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This article was published as part of the
Prebiotic chemistry themed issue
Guest editors Jean-François Lambert, Mariona Sodupe and Piero Ugliengo
Please take a look at the issue 16 2012 table of contents to access other reviews in this themed issue
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5404 Chem. Soc. Rev., 2012, 41, 5404–5415 This journal is c The Royal Society of Chemistry 2012
Cite this: Chem. Soc. Rev., 2012, 41, 5404–5415
Prebiotic chemistry in eutectic solutions at the water–ice matrixw
Cesar Menor-Salvan* and Margarita R. Marın-Yaseli
Received 29th February 2012
DOI: 10.1039/c2cs35060b
A crystalline ice matrix at subzero temperatures can maintain a liquid phase where organic
solutes and salts concentrate to form eutectic solutions. This concentration effect converts the
confined reactant solutions in the ice matrix, sometimes making condensation and polymerisation
reactions occur more favourably. These reactions occur at significantly high rates from a prebiotic
chemistry standpoint, and the labile products can be protected from degradation. The
experimental study of the synthesis of nitrogen heterocycles at the ice–water system showed the
efficiency of this scenario and could explain the origin of nucleobases in the inner Solar System
bodies, including meteorites and extra-terrestrial ices, and on the early Earth. The same
conditions can also favour the condensation of monomers to form ribonucleic acid and peptides.
Together with the synthesis of these monomers, the ice world (i.e., the chemical evolution in the
range between the freezing point of water and the limit of stability of liquid brines, 273 to 210 K)
is an under-explored experimental model in prebiotic chemistry.
Introduction
Life as we know it depends on interfacial redox and transport
processes between liquid water and a system of lipid membranes
with the associated protein machinery. It seems logical to
assume that life emerged from liquid water solutions where
relatively simple raw materials were synthesised or accumulated.
These solutions could be subjected to water–mineral matrix
interfacial chemistry or concentration and compartmentalisa-
tion processes, which ultimately leads to the emergence of life
in a complexity increasing process. Consequently, to deter-
mine the possible compositions of the raw materials for the
plausible first steps of abiotic evolution, pioneering experi-
ments on prebiotic chemistry have been conducted in water-
saturated atmospheres and liquid solutions,1 which are largely
supported by a reductive atmosphere model.
The criticisms regarding an efficient atmospheric-liquid
water origin for the organic components of the first biochemical
processes on Earth arise from the lack of a universally
accepted geochemical model for the Archean atmosphere.
Additionally, the classic prebiotic chemistry approach deals
Centro de Astrobiologıa (INTA-CSIC), INTA,E-28850 Torrejon de Ardoz, Spain. E-mail: [email protected];Tel: +32 91520 6458w Part of the prebiotic chemistry themed issue.
Cesar Menor-Salvan
Cesar Menor-Salvan studiedChemistry at the Universityof Alcala and obtained hisPhD degree in Biochemistryin 2004, working on themetabolism and toxicology ofthiolated purine bases. Since2007 he has been a ResearchScientist at the Centro deAstrobiologia (CAB) andstarted a line devoted to theprebiotic chemistry of nitrogenheterocycles and the origin ofcofactors and proto-metabolicpathways. His researchinterests include Prebiotic
Chemistry, the origins of biochemistry and the organic markersof biological evolution on Earth.
Margarita R. Marın-Yaseli
Margarita Roig Marın-Yaseliobtained her degrees inPharmacy and Biochemistry atthe University of Zaragoza. Nowshe is a PhD student at theCentro de Astrobiologia, focusedon the Prebiotic Chemistry ofnitrogen heterocycles.
Chem Soc Rev Dynamic Article Links
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This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 5404–5415 5405
with the problem of the concentration and stability in liquid
water of the plausible prebiotic reactants. These criticisms and
the lack of experimental evidence supporting a model for the
origin of biochemical pathways have led to two main schools
of thought.
The first concept is the possibility of an in situ origin on
Earth, which focuses on either water–mineral interfacial pro-
cesses as a way for concentration and compartmentalisation of
environmentally synthesised reactants2 or on the origin of
chemoautotrophic pre-biochemical systems.3
The second concept argues that amino acids, nitrogen
heterocycles and simple organic molecules and monomers
could be synthesised by irradiation at very low temperatures
in extra-terrestrial ice layers composed of water and other
condensates.4 Ice is the most abundant form of water beyond
the asteroid belt.5 The chemistry of ices at low temperatures
followed by the delivery of the organic molecules on Earth by
comets, meteorites and dust particles could have been an
important source of organics on the prebiotic Earth and could
have played a key role in early chemical evolution. The
photochemistry and radiochemistry of outer solar system bodies
and interstellar ices have received substantial attention.6
Despite the research into the photochemical transforma-
tions in ice from an astrochemical point of view, the study of
the chemistry in the range of stability of the ice–water interface
has not received much attention. This may be due to the
scarcity of the defined conditions in the Solar System during
the epoch of active prebiotic chemistry or the difficulties
for demonstrating that these cold conditions existed in
Hadean Earth.
The evidence for a liquid water subsurface ocean on
Saturn’s moon Europa7 and the possible presence of water–
ammonia eutectic brines or even a subsurface ocean in other
outer giant planet satellites such as Titan8 or Enceladus9
rekindled the interest in liquid water prebiotic chemistry.
