Photochemical reductive homologation of hydrogen cyanide using sulfite and ferrocyanide

Article abstract of DOI:10.1039/c8cc01499j

Photoredox cycling during UV irradiation of ferrocyanide ([Fe^II(CN)₆]^4-) in the presence of stoichiometric sulfite (SO₃^2-) is shown to be an extremely effective way to drive the reductive homologation

Full text of DOI:10.1039/c8cc01499j

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Photochemical reductive homologation of
hydrogen cyanide using sulfite and ferrocyanide†
Cite this:DOI: 10.1039/c8cc01499j
b
Jianfeng Xu,a Dougal J. Ritson,a Sukrit Ranjan,b Zoe R. Todd,
Dimitar D. Sasselovb and John D. Sutherland*a
Received 23rd February 2018,
Accepted 7th March 2018
DOI: 10.1039/c8cc01499j
rsc.li/chemcomm
Photoredox cycling during UV irradiation of ferrocyanide ([FeII(CN)6]4À
)
For reductive homologation of HCN 1 to have been wide-
in the presence of stoichiometric sulfite (SO32À) is shown to be an spread, an alternative to either HCN 1 or H2S as reductant
extremely effective way to drive the reductive homologation of hydro- would have to have been more globally available, and, if a
gen cyanide (HCN) to simple sugars and precursors of hydroxy acids catalyst was also required, it would ideally be based on a much
and amino acids.
more abundant metal. Here we describe a potentially wide-
spread prebiotic synthesis of simple sugars and amino acid
precursors from HCN 1 using sulfite (SO32À, deriving from
dissolution of atmospheric SO2) as stoichiometric reductant
with ferrocyanide ([FeII(CN)6]4À) promoting the production of
hydrated electrons (ESI 1.1†).
Our previous, potentially prebiotic, Kiliani–Fischer-like reductive
homologation of hydrogen cyanide (HCN 1) to the simple carbo-
hydrates glycolaldehyde 2 and glyceraldehyde 3, required the use
of either HCN 1 itself, or hydrogen sulfide (H2S) as stoichiometric
reductants to effect copper(II) 3 copper(I) photoredox cycling
(Scheme 1).1,2 In this chemistry intended to demonstrate ‘proto-
metabolism’,3 protons delivered by general acids facilitate direct
reduction of nitrile groups by photochemically-generated hydrated
electrons. The reaction network is initiated by reduction of HCN 1
to methanimine 4 and hydrolysis of the latter to formaldehyde 5.
Formation of the cyanohydrin of 5, glycolonitrile 6, is followed by
further reduction and hydrolysis to glycolaldehyde 2. Another cycle
of reductive homologation, via glyceronitrile 7, gives glyceralde-
hyde 3. Although prebiotically plausible,4 these syntheses are
either problematic as regards subsequent use of the sugars in
RNA synthesis, or invoke distinct and rather specific geochemical
scenarios. Thus, using HCN 1 as the stoichiometric reductant,
isocyanic acid 8 (formed upon hydrolysis of cyanogen 9) traps 2
and 3 in the form of cyclic adducts (Scheme 1).1 Using H2S as the
reductant presents difficulties associated with concentrating such
a species in water – its low solubility means that it could most
readily be concentrated as its conjugate base, hydrosulfide
(HSÀ, pKa of H2S (B7)5) in alkaline groundwater. Furthermore,
the relatively low abundance of copper in Earth’s crust would have
restricted either chemistry to copper-rich environments, such as
those enriched through impact metallogenesis.
We initially explored the photoreduction chemistry of HCN 1
with bisulfite/sulfite alone using direct analysis by 13C NMR
spectroscopy. After 2.5 h of irradiation, the expected first-stage
reduction products of HCN 1, namely methanimine 4 and its
hydrolysis product formaldehyde 5, were not observed by
13C NMR spectroscopy (ESI). Instead, aminomethanesulfonate 10
and hydroxymethanesulfonate 11, the bisulfite adducts of 4 and 5,
respectively, were observed together with aminomethane-
disulfonate 126 and iminodimethanesulfonate 13 (Scheme 1).
The identities of these products were confirmed by comparing
their spectral properties with those of authentic compounds
(ESI). After a longer irradiation time (5 h), the first-stage
Kiliani–Fischer homologation products, glycolonitrile 6, glycine
nitrile 14 and iminodiacetonitrile 15 were observed. Most
importantly, the second-stage product, glyceronitrile 7, was
also detected in the reaction mixture at this stage. Comparing
13C NMR spectra at different time points revealed that the
bisulfite adducts of the first-stage reduction products, amino-
methanesulfonate 10 and hydroxymethanesulfonate 11, were
gradually converted to the first-stage homologation products,
glycolonitrile 6 and glycine nitrile 14 as the bisulfite and sulfite
in the mixture were consumed.
