which of products that are generated by the reactions of cyana- are all consistent with the generation of afew functional mide and glyoxal, two small of astrochemicaland groupsthat are embedded into regularchains of five- and prebiotic significance, under differentexperimental condi- six-memberedrings, therebypointing to asupramolecular tions. The experimental data suggest that the formation of organization.Three different modelsofcross-condensation oligomeric structures is relatedinpart to the formation of and chain growth are suggested. These synthetic explora- insoluble in the presence of -containing mole- tions provide further insightsinto the formation of complex cules. Althougholigomerization proceeds well in , organic matter in interstellarscenarios and extraterrestrial productisolation turned out to be impractical. Instead, solid bodiesthat might have played apivotal role in chemical precipitates wereobtained easily in . Crude mixtures evolution. have been thoroughly scrutinized by spectroscopic methods,

Introduction withinthe contextofplanetary simulation experimentsthat lead to aerosol or solid deposits that contain organic constitu- Astrochemical observations of protoplanetary disks that sur- ents of variable chemical composition, usually with low C/N round distant stars along with space missions that targeted icy ratios.[8] However,these simulationsmay not reproduce the moonsand interstellar bodies provide enoughevidenceon actualconditions present on or Jovian moons, for in- these huge chemical factories to suggestthat complex organic stance. Analysesconducted so far on such complexmixtures chemistry is ubiquitous beyondour tiny planet.[1,2] In such sce- show that the formation of prebioticmolecules, including tria- narios, the chemistry appears to be influenced or largelydomi- zine bases or amino acids, is not uncommon alongside linear nated by surface and solid-state reactions (e.g.,ondust and cyclic macromolecular structures(PAHs among others), in [3] grains), which are clearly different from processes that occur whichCH2,NH, or CN functionalities serve as growth units.If in gas-rich atmospheres or wet environments.[4] Aplethora of one leaves aside these astrochemical reactions, combinations neutralspecies and have been detected in the interstellar of prebiotic precursors do represent plausible routes to medium, which range from simple diatomic molecules to poly- modelsofearly evolution, as exemplified by Sutherland’s ami- atomic -bearingspecies, such as , cyana- noxazole chemistry on the currently held view of the prebiotic mide, , or low-mass alcohols.[5] Theterm has formation of nucleosides and .[9] That chemistry, become synonymouswith complex organic matter,and they linkedtoglycolaldehyde, , and inorganic phospho- are often intractable mixtures.[6] In astrict sense,the term was rus, may subsequently triggerthe formation of nucleoside ana- first coined by Sagan and Khare in the late 1970s to describe loguesand other biomoleculesinthe presence of other small sticky brownish residuesthat were formedbyphotochemical precursors. irradiation or electrical discharges of cosmically relevant gas Prominent among prebiotic-like polymersare the so-called mixtures.[7] Accordingly,tholinsshould usually be defined HCN-oligomers, which have been the subject of numerous studies and structural proposals.[10] Heterooligomeric sequen- ces from two or more prebiotically credible speciesshould also [a] Dr.N.Lavado, Dr.J.C.Escamilla, Dr.M.valos, Dr.R.Babiano, yield other valuable, yet underestimated, polymers. The forma- Dr.P.Cintas, Dr.J.L.JimØnez, Dr.J.C.Palacios Departamento de Química Orgµnica eInorgµnica tion of such condensed phases would have served as asource FacultaddeCiencias-UEX and methodofaccumulationofprebiotic monomers. The pur- IACYS-Unidad de Química Verde yDesarrollo Sostenible pose of this article is to scrutinize in detail the chemical nature 06006 Badajoz (Spain) of the oligomeric species that are generated by reaction of E-mail:[email protected] [email protected] glyoxal and cyanamide in acetone, from which asolid material Supporting information and ORCID fromthe author for this article are can easily be isolated.Certainly,the direct condensations of cy- available on the WWW under http://dx.doi.org/10.1002/chem.201601999. anamide with have long been known,although

Chem. Eur.J.2016, 22,13632 –13642 13632  2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Paper the resulting reactionmixturesare often too complex for con- and trimeric hydrates form above 1m concentrations.[19] Hy- clusive analysis. In general, the base-catalyzed reactionof droxylated dioxolane and dioxanestructures coexistinsolution glyoxal with amides affords 1,2-bisacylamino-1,2-ethanediols.[11] in an equilibrium with their acyclic derivatives, andtheir rela- Similar reactions, conducted in the late 1960s, between glyoxal tive importance can be assessed by IR spectroscopy.[20] Glyoxal, and or sulfonamide derivatives gave rise to tetrahy- along with other and precursors, hasbeen de- droxypiperazines together with the corresponding N,N’-disub- tected recently in experiments that reproduce the photo/ther- stituted1,2-diamino-1,2-ethanediols (Scheme 1).[12] However, mochemical conditions of cometary ice analogues.[21] More- this protocol was not generalenoughand someamides failed over,cyanamide can undergo hydrolysis, although this appears to give the expectedadducts. As noted by the authors:“trifor- to be arelatively slow process, which would only be feasible mamidomethane,cyanamide, cyanacetamide, glycolamide, for- through its .[22] Also, cyanamide can un- mamidoxime, sulphamide, and ethanesulphonamidedid not dergo dimerization and cyclotrimerization reactions, often give solid precipitates on treatment with basic aqueous glyoxal, under hydrothermalconditions.[23,24] Cyanamide dimerizes to and evaporation of the solutions gave dark resinous residues give 2-cyanoguanidine (dicyandiamide) and stabilizes itself as which were not further examined”. However,fused piperazines acyclic (). The latter can hydrolyze to cyanuric as well as tetra-aza-5,10-dioxaperhydroanthracenes could be acid. Dicyandiamide can eliminate to give dicyana- identified later in the reactions of glyoxal and ethylenedia- mide. Cyanuric acid can aminolyzetoafford triuret;dicyandia- mines (Scheme 1).[13] Structurally related compounds arise from mide can hydrolyze to give biuret. Melamine, cyanuricacid, the condensation of a-diketones with ethanolamines, which biuret, and triuret are likely to be components of “biotars”, lead to trans-bis(morpholino) and trans-morpholino-dioxane which mightbecaged in the polymers. All in all, the existence rings.[14] of water molecules renders acomplex scenarioinwhich multi- ple equilibria may be involved. The coexistence of acetone molecules in -like scenarios mighthave taken place after cometary impacts or further chemicalevolution. Acetone belongs to one of the four organ- ic molecules (the others being , , and propanal) that were recently detected on 67P/Chur- yumov–Gerasimenko by the mission,which have never beforebeen observed on acomet.[25]