Moreover, the subsequent proposed steps for the emergence
of cellular life have a limited temperature range, and a hot
prebiotic Earth was regarded to be an unlikely environment
for the origin of life by some authors.10 Miller and Orgel stated
in 1974 that the emergence of biological organisation could
only occur at temperatures below the melting point of the
polynucleotide structure. After observing the instability of
organic compounds in the prebiotic stages, these authors
concluded that a temperature of 273 K would have been
beneficial and that temperatures near the eutectic point of
NaCl solutions (251.3 K) would have been even better.11
The low temperatures in planetary surface ices could be more
conductive to the origin and the preservation of molecules that
could be relevant for the emergence of life. In 1994, in one of
the first explorations of the idea of an ice world-based origin of
the life raw materials, Bada12 suggested that ice formations on
early Earth could have preserved organic compounds against
hydrolysis or photochemical degradation. Under plausible
planetary conditions, the presence of liquid water at T o 273 K
within an ice matrix creates a potential reactor where the
synthesis or polymerisation of molecules of biological interest
could occur. Herein, we will review our current knowledge of
the chemical models that simulate possible prebiotic synthetic
pathways in liquid water interfacial ice. The experimental
approaches developed in the literature are primarily focused
on the RNA-world hypothesis of an abiotic origin of nucleic
acids, as these studies provide experimental evidence for the
abiotic synthesis and polymerisation of nitrogen heterocycles
and nucleotides. Apart from the molecular evolutionary pers-
pective for the emergence of life, exploring the chemistry in
liquid inclusions confined in an ice matrix could explain and
predict the composition of objects in the inner Solar System
and icy planetary bodies.
The ice–liquid water system and its presence on the
early Earth and in the Solar System
The ice–liquid water system has not received much attention in
the literature, including the chemical physics and astrochemical/
astrobiological literature. In the latter case, the experimental
efforts are focused on low temperature condensates, where
there is no evidence of a liquid interface and the ice is in its
amorphous crystalline state. In the inner Solar System, including
on Earth, ice occurs naturally in the crystalline form with two
primary polymorphs, which are cubic and hexagonal. The
crystallisation of water under current Earth surface conditions
results in hexagonal ice Ih. The ice formed from liquid or
heated from amorphous ice at temperatures between 100 and
130 K is crystalline, with a diamond-type cubic structure Ic.13
Cubic ice is metastable at T o 70 K and undergoes a
transformation to the amorphous state (the stable form at
these temperatures) via cosmic ray bombardment and ultra-
violet irradiation.14 The irradiation diminishes the kinetic
barrier between the metastable cubic ice form and stable
amorphous ice form at lower temperatures.15 The crystalli-
sation of ice Ih leads to the formation of various interfaces,
such as ice–ice, ice–atmosphere and water–ice, as well as
water–ice–mineral, which results from crystallisation of solutes
by ice matrix exclusion or the presence of suspended mineral
grains.16 The ice–ice and ice–atmosphere interfaces are not a
distinct transition. Nuclear magnetic resonance studies of ice
crystals indicate the existence of a liquid transition between the
crystals or between the ice and the atmosphere. The thickness
of this liquid phase becomes monomolecular at To 243 K and
is thickened by dissolved solutes excluded from the ice matrix
to the interface during crystallisation.16
The unexpected presence of crystalline ice in the Quaoar
object at the Kuiper Belt, on Enceladus and its suggested
presence in Titan17 imply that the evolution of ices is subject to
occasional heating events. If crystalline ice and if even fluid
water solutions are unambiguously present, the conditions for
the increase in organic complexity from reactions between
precursors such as cyanide or cyanoacetylene may exist. The
young and active surface of the Jovian moon Europa suggests
the possibility of a subsurface water ocean from the observa-
tions of the Voyager mission and strengthened by the observa-
tions with the Galileo spacecraft.18 Recently, it has been stated
that Europa possesses an active dynamic ice–water system
with cycles of melting and refreezing. In addition, a lenticular
body of liquid brine in the TheraMacula region of approximately
20000–60000 km3 has been predicted.19 The composition of
Europa’s subsurface water, underlying an ice crust, could be rich
in sulphate salts, the source of surface evaporite deposits.20
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5406 Chem. Soc. Rev., 2012, 41, 5404–5415 This journal is c The Royal Society of Chemistry 2012
The details on water composition and temperature are
unknown, but estimations suggest a Mg–SO4–Na(K) rich
water with temperatures in the range 210–270 K.21 A model
for the formation of liquid ammonia–water pockets that cause
episodic cryomagmatism and a subsurface eutectic water–
ammonia solution has been proposed for the Saturn moon
Titan.22 Within this context, both Titan and Europa constitute
important astrobiological targets for direct exploration and
laboratory simulations to predict the chemistry that will be
found and to test our experimental prebiotic chemistry
models.23 A complex prebiotic chemistry has been predicted
for Titan that includes the formation of nucleobases24 and the
possibility of a methane–acetylene based chemical or biochem-
ical evolution.25 From these hypotheses based on atmospheric
or surface chemistry, the prebiotic possibilities of liquid water
brines entrapped under ice have received less attention and
are the object of speculative discussion regarding possible
biochemical evolution and the presence of chemoautotrophic
life.26
Some models suggest a Hadean terrestrial atmosphere
composed primarily of high pressure carbon dioxide. If liquid
water were present in oceans over a basaltic crust, a CO2
atmosphere would be unstable and could be depleted as
carbonates in a period of approximately 10 million years due
to hydrothermal circulation and reaction of the CO2 with the
crustal rock. Under these conditions, together with the
Hadean faint Sun, the model developed by Sleep and Zahnle27
agrees with the ideas suggested by J. Bada in 1994,12 predicting
ice-covered oceans and an average surface temperature of
approximately 220 K, with freeze–thaw episodes motivated
by occasional warming provoked by high energy impacts.