Our initial experiments with HCN 1 and bisulfite/sulfite had
simulated the delivery of SO2 from the atmosphere into ground-
water containing cyanide salts derived from the prior thermal
metamorphosis of sodium or potassium ferrocyanide salts in
the dry-state.6 Alternatively, bisulfite and formaldehyde 5,
produced atmospherically by photoreduction of CO2,7 could
a MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge
Biomedical Campus, Cambridge, CB2 0QH, UK. E-mail: johns@mrc-lmb.cam.ac.uk
b Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge,
MA 02138, USA
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8cc01499j
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Scheme 1 Reductive homologation of HCN 1. Colour scheme: previously observed chemistry using photoredox cycling of copper(II) 3 copper(I) with
the stoichiometric reductant being HCN 1 (blue), or H2S (red); previously observed transformations using either reductant (purple); additionally observed
new transformations (black).
have rained-in to cyanide containing groundwater as hydroxy-
methanesulfonate 11. We therefore explored the chemistry
starting directly from 11 and observed efficient production of
glycolonitrile 6 when a solution of 11 was mixed with potassium
cyanide.
Starting with an initial ratio of cyanide to bisulfite/sulfite
(all in the form of hydroxymethanesulfonate 11) of 1 : 1, the
ratio of glycolonitrile 6 to hydroxymethanesulfonate 11 in the
mixture had reached 4 : 1 after equilibration (ESI), liberating
free bisulfite/sulfite to act as a reductant in subsequent photo-
chemistry. To determine the extent of Kiliani–Fischer homo-
logation upon irradiation, we again used 13C-labelled reagents
with analysis by 13C NMR spectroscopy (Fig. 1).
Fig. 1 13C NMR Spectra of the reaction mixtures with 200 mM
13C-labelled KCN, 200 mM Na2SO3 and 100 mM 13C-labelled formaldehyde
(in 10% D2O in H2O). (a) 13C-Labelled 11; (b) as (a), then mixed with
13C-labelled KCN and NaH2PO4 at pH 7; (c) the mixture from (b) after
irradiation at 254 nm for 12.5 h; (d) the mixture from (c) after sparging with
argon for 13 h.
The equilibration reaction between hydroxymethanesulfonate
11 and cyanide with glycolonitrile 6 and bisulfite/sulfite was
mimicked by mixing 1 equivalent of 13C-labelled formaldehyde 5
with 2 equivalents of disodium sulfite and 2 equivalents of
13C-labelled potassium cyanide and adjusting the pH of the
solution to 7. Initially, only hydroxymethanesulfonate 11, glycolo-
nitrile 6 and excess HCN 1 were observed in the 13C NMR
spectrum. However, after irradiation for 12 h, nearly all the external standard, and the mixture was analyzed by quantitative
hydroxymethanesulfonate 11 had been converted into glycolo- 13C NMR spectroscopy (ESI). Reduced products constituted
nitrile 6, glyceronitrile 7, serine nitrile 16 (convertible to serine 34% of the mixture including glyceronitrile 7 (26%), serine
by hydrolysis) and iminodiacetonitrile 15. Interestingly, a small nitrile 16 (4%) and acetaldehyde cyanohydrin 17 (4%). Theore-
amount of acetaldehyde cyanohydrin 17 (convertible to lactate tically, reduced products could be obtained in up to 50% yield
by hydrolysis) was also produced in the reaction, which could from a 1 : 1 mixture of cyanide and bisulfite/sulfite, as the
lead to alanine nitrile (convertible to alanine by hydrolysis) if reduction of one nitrile group requires two electrons released
sufficient ammonia was present in the system at a later stage.2 from two equivalents of sulfite. After sparging argon through
We propose that acetaldehyde 18 originates from deoxygena- the reaction mixture for 13 h to expel HCN 1 from the solution,
tion of glycoaldehyde 2 (Scheme 1) as we had found using H2S free glycolaldehyde 2 could be observed in the 13C NMR
as the stoichiometric reductant in our earlier work.2 To quan- spectrum (Fig. 1d).
tify the yields of reduced products, a known amount of
In our previous synthesis using H2S as the reductant,
13C-labelled sodium formate was added to the solution as an copper(I) cyanide was found to accelerate the photoreduction
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of glycolonitrile 6, providing 2 in 42% yield after 4 h of
irradiation.2 In comparison, the new photoreduction with
sulfite alone as the reductant, gave reduced products in a lower
yield with longer irradiation times (12 h), and this raised
concerns about its prebiotic plausibility. We therefore looked
for an Earth-abundant compound to accelerate the sulfite
reduction chemistry.