Results and Discussion Syntheses and structural clues Scheme1.Ring patterninginreactionsofglyoxal with and amides. Different isomers (either cis-ortrans-fused) can be generated in piperazine– With the aim of simulating conditions akin to aprimeval terres- oxazineand bis(piperazine) heterocycles. trial scenario, we conducted preliminaryscreenings by mixing equimolar amountsofcyanamide and glyoxal (as 40 %aque- Glyoxal(as hydrate) reacts with in aerosol ous solution)inneat water.That mixture did not afford any phases (clouddroplet evaporation), which leads to high-molec- precipitate after prolongedtime, although monitoring by 13 ular-mass oligomers that contain 1,3-dimethylimidazol-5-ones CNMR spectroscopy (D2Osolutions) showed carbon peaks, that are substituted with formyl and N-methylglycineside which were absent in acontrol experiment with glyoxal alone chains. This oligomerization, which appears to be relevantin and suggest the formation of condensation products.Inpartic- the formationoforganic aerosols, occurs by repeated addition ular,quaternary peaks between 160 and 167 ppm presumably of units.[15] In arelatedcontext,the prebiotic-like con- point to carbonyl and imine derivatives, one carbon peak at densation of glycolaldehyde and cyanamide, reported by Su- around121 ppm would be consistent with the function- therland et al.,gave rise to the formation of complex mixtures, ality,and upfield shifts below 100 ppm could be attributed to althoughcontemporary NMR experiments did shed light into hemiacetalic or N C Ocarbons (in the range 93–80 ppm) and À À their putative composition with the identification of some key CH O peaks ( 65 ppm), which arise from the glyoxal core. 2À À  products (e.g.,nucleoside analogues, as noted above).[16] The reactionmixture evolvesslowly at room temperature, and Despite its inherent lability,glyoxal has been proposed as an one additional low-intensity resonance that is shifteddown- intermediate towards other carbonaceous structures in inter- field did appear after more than 10 days (d 174 ppm), which C  stellar bodies.[17] It should be pointed out that condensations most likely corresponds to or lactone groups (see below). of glyoxal with lower alcohols (also of extraterrestrial origin, Further experiments in which the proportion of cyanamide such as glycol) lead to cyclic structures (pseudosu- was increased (i.e.,2:1 stoichiometries) also gave positivere- gars), which would serve as astable reservoir of that dialde- sults, although the solutiondarkened progressively, and black, hyde.[18] Glyoxalisprone to hydration;asaresult, monomeric tarry mixtures were obtained after about one month at room hydratesare formedatlow molar concentrations,and dimeric temperature.