These cold conditions would be prevented if a methane-rich
atmosphere were present during the Hadean, as methane is a
potent greenhouse gas. Evidence thus far does not support an
atmosphere with a high enough concentration of methane to
avoid freezing of the ocean surface. This model would be
amenable for the development of prebiotic chemistry in an ice
matrix based on HCN, cyanoacetylene, acetylene, urea or
cyanate precursors synthesised on Earth or brought in via
extraterrestrial input.28
The freezing of ocean water is a complex process. Modern
sea water begins to freeze at 271.2 K and crystals of pure ice
(Ih) begin to grow, surrounded by liquid brine with sodium
chloride concentrations up to 25%. The liquid solution is
concentrated within the ice structure in channels, which have
been observed in stained samples under the microscope, with
diameters ranging from 10 to 100 mm.29 Based on observations
of microscopic ice layers, it is estimated that 1 m3 of sea ice has
a network of channels with a combined surface area of 105 to
106 m2. The volume of ice occupied by the brine channels and
the brine conditions within the channels are directly propor-
tional to the temperature; at 267 K, the brine salinity in sea ice
is 100 (on the practical salinity scale, i.e., dimensionless units
that are equivalent to the ratio between the sample solution
and a standard KCl solution; normal ocean water has a
salinity range of 30–35); at 263 K, the salinity rises to 145,
and at 252 K, the salinity reaches a maximum of 216.30 In sea
ice, the presence of interstitial channels filled with liquid water
and concentrated solutes has been observed over a range of
temperatures down to 243 K. Sea ice can lead to the formation
of solid mineral phases from the crystallisation of dissolved salts.
During freezing or thawing events, the temperature gradients
and density changes in the ice matrix lead to pressure gradients
and motion of the trapped liquid water that fills the channels and
pores. The freezing process led to the formation of potential
gradients, with pH variations of up to 3 units.31
The boundary between liquid and solid water has a different
refractive index and reveals an interface. Measurements of the
zeta potential (electric potential difference between the fluid
brine and the stationary liquid layer attached to the ice
crystals) showed that the interfacial properties of an ice–water
system are comparable to the interface with hydrophobic and
nonionogenic solids, such as diamond or hydrocarbons.32
These properties could be essential for the solute exclusion
from the interstitial brines in ice and the formulation of a freeze-
concentration model for explaining the prebiotic chemistry
observed in the ice matrix.
Observation of the behaviour of stains in ice shows that
organic molecules are excluded from the ice matrix and
concentrated in the interstitial brine, where chromatographic
separation has been noted. Another important property of the
behaviour of organic molecules in ice is that a dilute starting
solution of a given solute always reaches the same molal
concentration in the interstitial solution, which is determined
by the final incubation temperature.33 For example, a freezing
dilute urea solution tends to form an interstitial eutectic 8 m
solution with a melting point of 261 K. These properties of the
ice–water interface convert the ocean ices, at temperatures
within the range of existence of the interface with liquid brines,
into a potential reactor for the first steps responsible for the
emergence of life.
Prebiotic synthesis of nucleobases and other nitrogen
heterocycles in the ice matrix
Nucleobases are a small group of one-ring (pyrimidines) and
two-ring (purines) nitrogen heterocycles that, together with
sugars and phosphate, compose nucleic acids. The pyrimidines
include uracil, thymine and cytosine and purines include
adenine and guanine. Other heterocycles belonging to both
groups are important intermediates in the biochemistry,
including xanthine, hypoxanthine and orotic acid. It is generally
assumed that the earliest living forms on Earth used a genetic
code based on nucleobases.34 In addition, nitrogen hetero-
cycles could have been involved in the first metabolic pathways
as cofactors.35
Regardless of the controversy regarding whether life began
with a replicator, as suggested by the RNA-world hypothesis,
or with metabolism, as suggested by later authors,36 there is no
evidence to discard the hypothesis of a prebiotic source of
nucleobases or cofactors for the first living system. The first
logical hypothesis considers that the prebiotic synthesis took
place on Earth, although it is not clear if the environmental
conditions were consistent with efficient in situ synthesis.37 The
second logical hypothesis is the delivery of nitrogen heterocycles to
Earth by comets, meteorites and dust particles. This extra-terrestrial
delivery could compensate for a possible lack of availability
from in situ synthesis. Analysis of carbonaceous chondrites,
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a class of meteorites rich in organic carbon and water,38 has
demonstrated the presence of N-heterocycles. These hetero-
cycles include adenine, guanine and triazines (ammeline and
melamine), which were found in the Orgeil meteorite by
Hayatsu in 1964.39 Subsequent analyses performed from
1965–197540 show that the extraction conditions and sample
treatments determine the analytical results. However, the
presence of nucleobases in carbonaceous chondrites is widely
accepted. In 2008, Martins et al. demonstrated41 the extra-
terrestrial origin of xanthine and adenine in a Murchinson
meteorite sample using carbon isotope measurements.
Recently, Callahan et al. demonstrated that the suite of
purines found in carbonaceous chondrites is consistent with
those obtained using ammonium cyanide chemistry.42 The
questions that arise from these results include how were the
nitrogen heterocycles synthesised on Earth or other bodies in
Solar System, and how could the ice–water interface play a
role in this process?
Synthesis based on hydrogen cyanide
The synthesis of nucleobases and other nitrogen heterocycles
in the parent body of a meteorite could be a process that is
dependent on the water content and irradiation of precursors.
The seminal work of Juan Oro and co-workers demonstrated
that adenine can be easily synthesised from hydrogen cyanide
(Scheme 1).43 A prebiotic origin for the nucleobases was
thereafter regarded as a realistic possibility.44 Additionally,
a Fischer–Tropsch type synthetic mechanism catalysed by
mineral phases at high temperature has been suggested for the
origin of N-heterocycles in meteorites,45 but its actual signifi-
cance is unclear46 and currently is not a widely accepted route.
