View Online / Journal Homepage / Table of Contents for this issue NJC Dynamic Article Links Cite this: NewJ.Chem., 2011, 35, 1787–1794 www.rsc.org/njc PAPER Hydrothermal formose reactionw Daniel Kopetzki* and Markus Antonietti Received (in Montpellier, France) 1st March 2011, Accepted 11th May 2011 DOI: 10.1039/c1nj20191c The self-condensation of formaldehyde is a one pot reaction resulting in a complex mixture of carbohydrates. Based on a simple chemical, the reaction was previously considered as a prebiotic source for sugar generation. Usually, a high pH and the presence of catalytically active species are required. Here, the formose reaction was performed under hydrothermal temperatures up to 200 1C, and carbohydrates were obtained under even simpler conditions. We found no pronounced catalytic influence of active cations, and a slightly alkaline pH was sufficient to induce the reaction. Maximum yield was reached in very short times, partly less than 1 minute. No selectivity for a particular carbohydrate, although searched for, was found. Contrary to reactions performed at lower temperatures, hexoses were only formed in negligible yields, whereas the shorter carbohydrates accounted for the major fraction. Among the pentoses, ribose and the ketoses with corresponding stereochemistry were formed in higher yields compared to the reaction at lower temperature. Furthermore, we identified 2-deoxyribose in the product mix and found strong indications for the presence of other deoxy compounds. Hence, the hydrothermal formose reaction shows some remarkable differences compared to the conventional reaction at moderate temperatures. 1 Introduction Habitats with superheated water are available in submarine areas with volcanic activity and such hydrothermal environ- Downloaded by University of Oxford on 10 November 2011 As nearly 3.5 billion year old microfossils and typical isotope ments with temperatures around 200 1C at a pressure of 20 bar 1 Published on 16 June 2011 http://pubs.rsc.org | doi:10.1039/C1NJ20191C patterns in sediments indicate, life arose quite early on earth, or higher were also present at ocean sites in the hadean period.10 just about some hundred million years after the moon/earth The presented synthesis of carbohydrates is based on collision. Thus, the primary synthesis of biomolecules took formaldehyde, which can be clearly formed under hadean place at environmental conditions very different to the current conditions and is generally considered as a prebiotic molecule ones. The prebiotic chemistry community tries to resolve having contributed to the local chemistry.11 It can be synthe- the question, how complex organic molecules can be formed sized by photoreduction of CO2, but is also available via from simple precursors, and to elucidate plausible mechanisms electric discharges.12 This simple compound can be converted 2 proceeding in prebiotic environments. This is hampered by the to a mixture of different carbohydrates in a one pot reaction, lack of knowledge about the true conditions on the early earth, called the formose reaction. Under alkaline conditions and which includes the composition of the atmosphere, whether it with certain catalysts, formaldehyde polymerises to form 3 4 was neutral or reducing, or the temperature of the ocean. sugars.13 Due to the ease with which complex carbohydrates 5,6 In the famous Miller experiment, the generation of amino are synthesised from a very simple precursor, the formose acids was proven in a simple reducing atmosphere subjected to reaction has been considered to have contributed to the origin spark discharges. Recent work has mainly focused on the of life. However, due to the fast degradation of sugars and the 7 8,9 formation mechanisms towards peptides and nucleic acids, missing selectivity, this is doubtful.14–16 while the focus of this paper lies more in the formation and The kinetics of the formose reaction is quite complex, due to chemistry of carbohydrates. In this respect, we will investigate its autocatalytic nature.17 Formaldehyde usually does not whether high temperature is feasible as an energy source. react with itself establishing a carbon–carbon bond, so that the simplest sugar glycolaldehyde is formed slowly (see Scheme 1). Max-Planck-Institute of Colloids and Interfaces, Research Campus However, as soon as some condensation product is present, a Golm, D-14424 Potsdam, Germany. cascade of reactions is initiated, ultimately leading to the E-mail: [email protected]; Fax: +49 331 567 9502; formation of various straight-chain and branched carbo- Tel: +49 331 567 9538 hydrates,18,19 plus their decomposition products. Elongation w Electronic supplementary information (ESI) available: Moderate temperature experiments, NMR and GC data. See DOI: 10.1039/ of the carbohydrate backbone occurs via base-catalyzed aldol c1nj20191c condensation with formaldehyde, accompanied by isomerisations. This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011 New J. Chem., 2011, 35, 1787–1794 1787 View Online Scheme 1 Simplified