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Gratifyingly,when aqueous glyoxal and cyanamide were sus- final product. In short, RME (expressed in percentage) is the pended in acetone and stirred at RT,weobserved an off-white quotient between the mass of the product and the masses of precipitate. The three molecules are obviously of prebiotic sig- the startingmaterials (glyoxal is expressed as CHO CHO units). À nificance, and one would clearly expect their condensation. The highest RME values were found for 1:1stoichiometries To optimize the experimental conditions, our initial studies (both in 25 and 50 mL of acetone) and the lowest ones were on the ternary system involved nine assays of varying cyana- for 2:1cyanamide/glyoxal mixtures. Obviously,these results mide/glyoxal molar ratios (2:1, 1:1, and 1:2) and volumes of are overestimated because samples occlude water and ace- acetone(5, 25, and 50 mL), the latter determinedthe precipita- tone;therefore, RME values that are focused on only tion times (Table 1). Irrespective of the initial conditions, all (Table 1, last column) better reflect the mass profits,which are solids showed comparableproperties and, as deduced from attainedfor 1:2cyanamide/glyoxal mixtures. This suggests that the NMR peak integrations, they occlude significant amounts an excessofglyoxal also triggersthe incorporation of cyana- of water and acetone. The solids darkenupon heating, and yel- mide molecules into the growingframework, which leads to lowish (or brownish) colors are observed from 1458Con- insoluble species. Overall, optimal efficiencies correspondto  wards;this may reflect degradation and/or cross-linking pro- 1:1ratios in 25 and 50 mL of acetone(Table 1, entries 5and 6). cesses, which are characteristic behaviors of thermally sensitive Under those conditions, both partners would react without ap- polymericsubstances. As shown later,the lowest darkening preciable extrusion of the cyano groups.AsRMEs are far from temperatures (LDT,Table 1) are also consistent with thermogra- being quantitative, mass losses could also be attributed to vimetricdata, because mass loss and concomitant release of low-molecular-weight oligomers, which are poorly assembled gaseous speciesare detected at 1508C. in supramolecularentitiesand remaininsolution.  Notably,the solventmolecules remain in the solids after two monthsunder vacuum (desiccator,over anhydrous SiO ). Ace- 2 Identification of functional groups tone is adsorbed and occluded into the solid, and manifests itself by its essentially quantitative removal (rotary evapora- The spectroscopicdata of the insoluble powders isolated from tion) from [D6]DMSO solutionsbefore recording the corre- different batches were similarwith no salient differences sponding NMR spectra. At this stage,wealso wondered among them (Table 1, entries 1–9;see the SupportingInforma- whether cyanamide was actually part of the oligomeric net- tion). The FT-IR spectra allowed us to scrutinize the main func- work or merely occluded into amaterial that was essentially tional groups that were presentinsuch oligomers;Figure 1 composed of glyoxal oligomers. To check this surmise,glyoxal shows the IR spectra of samples 2:1@50, 1:1@50,and 1:2@50 (23.6 mmol, 40 %aq. solution) was kept in acetonefor the (Table 1, entries 3, 6, and 9), for which high mass efficiencies 1 same reaction times and conditions as specified in Table1,and were obtained. The broad band that is centered at 3345 cmÀ we did not observe the formationofany precipitates. More- can be assigned to stretching bands of OH- and NH-containing over,the elemental analyses showed smallvariations in the C functional groups, although that band also accountsfor the and Hpercentage, whereas the nitrogen content increased presence of water that has been occluded within the hydro- 1 (from 14 to 26 %) as the cyanamide/glyoxal ratio increased. philic chains. Bands justbelow 3000 cmÀ are characteristicof  As we dealt with oligomeric mixtures, neither empirical for- aliphatic C Hbonds, in particularthe band at about 1 À 3 mulas nor chemical yields could be estimated with accuracy. 2960 cmÀ can be attributed to CH(sp )groups,which would

However,mass balances could be rationalized in terms of reac- correspond to CH3 asymmetric stretching of occluded acetone 13 tion mass efficiency (RME) values, auseful concept in green as well as CH2 groups,whichwere observed in the CNMR [26,27] 1 chemistry metrics, whichtogether with atom economy, spectra (see below). Bands at 2850 and 2750 cmÀ can be due measures how much of the starting materialsend up in the to the C HstretchinCHO and CHN functionalities. The pres- À

Table 1. Experimental results for the series of solid oligomeric mixtures prepared from cyanamideand aqueousglyoxal.

Entry[a] Cyanamide Glyoxal[b] Acetone t LDT[c] Elemental analysis [%] RME[%][d] [mmol] [mmol] [mL] [h] [8C] CHNtotal nitrogen[e] (1) 2:1@5 12.06.0 512 149.2 32.55 4.81 26.04 35.7 23.5 (2) 2:1@25 12.06.0 25 24 148.7 34.05 4.71 22.0640.8 22.7 (3) 2:1@50 12.06.0 50 60 147.3 34.57 4.51 21.4140.0 21.6 (4) 1:1@5 12.012.0 512 148.3 33.14 4.78 23.08 54.5 44.7 (5) 1:1@25 12.012.0 25 24 145.4 33.55 4.67 21.6171.9 55.1 (6) 1:1@50 12.012.0 50 60 145.7 33.49 4.53 19.2975.8 51.3 (7) 1:2@5 12.024.0 512 146.9 35.19 5.07 13.78 53.0 40.5 (8) 1:2@25 12.024.0 25 24 146.1 33.43 4.65 16.7663.8 59.7 (9) 1:2@50 12.024.0 50 60 145.8 33.20 4.74 16.6965.1 60.1

[a] Molar ratios of cyanamide and glyoxal in agiven volume (mL) of acetone. [b] Employed as 40%aqueous solution. [c] Lowest darkeningtemperature. [d] Reaction mass efficiency:(mass of product)/(massesofstartingmaterials). [e] Reactionmass efficiencies (RMEs) based on nitrogen content (determined by elemental analyses) can be obtained by RME(N) =(mass of product ”%N ”100)/(mass of cyanamide ”%N).

Chem. Eur.J.2016, 22,13632–13642 www.chemeurj.org 13634  2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Paper ence of anitrile triplebonds can be inferred from the band at 1 2188 cmÀ ;this absorption is more intense in spectra of sam- ples that were obtained from 2:1cyanamide/glyoxal mixtures (Figure 1). Likewise, one should also note abroad band that is 1 centeredatabout 1700 cmÀ ,which can be assignedtoC=O groups that are present in the occluded acetone as wellaslac- tone and urethane functional groups. Finally,the broad band 1 at 1068 cmÀ is characteristic of the C Obond stretch. À

Figure 1. Transmission FT-IR spectra of solid oligomers(KBr pellets) prepared from different cyanamide/glyoxalratios.