Cyanide is the primary precursor involved in our current
models for prebiotic synthesis of nitrogen heterocycles and a
possible precursor to the organic molecules that gave rise to
biochemistry. Cyanide could be generated photochemically or by
spark discharges in methane/nitrogen planetary atmospheres.47
In addition, free HCN and cyanide polymers have been observed
in comets, dust particles48 and in the Titan atmosphere.49
The mechanism of synthesis of adenine from HCN implies
that the first step is polymerisation to the HCN-tetramer
diaminomaleonitrile (DAMN; Scheme 1). This intermediate
could undergo further polymerisation to form dark brown
solid polymers, which upon hydrolysis release nitrogen hetero-
cycles, including adenine.50 This hydrolysis could take place in
the ice–water interface in the parent body of comets or
meteorites during their journey in the inner Solar System or
after these objects impacted the Earth. Another possible mecha-
nism is the reaction of DAMN with formamidine51 to afford a
4-amino-5-cyanoimidazole (AICN) intermediate. This reaction
yields adenine through the coupling of HCN or formamidine.
The hydrolysis of AICN leads to 4-aminoimidazole-5-carbox-
amide (AICA), which could be a xanthine and hypoxanthine
precursor52 (Scheme 1). Formamidine has also been identified
Scheme 1 Synthesis of purines by polymerisation of cyanide to the HCN tetramer and formation of cyanoimidazole derivatives. The related
formation of glycine, formamidine and glycolonitrile was observed in ice–water experiments.
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as an organic precursor found in comets53 and prebiotic
chemistry laboratory simulations.54 A possible major mecha-
nism for the formation of adenine from HCN, which was
elucidated by Voet and Schwartz in 1982, is the reaction
between the HCN tetramer and its cyanoimino tautomer or
diiminosuccinonitrile (an oxidation product of the HCN
tetramer) to yield the carbamimidoyl cyanide derivative. This
molecule cyclises to 4-amino-2-cyanoimidazole-5-carbimidoyl-
cyanide. Further addition of the cyanoimino derivative and
ring closure affords adenine-8-carboxamide (Scheme 1).55 This
product is quantitatively converted to adenine by hydrolysis.
The above mechanism was supported by the structural eluci-
dation of 4-amino-2-cyanoimidazole-5-carboxamide and its
hydrolysis product, 4-aminoimidazole-2,5-dicarboxamide.
However, the adenine-8-carboxamide has not yet been identi-
fied in HCN oligomerisation experiments.
The last proposed mechanism is the UV-induced photo-
isomerisation of the HCN tetramer to 4-amino-5-cyanoimidazole.
The reaction of this imidazole with HCN or with its hydrolysis
product ammonium formate in a melt directly yields adenine.56
Because it is the key reaction in the pathway, the formation of
the HCN tetramer requires a high HCN concentration to avoid
the volatilisation or hydrolysis to ammonium formate, which
competes with the formation of diaminomaleonitrile in dilute
solutions. Therefore, it would have been impossible to reach
sufficiently high HCN concentrations in the open oceans or by
water evaporation.57
One solution to this problem could be to consider alter-
natives to aqueous HCN chemistry. The formation of nucleo-
bases from formamide in the presence of inorganic catalysts at
high temperature creates a robust pathway for adenine,
hypoxanthine, uracil and cytosine among other N-heterocycles.58
One solution to this problem could be concentrating HCN
using the liquid–ice interfacial properties. During the first
attempt to test this possibility, Sanchez et al. (1966) showed
that HCN concentrates in a frozen eutectic solution. The
eutectic solution, which has a mole fraction of 70 to 80% in
HCN, is formed at 249 K and deposits a dark HCN polymer.59
Considering the activation energy of the HCN polymerisation
and the rate constants, the formation of the HCN tetramer in
eutectic fluids should be complete in a few years. At 173 K, the
reaction occurs over the order of hundreds of millions of
years.60 The advantageously stable conditions in a water–ice
interface could surpass the handicap of prebiotic synthesis
at low temperatures and the problem of concentration and
stability at high temperatures.
Additionally, the freezing of dilute glycolonitrile solutions,
produced by addition of HCN and formaldehyde, produces
adenine in low yield (0.004%).61 In a long duration experi-
ment, Miyakawa et al. maintained a frozen solution of
ammonium cyanide at 195 K over 27 years and at the end of
this time period, identified adenine as well as other purine and
pyrimidine products.62 Although the HCN pathway has been
extensively studied for the synthesis of purines, it has been
demonstrated that the polymerisation of cyanide could pro-
vide a pathway for the formation of the pyrimidines including
uracil, 5-hydroxyuracil and orotic acid.63 The freezing of
cyanide solutions could also provide a source of amino acids.
In 1972, another long-term experiment involved a solution of
NH4CN prepared from HCN and NH3. These reagents were
frozen and subjected to variable temperatures of 253 K and
195 K for 25 years. The analysis indicated the formation of
glycine and small amounts of alanine and aspartic acid.64 The
mechanism for the cold synthesis of amino acids from HCN
has not been elucidated, but may include the hydrolysis of
HCN polymers65 and the hydrolysis of 2-aminoacetonitrile,
which is formed during HCN tetramer evolution, to glycine
(Scheme 1).
Prebiotic laboratory synthesis from frozen cyanide solutions
could be a model for the prebiotic synthesis of nucleobases.
This synthesis could also explain the chemistry observed in ice-
covered objects within the inner Solar System, such as asteroids
and comets during their closest passage to the Sun, and in objects
with complex chemistry, including Titan or Enceladus. To
efficiently serve both goals, more experimental work should be
performed to elucidate the mechanisms involved in frozen HCN
solution, to test if the classic pathway through cyanoimidazole
derivatives is reproducible in the ice matrix scenario and to
determine if alternative pathways should also be examined.