mechanism of the formose reaction. In alkaline medium retro aldol reactions take place as well, A 0.5 M formaldehyde solution was heated to 200 1C under a whereupon both resulting fragments can act as initiators pressure of 100 bar. It should be noted that such a high again, thus leading to an autocatalytic system. Due to their concentration is not along with prebiotic conditions. To vary relative stability pentoses and hexoses are the main products. the pH and to probe for the potential catalysis of simple ions, For prolonged reaction times however they decompose, recogni- salts were added. Despite the fact that certain cations are sable by the yellowing of the solution. necessary at moderate temperatures, we first used inactive Often, Ca(OH)2 is used as base because of its high catalytic sodium or potassium salts. Control experiments were conducted 2+ activity. Ca can coordinate the enediol form of carbo- at 60 1Cin0.05MCa(OH)2 or 0.1 M NaOH, respectively hydrates and thus stabilises the deprotonated species.20 (ESIw, Fig. S1–S3). Performing the reaction in NaOH in the absence of other The conversion of formaldehyde in different salt solutions is catalytically active cations does not yield any sugars. Apart shown in Fig. 1. In pure water and even under acidic conditions from Ca(OH)2 many other catalysts of the formose reaction (such as diluted acetic acid), formaldehyde is consumed relatively have been identified.21 Naturally occurring minerals and clays, fast within a timescale of minutes. An induction period, as quite abundant in nature, can also evoke the formation of described for the formose reaction at moderate temperatures, carbohydrates when refluxing a formaldehyde solution.22–24 is not observed. With increasing basicity of the added salts, the It is even possible to induce the formose reaction photo- conversion is accelerated. Even the barely basic sodium sulfate chemically, resulting in the formation of highly branched sugar shows some effect. This trend is continued following the series alcohols.25 Apart from formaldehyde other small molecules can acetate, hydrogen carbonate and hydrogen phosphate. In a also be employed to build up carbohydrates. Using short carbonate buffer (50 mM NaHCO3,50mMNa2CO3), the sugars, like glycolaldehyde or glyceraldehyde, other catalysts formaldehyde is consumed in less than one minute. and less harsh conditions are sufficient. Examples include zinc Of course, the fact that formaldehyde vanishes does not prolate,26 silicate27 or dipeptides,28 but in none of these cases a prove the formation of carbohydrates. In fact, the NMR Downloaded by University of Oxford on 10 November 2011 successful formose reaction using solely formaldehyde could spectra of the reactions performed in pure water, in acetic Published on 16 June 2011 http://pubs.rsc.org | doi:10.1039/C1NJ20191C be performed. acid and also when sodium acetate was added, just show the The formose reaction is usually performed at moderate Cannizzaro products formic acid and methanol (ESIw,Fig.S4). temperatures or occasionally at around 100 1C.29 In recent These solutions remained clear and colourless even for work, we have presented a continuous flow reactor which prolonged reaction times and did not show the typical yellow- allows us to perform organic reactions in water at high ing point, resulting from decomposition products when temperatures and pressures with high control and precision.30 carbohydrates were formed. This colour change was however It was for instance shown that formic acid acts under such observed for all more basic salts, indicating a successful conditions as an effective hydrogenation agent, while simple salts can take an unexpected role of being a catalyst. In the present attempt, we will apply this set-up to the formose reaction. Using simple hydrothermal reaction conditions and formaldehyde without additional initiators in the presence of only simple salts, reaction sequences are analysed. The moti- vation to study the formose reaction under such conditions is based on the lack of data on the hydrothermal behaviour of formaldehyde yielding complex molecules,31,32 but also on the fact that early earth conditions might have included various aqueous environments under similar conditions. 2 Results and discussion Effects of added salt To establish hydrothermal conditions with high precision and Fig. 1 Conversion of formaldehyde in the presence of various salts at control, reactions were conducted in a continuous flow reactor. 200 1C and 100 bar. 1788 New J. Chem., 2011, 35, 1787–1794 This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011 View Online formose reaction despite the absence of catalytically active carbohydrate formation is reached well before complete cations. In a control experiment with microwave heating, this formaldehyde consumption. yellowing occurred in glass vessels as well, suggesting that it is At moderate temperatures, the presence of Ca2+ is crucial not the reactor material which causes the observed effects. for a successful formose reaction.