Figure 2. Top: UV/Vis absorption spectra of 1:1@25 oligomersinwater 1 UV/Vis absorption spectra(Figure 2) were recordedinaque- (0.02 gLÀ ). Bottom:tabulated absorbances for differentoligomers. ous solutionsand had some diagnostic value that supported data from other techniques. Absorption spectra were simple, and both, what we can and cannot see, are relevant for this in- tortionless enhancement by polarization transfer) experiments vestigation.The band at about 190 nm, whose intensity de- and compared with those of reference compounds. Notably, creasessharply,could be consistentwithn s*transitions, resonances in the approximate range 90–100 ppm confidently ! which are typical of saturated functional groups,such as mirror the expected values of anomeric positions and glyco- ethers, alcohols, and amines. The broad shoulder that is cen- pyrano rings,[29] therebyevidencing the putative existence of tered at about 215 nm may be accountable for both n s* pseudosugar units,like the above-mentioned oxazine and di- ! transitions of tertiary amines and n p*transitions of acyl oxane structures.[18] ! fragments. The molarabsorptivity could not be determined be- cause the molecular weightisunknown;alternatively, the spe- 1 1 cific absorptivity coefficient (E,LgÀ cmÀ )was measured at l= 215 nm. Remarkably, E increased as the cyanamide/glyoxal ratio increased;thus, E varies from 13.0, 24.3, and 34.0 for 1:2; 1:1, and 2:1cyanamide/glyoxal solutionsin50mLacetone, re- spectively.This variation could also account for agreater popu- lation of nitrogen-containing functional groups. The absence of significant bands above 240 nm evidence the lack of UV sig- naturesfor carbonyl groups as wellasaromatic/heteroaromatic fragments, at least in appreciable amounts. Aldehydegroups should be present as hydrated species, although trapped ace- tone could still be identified in the long-wavelength zone. However,for aliphatic ketones, the n p*transition is forbid- ! den with low molar absorptivities (10–100).[28] Only large amountsofacetone, relative to the whole oligomer,would give rise to noticeable absorptions. 13 More illuminating data emerged from the 13CNMR spectra, Figure 3. CNMR spectra(bothdecoupledand DEPT) of (1:1@25) oligomers in [D ]DMSO. which were similarfor all samples (see the Supporting Informa- 6 tion). As arepresentative example, Figure 3shows the 13CNMR spectrumofasolid isolated from the 1:1cyanamide/glyoxal Resonances at 207 and 30 ppm correspond to entrapped mixture after one month under vacuum.The nature and multi- acetone.Inaddition, the DEPT spectrum reveals that all de- plicity of the carbon resonances can be assessed by DEPT (dis- shielded peaks correspondtoquaternary . Signals be-

Chem. Eur.J.2016, 22,13632–13642 www.chemeurj.org 13635  2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Paper tween 110and 70 ppm are attributed to tertiarycarbon atoms, Table 2reports50peaks that were detected by ESI in all the whereas the group of signals around 62 ppm can be ascribed oligomerization experiments (Table 1, entries 1–9) upon varia- to secondarycarbon atoms. Broad signals at 157, 116, 78, and tion of the cyanamide/glyoxal ratio. Arepresentative mass 76 ppm, whichwere identified upon zooming, could likely be spectrum is shown in Figure 4. Theexact composition of all in- attributedtoasingletype of functional group that is in differ- vestigated reactionmixtures is included in the Supporting In- ent chemical environments, although various functional formation.The molecules are ordered by increasing molar groups might also be envisaged(see below). mass and filtered above an intensity threshold (the intensity range is given too).Data were collected at 300 V, as this spray voltageincreasedthe relative intensity of peaks with higher m/ Monomer assembly and growth:mechanistic models z values;however,the same peak profile could be observed at The use of mass spectrometry,often hyphenated LC-MS or GC- 140 V. MS, is customary to deconvolute the complex mixture into In each case, structuralassignmentswere proposed through fractionsofsignificant intensity;the resultant masses could addition reactions that involve appropriate nucleophilic and subsequently be fitted to fragments of known structures. Elec- electrophilic partners, which were often accompanied by sub- trospray (ESI) enables direct probingofreaction mix- sequent reactions, such as hydration/dehydration, reduction, tures by combining high sensitivity and little fragmentation at occasionally decyanation, and functional-group conversions, low voltages. Therefore, ESI is suitable for fishing out reaction thereby allowing formation of extended macrostructures. intermediates,[30] although its main limitation is the lack of Three different rationales, denoted hereafter as Models 1, 2, quantitative estimations, because peak intensities do not nec- and 3, are tentatively suggested, which satisfactorily account essarilycorrelate with the concentrationsofthe sprayedsolu- for the generation of the listed molecules startingfrom higher tion. In any case, electrospray techniques have proventobe cyanamide/glyoxal ratios followed occasionally by other trans- extremelyuseful[31] for shedding light on the sequence and for- formationsasnoted above. This range of structuralmotifs dis- mation mechanisms of prebioticoligomers, as shown by closes the reactivity of chemical species that are present in recent studies,[32] as well as in protein mapping.[33] equilibrium in aqueous glyoxal against cyanamide. Binucleo-

Table 2. Peak (m/z)assignments in ESI (positive mode) spectra obtained for cyanamide/glyoxaloligomers.