Synthesis based on cyanoacetylene/acetylene and the role of
urea
Cyanoacetylene is the other primary precursor considered for
the synthesis of nucleobases. Cyanoacetylene can be obtained
in the laboratory from methane–nitrogen mixtures by spark
discharges66 by irradiation with short-wave ultraviolet radia-
tion at 185 and 254 nm;67 the spectrum of this molecule has
been observed in the interstellar medium68 and by the Voyager
mission in Titan’s atmosphere,69 where crystalline condensates
of cyanoacetylene with acetylene may exist.70
The potential prebiotic relevance of cyanoacetylene in origin
of life studies was pointed out by Ferris, Sanchez and Orgel
in 1968. They observed that the reaction of cyanoacetylene
with aqueous 1 M sodium cyanate or 1 M urea gave cytosine
in up to 5% yield (Scheme 2).71 The prebiotic availability of
cyanate could be explained by the hydrolysis of cyanogen and
urea, which may also be present in cometary and interstellar
ices.72
The mechanism of this reaction could be explained by
cyanoacetaldehyde, generated by hydrolysis of cyanoacetylene.
The Miller research demonstrated the eutectic concentration
and reaction of cyanoacetaldehyde with urea in an ice matrix at
253 K to give cytosine and uracil in 0.005% and 0.02% yields,
respectively.73 In the same report, cyanoacetaldehyde reacted
with guanidine at 253 K to give cytosine in 0.05% yield and
uracil in 10.8% yield, as well as lesser amounts of isocytosine
and 2,4-diaminopyrimidine after 2 months.74 This reaction
may proceed through the cyanoacetaldehyde dimer, 4-(hydroxy-
methylene) pentenedinitrile, easily formed by concentrating
the cyanoacetaldehyde solutions (Scheme 2).72
The basis of these experiments is the freezing of a urea or
guanidine solution. This process provides a concentration
mechanism because the crystalline ice excludes the solute
and a eutectic solution is formed. At 262 K, urea forms an
8 m eutectic solution in water. This effect could be significant
from a prebiotic point of view, despite the slower reaction
rates, as has been shown in recent experiments.
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An unresolved issue with the cyanoacetylene pathway in the
synthesis of nucleobases is its reactivity to nucleophiles,75
which suggests a high number of competitive reactions
that lead to the formation of amino- or hydroxyacrylonitriles
and subsequent polymers or hydrolysis products; on the
other hand, the prebiotic origin of cytosine was questioned,
at least in the liquid water medium, because its spontaneous
and rapid deamination to uracil.76 In part, the reactions in the
water–ice interface could overcome the problem of dilution
and degradation associated with solutions in liquid water
pools.
Although much time has elapsed since the first proposal in
1966 of a low temperature prebiotic environment for the origin
of nucleobases, it was not until 2000 that the product of the
classic approach of spark discharges in a methane/nitrogen
based atmosphere was subjected to eutectic freezing77 at 253 K
for 5 years. The frozen spark discharge product showed a
more extensive mixture of amino acids and the presence of
adenine, which was absent in the control experiment at room
temperature.
The first experimental simulation of prebiotic synthesis in
ice–liquid water directly from a nitrogen/methane atmosphere
by spark discharges was performed in 2009.78 The sparking on
a freezing dilute urea solution under a nitrogen/methane
atmosphere leads to the formation of cytosine, uracil and
2,4,6-trihydroxypyrimidine (barbituric acid) as the main
identified pyrimidines, in addition to adenine. The experi-
ments showed that using the freeze–thaw conditions, the
observed sequence of pyrimidine yield obtained was cytosine >
uracil > 2,4-diaminopyrimidine > 2,4,6-trihydroxypyrimidine.
The formation of pyrimidines by oxidative alteration of
cytosine (UV irradiation, hydroxyl radical addition or other
free radical mechanisms and further oxidation to barbituric
acid) could explain the results observed.79 The formation
of cytosine as the main pyrimidine suggests that the low
temperature conditions could reduce the rate of deamination
to uracil and favour subsequent chemical evolution steps, as
suggested by Bada.12
The triazine series (cyanuric acid, ammelide, ammeline
and melamine) are also obtained in high yields (Scheme 3).
The formation of triazines appears to be dependent on
the freezing of urea solution. The triazines are not bio-
logical compounds, but they could mimic nucleobases
behaviour in nucleic acids and their potential prebiotic role
has been discussed.80 Their presence in meteorites remains
contentious.81
The key factor appears to be the freezing process itself and
not the temperature of the final ice obtained, as the temperature
was selected to be right below the freezing point of 0.1 M urea.
In a liquid urea solution at room temperature, there is no
evidence of nucleobases. Instead, the formation of hydantoins,
nitriles and tholins (reddish-brown, insoluble, heteropolymeric
or macromolecular materials formed by sparking or irradiation
of simple carbon sources, such as methane) is prevalent.
The behaviour of urea in the ice–water interface is the key
factor because urea tends to form dimers or oligomers in a
concentration-dependent manner.82 Urea molecules in aqueous
fluids tend to form hydrogen bonds with neighbouring water
molecules at both the amino and the carbonyl groups.83
Spectroscopic studies show that at urea concentrations higher
than 1 M, the urea–urea molecular interactions are significant.
The urea–urea molecular interaction with subsequent forma-
tion of dimers or clusters of urea molecules becomes dominant
at eutectic concentration.84 During freezing, the urea is segre-
gated from pure ice to accumulate in supercooled microfluid
inclusions of a supersaturated solution. This system is governed
by dehydration and association of solute molecules.85 Thus, the
extent of urea dimerisation (18% in 0.1 M urea solution at
standard temperature86) is expected to increase and to become
quantitatively a few degrees below the onset of freezing.
Consequently, we expect an apparently paradoxical similarity
between the process observed in molten urea84 and urea
clusters entrapped in an ice matrix when the latter are sub-
jected to direct sparking or irradiation.
This behaviour could explain the sequence of products
obtained (cyanuric acid> ammelide> ammeline>melamine),
which is the same sequence observed when urea is heated
above its melting point. The spark discharges into the ice,
then, could thermally decompose urea clusters into ammonium
cyanate. Further decomposition of ammonium cyanate leads
to cyanic acid. The cyanic acid reacts with urea to form the
biuret and with the formed biuret to form cyanuric acid
(a cyanic acid trimer), which is the main triazine observed.84
Several routes to ammelide are possible: reaction of cyanuric
acid and ammonia or cyanic acid and urea or biuret. The process,
in which the decomposition products accelerate the formation of
triazines, could explain the high concentration of cyanuric acid
obtained in these conditions. Another parallel pathway is
the formation of melamine by cyanamide polymerization.
Scheme 2 Cyanoacetylene as a precursor for pyrimidines. The reaction
of cyanoacetylene with urea or ammonium cyanate yields cytosine,
whose deamination leads to uracil. The reaction with guanidine directly
forms 2,4-diaminopyrimidine and goes through a pentanedinitrile
intermediate.
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5410 Chem. Soc. Rev., 2012, 41, 5404–5415 This journal is c The Royal Society of Chemistry 2012
The melamine hydrolysis yields cyanuric acid (Scheme 3).
These pathways and the same reaction sequence, with the
same relative abundance of triazines, have been studied in
molten urea87 at temperatures between 406 and 460 K. In this
case, an alternative route for forming purines could result
from the condensation of amino acids and biuret, a reaction
that occurs at high temperature;88 however, this alternative
still has not been studied in ice–water systems and could be an
unlikely possibility because of the high activation energy of
such condensations. We also cannot discard other alternative
pathways parallel to the polymerisation of concentrated urea
solutions. For example, the production of cyanic acid during
atmospheric discharges or thermal alteration of tholins89 and
the subsequent reaction in freezing urea solutions could be an
alternative source of cyanuric acid. Additional laboratory
studies are necessary for clarifying the mechanisms involved
in the cold synthesis of triazines and purines in the ice matrix.
The effect of concentration of solutes on the ice matrix,
together with the low availability of water vapour, could
explain the preferential synthesis of polycyclic aromatic
hydrocarbons (PAHs) by sparking a methane/nitrogen
atmosphere over an ice matrix.90 The model of PAH synthesis
is interesting because it could confirm the theoretical synthesis
of aromatics by acetylene insertion mechanisms proposed for
Titan’s atmosphere.91 In laboratory experiments at sub-zero
temperatures,65 the acetylene addition mechanism could explain
the preferential formation of aromatics and poly(triacetylene)
polymers (Scheme 4) by two possible mechanisms. First, a single
aromatic ring could be generated from acetylene and vinyl
radical and PAH growth by H abstraction and acetylene
addition (Berthelot synthesis, similar to PAHs formation in
flames). The second mechanism involves polyyne growth.
The presence of water ice induces oxidations leading to the
formation of aromatic polar species such as benzaldehyde or
acetophenone. The reaction in ice, in contrast to the dry high
temperature synthesis of PAHs, leads to hydroxyl-rich
poly(triacetylene) based polymers. Overall, these ice–water
laboratory experiments reveal the expected chemical species
in surface or subsurface ices on solar system objects or
extrasolar planetary bodies.
The activation of methane/nitrogen atmospheres by spark
discharges could lead to various chemistries involving reactive
intermediates, including HCN, cyanoacetylene and acetylene.
The preference for the hydantoins in liquid urea solutions
at room temperature versus pyrimidines in frozen solution
experiments could be due to the acetylene formation and
subsequent alteration by means of ozone and hydroxyl radicals
at higher temperatures to form a-dicarbonyl compounds such as
glyoxal.92 The reaction of glyoxal with urea under mild acidic
conditions yields hydantoin,93 whose further oxidation yields
5-hydroxyhydantoin and parabanic acid (Scheme 3). These three
hydantoins are always found together in all the experiments
reported in the literature. Its formation could be explained also as
alteration products of uracil by hydroxyl and other free radicals
Scheme 3 Urea as precursor of nitrogen heterocycles. Possible pathways to pyrimidines, hydantoins and triazines in frozen urea solution under a
methane/nitrogen atmosphere.
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generated in water solutions by photolysis or irradiation.79,94
At lower temperatures, the degradation of pyrimidines
to hydantoins and the oxidation of acetylene could be
diminished, due to the lower availability of reactive oxygen
species generated from the excitation of water. As a con-
sequence, hydantoins could be the final products of alteration
of pyrimidines under prebiotic conditions subjected to
UV-irradiation or other energetic processes. Regarding
acetylene, the polymerisation could be the preferred reaction
pathway, as shown by the formation of poly-triacetylene and
aromatic hydrocarbons at the ice–water matrix previously
described. In this environment, the HCN or cyanoacetylene
pathways could dominate other alternative mechanisms as
the synthesis of uracil by reaction of urea with acetylene
dicarboxylic acid.95 This acid is the aqueous hydrolysis
product of dicyanoacetylene, which is an exotic product
of methane/nitrogen atmospheres observed in the Titan
atmosphere.96 The role of acetylene derivatives has not been
studied in the ice–water scenario, and further experiments are
necessary to explore the possible alternative pathways related
to acetylene in prebiotic synthesis in an ice matrix and to put it
in context with the classic mechanisms involving cyanide and
cyanoacetylene. The products identified in the simulations of
methane/nitrogen atmospheres over the ice–water interface
include dicarboxylic and hydroxycarboxylic acids, amino acids
and pyrazines, suggesting an additional mechanism to those
suggested above.