m/z Formula[a] Intensity Model[b] m/z Formula[a] Intensity Model[b] (calcd) range 123(calcd)range 123 125.0463 C H N O 17–99 2:1 H O2:1 H O2:1 H O 541.1391 C H N O 6–23 5:6 H O[c] 5:6 H O[c] 4 5 4 À 2 À 2 À 2 17 21 10 11 À 2 À 2 143.0569 C4H7N4O2 16–82 2:12:12:1 577.1603 C17H25N10O13 5–25 5:6+H2O

182.0678 C6H8N5O2 10–54 3:2 CN H2O 601.1715 C18H25N12O12 2–21 6:6(HM) À À [c] [c] 183.0518 C6H7N4O3 7–43 2:22:2 617.1552 C19H25N10O14 5–20 5:7 H2O 5:7 H2O À [c] À [c] 200.0784 C6H10N5O3 17–100 3:2 CN 3:2 CN (U) 619.1708 C19H27N10O14 2–23 5:7 H2O(HM) 5:7 H2O(HM) À À À[c] À[c] 201.0624 C6H9N4O4 11–86 2:2+H2O2:2 2:2+H2O 635.1657 C19H27N10O15 3–21 5:7 5:7

219.0729 C6H11N4O5 9–57 2:2(U) 683.1882 C21H27N14O13 1–11 7:7

225.0736 C7H9N6O3 5–50 3:2 693.1627 C24H21N16O10 3–14 8:8 241.0573 C H N O 22–43 2:3 H O2:3 H O 695.1981 C H N O 2–14 6:7+2H O 8 9 4 5 À 2 À 2 20 31 12 16 2 283.0791 C9H11N6O5 9–61 3:33:3 3:3 711.1732 C24H23N16O11 2–11 8:8(U/G) 299.0628 C H N O 17–76 2:4 H O2:4 H O 735.1845 C H N O 2–14 9:8(U/G) 10 11 4 7 À 2 À 2 25 23 18 10 317.0733 C H N O 8–62 2:4 H O 735.1930 C H N O 2–14 6:8[c] 6:8[c] 10 13 4 8 À 2 22 31 12 17 318.1162 C H N O 11–71 4:3 CN 761.2199 C H N O 1–10 7:8(HM) 9 16 7 6 À 23 33 14 16 (2(U/G))

319.1002 C9H15N6O7 8–36 3:3(2(U/G)) 777.2148 C23H33N14O17 1–14 7:8+H2O 341.0846 C H N O 24–76 3:4 H O3:4 3:4 817.2097 C H N O 2–8 7:9 H O[c] 7:9 H O[c] 11 13 6 7 À 2 25 33 14 18 À 2 À 2 399.0901 C13H15N6O9 14–50 3:5 835.2203 C25H35N14O19 1–9 7:97:9 417.1006 C H N O 9–50 3:5 H O[c] 3:5(U) 3:5 H O[c] 837.2359 C H N O 1–8 7:9(HM)[c] 7:9(HM)[c] 13 17 6 10 À 2 À 2 25 37 14 19 441.1118 C H N O 12–36 4:5 H O[c] 4:5(U) 4:5 H O[c] 853.2309 C H N O 1–10 7:9+H O[c] 7:9+H O[c] 14 17 8 9 À 2 À 2 25 37 14 20 2 2 457.0955 C15H17N6O11 4–21 3:6 859.2315 C26H35N16O18 1–9 8:9 [c] [c] 459.1224 C14H19N8O10 7–32 4:5 4:5(2U) 4:5 861.2472 C26H37N16O18 1–8 8:9(HM)

477.1330 C14H21N8O11 5–32 4:5+H2O 875.2066 C30H27N20O13 1–5 10:10 (U/G)

483.1336 C15H19N10O9 3–27 5:55:5 (2(U/G)) 877.2421 C26H37N16O19 1–11 8:9+H2O

499.1173 C16H19N8O11 10–22 4:6(U) 901.2533 C27H37N18O18 1–6 9:9+H2O

501.1442 C15H21N10O10 3–34 5:5+H2O 911.2363 C27H39N14O22 1–8 7:10 7:10 [c] [c] 517.1279 C16H21N8O12 7–28 4:6(2U) 937.2632 C28H41N16O21 1–7 8:10 (HM) 8:10 (HM) [a] Formulas correspond to M+H; full details for cyanamide/glyoxal oligomersare provided in the SupportingInformation. [b] Mechanistic proposals ac- cording to Models 1, 2, and 3(see main text); m:n denote the cyanamide/glyoxal ratio that generates the corresponding structure with agiven formula and molecular weight. Codes: H O(water elimination, usuallygivingrise to lactone rings); CN (cyano replacementbyH); U(transformation of cyanami- À 2 À do groups into , typicalofModels 2and 3);G(conversion of cyanamido groups into units); +H2O(addition of water,usual hydration of al- dehyde groups);HM(reduction of aldehydetohydroxymethyl, typical of Models 1or3). [c] In Model 1, these structuresrequire, in addition to six-mem- bered rings,the presence of dioxolano/lactone units (like that of structure 3:5depicted in Scheme 2).