In summary, the advantages of an ice–water interface in
prebiotic synthesis include the reduction in the formation of
polymers and tholins with a preference for ring systems
(nitrogen heterocycles or aromatic rings) by the effect of
concentration of diluted reactants such as HCN, urea or
cyanate. Combined with other rocks or minerals, the freezing
of liquid water solutions could favour mineral surface–organic
solute interactions.97
The ice–water system in the origin of nucleic acids
The ice matrix is an appropriate environment for the synthesis
of nitrogen heterocycles, as demonstrated by the synthesis of
triazines and nucleobases in freezing urea solutions. Could the
ice–water interface be a favourable environment for the assembly
of the first biologically relevant informational polymers?
The success in the synthesis of nucleobases from a feedstock
of active nitrogen species available prebiotically led to the
establishment of a similar retrosynthetic analysis for RNA and
to the search for prebiotically plausible syntheses of a primor-
dial informational, self-replicating polymer. If the discovery of
an abiotic pathway to the origin of the first nucleotides and the
constitutional self-assembly of RNA is achieved, the RNA-
world hypothesis (a term coined by Walter Gilbert in 1986),98
which proposes a molecular evolutionary step involving
autocatalytic RNA molecules prior to the origin of protein
synthesis and metabolic machinery, will be strengthened.
The current state of prebiotic chemistry does not provide a
complete model for an abiotic origin of RNA, and the first
formulations of an RNA world have been re-evaluated.99
However, some argue that it may be premature to conclude
that the prebiotic RNA world is unlikely to be a step in the
emergence of life.100
In this context, the ice–water interface has been evaluated
thoroughly as a matrix for the polymerisation of highly
activated nucleotides. The first demonstration of this possi-
bility was performed by Gryaznov and Letsinger in 1993.101 In
their experiment, the coupling of an a-bromoacyl-activated
oligonucleotide (bromoacetylamino-30-desoxythimidine in
the 30-terminus) with another oligonucleotide with a phos-
phorothioate group in the 50-terminus proceeded without a
template in a frozen saline solution at 255 K in 5 days. The
reaction was explained as a result of the high local concen-
tration of reactants in the fluid cavities in the ice matrix.
Scheme 4 Polycyclic aromatic hydrocarbons and acetylene polymers detected from sparking a methane/nitrogen atmosphere on the water–ice
matrix.
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5412 Chem. Soc. Rev., 2012, 41, 5404–5415 This journal is c The Royal Society of Chemistry 2012
The enhancing effect of the ice matrix on the formation
of RNA oligomers was demonstrated by Kanavarioti et al. in
a very remarkable experiment in which oligouridylates up
to 22 bases long were synthesised by incubating a uridine
50-monophosphorimidazolide solution at 255 K at a pH range
between 6 and 8 in the presence of magnesium and lead cations
(Scheme 5).102
The study of the ribonuclease A digestion products showed
that the oligomers obtained are mainly linear and that 30%
carry at least one 30–50 linkage. The fluorescence microscopy
observation of an ice layer under the experimental conditions
with acridine orange staining indicated that the organic solutes
were concentrated in the eutectic lattice structure included in
the ice matrix. The authors concluded that the formation of
eutectic solutions of reactants in the ice matrix facilitated the
oligomerisation. The polymerisation most likely occurs in the
liquid concentrated solutions between the ice crystals, and not
by the adsorption of reactants onto the ice surfaces, as
previously suggested by Stribling and Miller,103 who studied
the template directed synthesis of poly(U) in diluted solutions
concentrated by freezing close to the NaCl eutectic. The ice
also has an effect on the metal catalysis. The reaction in the
ice–water medium requires Pb2+ as a catalyst and not Mg2+.
This phenomenon is different from reactions in solution, which
require both magnesium and lead cations. A possible interpre-
tation of this observation is that the molecular associations in
an ice matrix tend to be more stable than the corresponding
ones in solution. An open question that arises is the role of
certain metal cations (for example lead) as prebiotic catalysts.
The lead catalysis in the polymerisation of activated nucleotides
could be related to the mechanism of leadzymes104 and suggests
that metal ion catalysis is central in a hypothetical RNA world.
If pyrimidine and purine-activated nucleotides are used in
the water–ice interface at 255 K during 38 days in the presence
of Mg2+ and Pb2+, a mixed-sequence polynucleotide with
approximately the same proportion of purine and pyrimidine
residues is obtained.105 Monnard and Szostak106 studied
the template-directed RNA polymerisation in water–ice at
256.4 K, a temperature that permits the maintenance of a
stable water–ice interface for long periods of time. They found
that lead and magnesium ions catalyse the elongation of a
RNA hairpin with a 50-overhang as a template.
Similarly, the non-enzymatic synthesis of polyadenosine in a
sea–ice matrix, directed by poly(U), was performed, using
adenosine-50-monophosphate (2-methyl) imidazolide asmonomer.
Temperature fluctuations established the freeze–partial thaw
cycles during one year. The results show high molecular weight
poly(A) formation, with chain lengths of as many as 420 residues
(Scheme 6).107
The freezing-concentration model could also govern the
conformational rearrangement pathway of the formed polymers.
Freezing a 21-nt RNA hairpin solution at 203 K followed by
incubation at 263 K results in the conversion to the duplex
dimer form.108 The formation of frozen microenvironments
during prebiotic evolution could be a key factor in the possible
prebiotic evolution of informational polymers.