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growingmolecular framework by reaction with free groups,therebyaffordingcyanoimines, which would then react with other units of glyoxal hydrate or carbaldehyde ter- mini. These transformations lead ultimatelytoelongatedimino dioxazine units that are linked by carbon carbon single bonds. À The mass spectra feature peaks that are consistent with this mechanism, which includes the formation of lactones after de- hydration in oligomers that contain ahigherproportion of glyoxal than cyanamide. Different isomeric structures cannot be excluded apriori, and thus, as highlighted in Scheme 2, tri- cyclic arrangements agree with glyoxal-rich formulas (e.g.,3:5 ratios). Less frequentpeaks are consistent with the reduction of terminal aldehydes to hydroxymethylene groups, because Figure 4. Representative MS (ESI) recorded for acyanamide/glyoxal(1:1@25) oligomer. this derivatization hinders further growth at those positions. As notedbefore, most peaks, high m/z valuesinparticular, can easily be interpreted by using this Model1,whereas lower philes that comprise geminal or vicinal hydroxyl groups along m/z peaks could be better rationalized by other mechanisms. with amino groups do react with unsaturated, both isolated Oligomers that are rich in glyoxal show an intense 13Creso- and conjugated, carbonyl, imino, and cyano functional groups nance at 197 ppm, which identifies the carbaldehyde func-  to yield different heterocyclic scaffolds. tional group.[34] The existence of dynamic equilibria between Model 1does explain most condensations that give rise to carbonyl groups and their hydrateshas also been studied in chain elongation, whereas the relative importance of Models2 both solution and the solid state,[35] and they show typical 13C and 3decreases as the increases. resonances at 180 ppm andinthe range 60–70 ppm, which is Model 1(Scheme 2) is based on the formation of six-mem- similar to those observed for cyanamide/glyoxal oligomers. bered rings, especially 6-imino-1,3,5-dioxazinanes,by[3+3] Moreover,the signalatabout 173 ppm justifiesthe formation cyclizationsthat involve the nucleophilic attack of oxygen of lactonegroups, which were detected in 3:4(cyanamide/ atoms presentinglyoxal hydrates on electrophilic carbons of glyoxal) oligomers after dehydration.[29] 13Cresonances around imino and cyano groups in monoimines. This model also ac- 62 ppm, which represent secondary carbons by inference from counts for the successive incorporation of cyanamide into the DEPT experiments, are deshielded enough to indicate their

Scheme2.Formation of iminodioxazinaneoligomers(Model 1) by [3+3] cyclizationofglyoxal hydrate and its .Bothlactone andCH2OH (HM) terminal groupscould also be generated. Glyoxal-rich formulas (such as 3:5) would also account for additionalfused ring structures, like the tricyclicfragment shown.

Chem. Eur.J.2016, 22,13632 –13642 www.chemeurj.org 13637  2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Paper proximity to oxygen-based functional groups. Such peaks can tions (Scheme 3). The fact that nitrile groups decorate the line- be attributed with confidencetothe units of lac- arly fused polycyclic framework was confirmed by the IR ab- 1 13 tone rings (e.g.,3:5 oligomers after dehydration)aswell as hy- sorptionat2188 cmÀ and the Cresonance at 117.8 ppm. Cy- droxymethylene groups (4:4 oligomers followed by carbalde- anamido groups could then undergohydrolysis to give hyde reduction), which exhibit similar resonances to those .[37] In stark contrast,the existence of repeating units that [29] found for CH2OH groups in sugar rings. Furthermore, the are based on piperazine-1,4-dicarbonitriles (generated by the transformationofglyoxal into has been report- addition of glyoxal hydrate to its diimine), if not completely ed.[36] Therefore, both groups couldhave arisen from Canni- impossible, would be highlyimprobable, because such hetero- zzaro-type aldehyde disproportionreactions. cycles are expectedtoeliminate two HCN molecules under the However,the complexity of NMR spectra points to agreater reactionconditions, which would lead to aromatization. We structural diversity,which cannot be circumscribed to asingle did not find any (significant or diagnostic) UV or 13CNMR sig- model.Accordingly,cyanoimino groups cannot be easily iden- nature for aromatic heterocycles, which reflects the low proba- tified in 13CNMR spectra,even though 1HNMR signals provide bility (if not absence) of forming piperazine-1,4-dicarbonitrile some support for these functionalities (see below), because all scaffolds. Moreover,the removal of cyano substituents is con- resonance signals between 150 and 172 ppm are due to qua- sistent with oligomeric formulas that were detectedinthe ESI ternary carbon atoms. DEPT experimentsdonot show tertiary spectra (Table 2). An extra argumentthat supports the exis- carbons, althoughthe broad signals between 154 and tence of oxygenated rings is the fact that oxazines, like diox- 158 ppm may include signals from non-quaternary carbon anes, cannot stabilizethemselves through aromatization. Final- atoms together with complex equilibria that involve both ly,itshould be noted that these structures are also susceptible inter- and intramolecular associations. Owing to their high re- of furtherintramolecular cyclizations, whichproduce isoureido activity,cyanoiminogroups could either react with existing and guanidinolinkages and would impede chain growth to- glyoxal molecules or undergo hydrolysis, which would account wards oligomers with highmolecular masses. for their scarce abundance. However,the aforementioned mechanism will invariably An alternative proposal, Model 2, is based on [4+2] cycliza- give rise to cyanamide/glyoxal ratios that are enrichedinthe tions that involve the nucleophilic attack of glyoxal hydrate (or latter.MSdata indicate that peaks with identical ratios that are its oligomers) onto the corresponding imines, which are gener- enriched in cyanamide may also occur,especiallyfor higher ated by the addition of cyanamide to glyoxal monomers. It is masses, which would otherwisebeless prone to fragmenta- plausible to believe that the resulting oligomeric chains will tion. Under this premise, arationalethat accounts for such cy- consist of N- and O-rich fused 1,4-dioxane and 1,4-oxazine anamide excessesisrequired. Thus, self-condensation of hy- (strictly morpholino-N-nitrile) units accompaniedbyhydroxy drated monoimines enables the formation of structures that in- and N-monosubstitutedcyanamido groups at terminal posi- corporate equimolar amountsofcyanamide and glyoxal units

Scheme3.Mechanistic proposal(Model 2) that accounts for the formation of fused six-membered heterocycles, such as 1,4-dioxane and morpholino-N-car- bonitrile,among others,byreaction of either glyoxal or glyoxal oligomers with cyanamide. UorGdenotesthe conversionofcyanamido into ureido or guani- dino groups, respectively.