The formation of peptides in the ice matrix
The linking of monomer units to form simple polymers likely
defined an important step in the origins of life, and many
conditions have been proposed, including dehydration
agents,109 sulphide minerals,110 melting111 or hydrothermal
systems.112 Further studies suggest important roles of catalytic
surfaces, such as clays, or interfaces created by wet–dry cycling
of monomers on mineral surfaces.113
Based on this idea, Schwendinger and Rode found a parti-
cularly simple process of salt-induced peptide formation, using
40–50 mM amino acid solutions where NaCl at concentrations
above 3 M can act as a dehydrating or condensation agent,
using dissolved Cu(II) as a catalyst.114 Experiments carried out
by Fox demonstrated that the melting of amino acids at
temperatures in the range of 400 to 433 K, to allow melting
without decomposition, produces a type of polymer called
‘proteinoids’. This phenomenon will occur provided that
acidic or basic amino acids are present in excess.115 However,
the so-called ‘proteinoids’ are mainly heteropolymers containing
only very small quantities of peptide bonds.116 The melting of a
mixture of urea and alanine yields the dipeptide Ala-Ala.81
The largest number of proposals and related experiments
performed in order to model the prebiotic peptide formation
in solution involves the postulated existence of coadjutant
condensation reagents in a homogenous catalytic process.
These reagents include cyanamide and cyanoguanidine, which
may act as prebiotically plausible condensing agents.117
A problem associated with high temperature processes is the
decomposition of amino acids and the hydrolysis of peptides,
which constitutes a limitation for the organisation of larger
polymers.118 The synthesis in freezing solutions could prevent
undesirable side reactions, hydrolysis of the formed peptide
bond, and the decomposition of amino acids as well as reduce
the rate of amino acid racemisation.119 This idea is connected
to a different approach to the problem of amino acid con-
densation that was introduced years ago: the salt-induced
peptide formation reaction. Salty brines could have played a
role in the polymerisation of amino acids. However, the
formation of a peptide bond is not straightforward at low
temperatures without condensing agents, and the experiments
performed were carried out at high temperatures under drying
conditions.
Could freezing of the primitive oceans have produced the
concentrated salty brines with the associated condensing agents
needed to promote the salt-induced polymerisation process?
Scheme 5 Scheme 6
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Liu and Orgel studied the oligomerisation of b-amino acids in
aqueous solutions under eutectic conditions using activation
by the water-soluble reagents EDAC (1-ethyl-3-(3-dimethyl-
aminopropyl)-carbodiimide) and carbonyl-diimidazole.120 The
oligomerisation of b-amino acids (L-aspartic acid, b-amino
adipic acid, b-glutamic acid) using these condensing agents
proceeds efficiently at 253 K (under eutectic freezing), even
from dilute solutions of the substrates. This reaction produces
peptides in the range 15 to 20 units (maximum: 45) in length
with a yield of over 50%. The efficiency of polymerisation and
the length distribution of the oligomers were almost unaffected
by the solute concentration over a broad range of 0.1 to 100 mM
at 253 K. According to these results, the EDAC reagent
constitutes the model of a group of activating agents whose
function is the direct reaction with the carboxyl group of
amino acids. Cyanogen, cyanamide and cyanoguanidine are
prebiotically plausible members of this group. The elucidation
of the pathway shows that the first step is the direct attack of the
carboxyl group on the carbodiimide to form an O-acylisourea.
The free amino group of another amino acid attacks this
activated species to form a peptide bond. In the case of a-amino
acids, the carboxyl group of the dipeptide can be activated and
then cyclise efficiently to give a diketopiperazine, thus inhibiting
oligomerisation.121 Cyclisation of an activated dimer of b-amino
acids is not straightforward because an eight-membered ring
does not form readily.
In 1996, Vajda et al. synthesised four protected dipeptides
and a protected tripeptide in frozen dioxane and other organic
solvents.122 The data demonstrated that the coupling rates in
frozen dioxane at 254 K exceed by approximately one order of
magnitude of the rates in liquid solution at 313 K. Vajda
suggested that enhanced reaction rates and/or yields, diminution
of racemisation, and the suppression of side reactions can be
expected in frozen systems, and these possibilities substantially
increase the importance of peptide formation in eutectic frozen
solutions.123 However, no further investigation on these
possibilities has been performed.
Concluding remarks
Prebiotic chemistry in the range of stability of a liquid
water–ice interface (277 to 243 K under common laboratory
conditions) has been proposed since the pioneering experiment in
the field. These ideas were proposed to overcome the concentration
and stability problems associated with liquid water prebiotic
chemistry. The experiments performed demonstrated that the
synthesis of aromatic hydrocarbons, purines and pyrimidines
and other nitrogen heterocycles of potential prebiotic interest
(such as triazines) is favoured in the ice matrix by classic cyanide
and cyanoacetylene pathways following a freezing-concentration
model. Despite these results, the experimental prebiotic chemistry
in the solute-concentrated solutions that fill the space confined by
the ice matrix has received relatively little attention in the
elaboration of the models for the origin of organics in Solar
System bodies and prebiotic evolution. Consequently, it is
necessary to clarify the mechanisms involved and the role of
reactants as well as to performmore experiments under plausible
prebiotic conditions, especially if geochemical models support
stable icy environments on the prebiotic Earth.
The concentration of reactant solutions by freezing also
enhances the polymerisation of activated nucleotides and the
formation of small peptides in the presence of an activating
agent. The prebiotic relevance of these polymerisation reac-
tions and the gap between the nucleobase synthesis and the
organisation of the first biopolymers is a matter for discussion.
Nevertheless, the ice world constitutes an interesting prebiotic
chemistry scenario that awaits further investigation.
Acknowledgements
We acknowledge the Centro de Astrobiologia (CSIC-INTA)
and the grants of the project AYA2009-13920-C02-01 from
the Ministerio de Ciencia e Innovacion (MICINN, Spain).
Notes and references
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