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(Scheme 3, middle), whereas Model 2(bottom)might also tic, often diagnostic, signals of anomeric positions in monosac- easily explain the incorporation of cyanamide fragments into charides[29,41] as well as in furanoid and pyranoid glycosyla- the growing chain, which would afford guanidine functional mines and their analogues,[42] which are all consistentwith the groups and allow subsequent cyclizations.The resulting het- carbon atoms in the pseudosugarfragments that were predict- erocycles are not expected to undergo facile aromatization, ed by Models1–3. Carbon peaks of O C Nand N C Nmoiet- À À À À and such functional groups (eitherureido or guanidino) are ies could nevertheless be shifted upfield( 79–87 ppm).[42a,43]  consistentwith 13Cresonances andUVspectra. Even though it is less informative than 13CNMR spectra, 1H Additional variations and crossed reactions between Models resonances (see the Supporting Information) provide addition- 1and 2would also be feasible. Accordingly, guanidine struc- al support for the oligomeric structuresthat feature the above- tures that are analogoustothe 4:3unit (G, Scheme 3) could mentioned functional groups (Figure 5). All samples (nine syn- be generated from the 3:5unit (contains apiperazine subunit, theses)gave rise to similarspectralpatterns irrespective of Scheme 2) by successive condensations with glyoxal monoi- their storageunder vacuum (either one day or one month) mine andcyanamide. Moreover,the 4:3variant (2,6-diimino tri- and showbroad signals between 4.4 and 8.4 ppm. This region azinane-1-carbonitrile derivative)could undergo further N3 C4 may well comprise both pseudoanomericprotons and methyl- À oxidation, whichwould lead to an aromatic compound; 13C ene or methine protons that are adjacent to O/N atoms. Reso- resonances could be ascribed to the triazine derivatives, but nances at about 9.4 ppm (aldehyde) and in the range 8.2– UV data are not consistent with such heterocyclic rings (very 8.7 ppm (imine) are observed in all cases. There is invariably an low concentration at most). intense and broad singlet centered at 3.34 ppm (HDO) as  Another mechanistic variation, Model3,that involves [3+2] well as another peak at 2.09 ppm (acetone);the latter signal cyclizationsofhydrated glyoxal substrates, which would also disappeared after partial evaporation of the [D6]DMSO solution. lead to five-membered substructures, also appearstobeplau- H/D exchange removes virtually all signals above 6ppm with sible (Scheme 4). In short,this proposal is based on the nucleo- the exception of imine and aldehyde protons. philic attack of geminal OH groups ontothe electrophilic It is worth mentioning that similar NMR patternswereob- carbon atoms of imine and aldehyde units of amonoimine. tained from acetonesolutions of 2,3-dihydroxy-1,4-dioxane, This model unifies the precedingmechanisms; vicinal 1,2-dihy- asugar-likemolecule,[18] and cyanamide, the former being droxy,1,3-diamino, and 1-hydroxy-2-amino groups enablethe amasked and anhydrous form of glyoxal.[44] facile generation and chain growth of fused five- and six-mem- Before concluding the structural analysis, it should be high- bered heterocycles. lightedthat some sort of supramolecular arrangements have However,free carbaldehyde groups could bias oligomer for- to be assumed, which would explain the existence of tightly mation through Model 1asthe prevalent route. Like in Model boundwater and/or encapsulated water and acetone mole- 2, the existence of equilibria that favor isoureido and guanidi- cules, even thoughthe specificweak interactions that are in- no units would hinder further elongation. volvedcannot be determined with accuracyright now. It should be emphasized again that NMR signals between 156 and 162 ppm (C=Nbonds)[38] would reflect, on the one Thermogravimetric analysis hand, the putative existence of iminodioxazinanes, according to Model 1, butalso both 2-iminoxazolidines and 2-iminoimi- Like other prebiotic polymers,[10c] the ability of cyanamide/ dazoles,the formation of which slows down subsequent ring glyoxal oligomers to retain water and other low-molecular- fusion. Guanidino carbon atoms usually resonate between 151 weightpolar solvents can be assessed by thermogravimetric and 162 ppm,[39] and cyclic that bear exo-imino (TG) analysis followed by GC-MS measurements. The TG curves groups display typical resonances at 151–158 ppm.[40] Carbon (Figure 6; see theSupporting Information) were observed to resonances in the narrow range of 91–103 ppm are characteris- be similar for all oligomers, regardless of the initial cyanamide/

Scheme4.Mechanistic proposal(Model 3) that accounts for oligomer formationby[3+2] cyclizations of hydrated carbonyls to monoimine derivatives.

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1 Figure 5. HNMR spectrumof1:1@25 oligomers recorded in [D6]DMSOat

500 MHz (bottom) and after D2Oexchange (top).

glyoxal ratio, and showedagradual weight loss between room temperature and 400 8C(about 40–50 %), which became less pronounced as the glyoxal contentincreased to 1:2stoichiom- etry.The material contains asignificant amount of adsorbed water (up to about30%), although above 1508C, the released water may be due to structural changes as other oxygenated Figure 6. Top: thermogravimetric curve for 1:1@25 oligomersdried under 1 compounds are detected together with variable amounts of vacuum;the heating rate was 108CminÀ under air.Bottom:detectionof H2O(g) and otherlow-molecular-weight gaseousspeciesbyusing GC-MS CO2 and CO depending on the reactiontimes. Notably,the ni- 1 (quadrupole) upon heating;Hecarrier with aflow rate of 50 mLminÀ . trogen-containing compounds are seldom lost. Mass peaks that are attributed to H2 (m/z 2; presumably obtained by atomic recombinations), nitrogen and oxygen atoms, and CH2 and decyanationtoaminor extent,appear to be substantially and CH3 groups(m/z 14, 15) indicatethe chemical composition supported by spectroscopic data together with termination of the polymeric matrix. Moreover,peaks at m/z 43 and 58 steps, such as formation of ureido/isoureido and guanidine would also be consistent with the presence of acetone or C3H7 subunits. ions. Our work complementsprevious efforts that have focused on spotting prebiotic polymers, such as the ubiquitous HCN Conclusions polymers, polymers, or polycyclic aromatic hy- drocarbons(PAHs) among others. The fact that tholins and Mixtures of cyanamideand glyoxalinacetone give rise to solid solids that are scrutinized by astrochemical analysis and space oligomeric species that can easily be isolated. The carbona- missionsare intractable mixtures often prevents the structural ceous macrostructures are decorated with C Nand C O identification of such complexmaterials. Lab simulations, like À À bonds with variable degrees of unsaturation. These solids are the one describedhere, proves that homopolymers and heter- capable of absorbing solventmolecules and water (largely ocopolymers could be obtainedfrom awidevariety of prebiot- present in the glyoxalsolution or as aresult of condensation ic monomers. reactions), which remain adsorbed even after prolonged In addition, these carbonaceous networks may offer inherent drying. Through adetailed analysis, which includedIRspectra astrobiological implications. In particular,these materials could to identify key functional groups, NMR spectroscopy,and elec- serve as catalysts and informational polymers that are capable trospray ionization mass spectrometry,some well-established of releasing primordial substances required for protometabolic stepwise condensation mechanismscould be formulated. Data cycles. Although these hypotheses need to be confirmed, they allowed us to suggest three mechanistic pathways (Models 1– are doubtless worthwhile. Our currentactivities concentrate on 3) that involvedifferent cyclizations between glyoxal hydrates, similar transformations that deal with other prebiotically plau- which serve as the nucleophilicpartners, and imine derivatives, sible monomers, the ability of the resulting oligomers to act as which act as the electrophilic agents. Model 3constitutes auni- organic catalysts, and an indepth study of such oligomeriza- fying approach that accountsfor five- and six-membered-ring tions in water. formation,although construction of fused rings in alinear se- quenceisbest explained by Model 2. Post-condensation reac- tions, such as hydration/rehydration, lactonization, reduction,

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Experimental Section chemistry and homochirogenesis (Grant CTQ2013-44787-P). Fi- nancialassistance from the AutonomousGovernment of Ex- Materials and synthetic preparations tremadura (Grant GR15022)isalso greatly appreciated. J.C.E. Reagents and solvents were purchased from commercial suppliers thanks the University of Extremadurafor an “Alianza delPacíf- and used without further purification. Synthetic protocols were ico” (Mexico-Spain) grant to carry out postgraduate research. performed as follows (representative example for cyanamide/glyox- Last, but not least, we thank an anonymous reviewerfor astim- al, 2:1@5): Glyoxal ( 40%aqueous solution, 8.8m,0.35 g,   ulating feedback and constructivecommentsduring the peer- 0.7 mL, 6.0 mmol) was added to asolution of cyanamide (0.51 g, review process. 12.0 mmol) in acetone (5 mL), and the mixture was stirred at room temperature (and under ambient atmosphere) until the appear- ance of white solids. After 12 h, the precipitate was collected by fil- Keywords: cyanamide · glyoxal · heterocycles · tration, washed with acetone, and dried under air (0.30 g). Reac- oligomerization · prebioticchemistry tions in larger volumes of acetone (25 or 50 mL) were conducted in asimilar manner,although solid precipitates were isolated after 24 or 48 h, respectively.Reaction mass efficiencies (RME) are gath- [1] U. Meierhenrich, Cometsand Their Origin,Wiley-VCH, Weinheim, 2015. ered in Table 1. [2] For arecentand special issue on :E.Herbst, J. T. Ya- tes, Jr., Chem. Rev. 2013, 113,8707 –9150. Evaporations were conducted on arotary evaporator at tempera- [3] D. Williams, S. Viti, Phil. Trans. R. Soc. A 2013, 371,20110587. tures below 408Cand estimated pressures (external manometer) [4] K. Ruiz-Mirazo, C. Briones, A. De La Escosura, Chem. Rev. 2014, 114,285 – between 15 and 30 mmHg. Darkening temperatures were deter- 366. mined on Gallenkamp and digital Electrothermal IA 9000 apparatus [5] R. I. 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