It is known that photoionization of ferrocyanide ([FeII(CN)6]4À
,
ESI 1.2†), effected by UV irradiation at short wavelengths, provides
ferricyanide ([FeIII(CN)6]3À) and hydrated electrons.8 Indeed we
had previously attempted using ferrocyanide for reductive homo-
logation chemistry, but it proved inefficient on its own, which we
put down to efficient geminate recombination of the electrons and
ferricyanide regenerating ferrocyanide. However, in the context of
using sulfite as the stoichiometric reductant, ferrocyanide piqued
our interest again because it is known that sulfite reduces ferri-
cyanide to ferrocyanide and, in the process, is converted to
sulfate.9–11 Thus, depending on the relative rates of several pro-
cesses, added ferrocyanide might double the reducing capacity of
Fig. 3 1H NMR Spectra of the reaction mixtures with 25 mM of 11, 25 mM
KCN and 100 mM NaH2PO4 in D2O/H2O (10% D2O in H2O) after irradiation
for 1 h. (a) The reaction with no K4Fe(CN)6; (b) the reaction with 10 mol%
K4Fe(CN)6.
sulfite and accelerate the photochemically-driven reductive homo- considerably less efficient reduction in the same period of time
logation of HCN 1. To investigate whether ferrocyanide might act (ESI). In order to quantify the effect of ferrocyanide on the
in this way, a solution of 1 equivalent of 13C-labelled KCN and photoreduction, the reaction of hydroxymethanesulfonate 11 with
1 equivalent of Na2SO3 in phosphate buffer was divided in two and KCN was repeated with unlabelled 11. Hydroxymethanesulfonate
10 mol% K4[Fe(CN)6] was then added to one portion. The two 11 was mixed with 1 equivalent of KCN in phosphate buffer and
solutions were then irradiated side-by-side for 3 h (Fig. 2). The the resulting mixture was again divided into two parts, into one of
reaction mixture lacking ferrocyanide gave only the first-stage which was added 10 mol% K4[Fe(CN)6]. Reactions were monitored
reduction products 6, 10, 11 and a trace of 13, while the reaction periodically by 1H NMR spectroscopy and yields of products were
mixture including ferrocyanide furnished mainly the second-stage calculated by relative integration of their proton resonance signals
reduction product glyceronitrile 7 together with a third-stage (Fig. 3).
reduction product 19, the cyanohydrin of glyceraldehyde 3. A
Comparing the reactions after only 1 h of irradiation, the
similar comparison (ESI) was also made of the reactions starting catalyzed, or promoted reaction was found to have proceeded
from mixtures of 13C-labelled hydroxymethanesulfonate 11 and rapidly, affording 68% yield of total reduced products (glycero-
13C-labelled HCN 1 with and without added ferrocyanide. In the nitrile 7 in 40% yield and glycolaldehyde sulfite adduct 20 in
reaction mixture including ferrocyanide, most of the HCN 1 and 28% yield), while the control reaction gave only 20% yield of
the hydroxymethanesulfonate 11 had been consumed within 3 h, reduced products, eventually increasing to 25% after 3 h.
providing the reduced product glyceronitrile 7 as well as free
In the control reaction starting from HCN 1 and sulfite,
glycolaldehyde 2 and the cyanohydrin of glyceraldehyde 19. By third-stage reduction products such as glyceraldehyde 3 and its
comparison, the reaction mixture lacking ferrocyanide showed cyanohydrin 19 could barely be detected in the photoreduction
mixtures. To investigate the effect of ferrocyanide on the later
stages of the overall synthetic scheme, we simply mixed glyco-
laldehyde 2 with 1 equivalent of KCN and 1 equivalent of
Na2SO3 in phosphate buffer. In the dark, the ratio of the sulfite
adduct 20 to cyanohydrin 7 was 2.4 : 1. As before, the mixture
was divided into two parts, into one of which was added
10 mol% K4[Fe(CN)6]. After 1 h of irradiation, the photoreduc-
tion reaction including ferrocyanide afforded 30% of 19, the
cyanohydrin of glyceraldehyde and the ratio of 20 to 7 had
changed to 0.6 : 1 (ESI). The sulfite in the mixture was efficiently
consumed (as reductant) and the equilibrium was in favor of
the formation of cyanohydrins 7 and 19. In comparison, the
control reaction afforded no detectable 19 after 1 h of irradia-
tion, but afforded 3% of deoxygenated products (acetaldehyde
sulfite adduct 21 and acetaldehyde cyanohydrin 17) deriving
Fig. 2 13C NMR Spectra of the reaction mixtures with 25 mM 13C-labelled
from glycoaldehyde 2. After 3 h of irradiation, 10% of 19 and
KCN, 25 mM Na2SO3 and 100 mM NaH2PO4 in D2O/H2O (10% D2O in H2O)
8% of acetaldehyde derivatives were observed. Based on our
experimental findings and results from the literature, reaction
after irradiation for 3 h. (a) The reaction with no K4Fe(CN)6; (b) the reaction
with 10 mol% K4Fe(CN)6.
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This work was supported by the Medical Research Council
(no. MC_UP_A024_1009 to J. D. S.) and the Simons Foundation
(no. 290362 to J. D. S. and no. 290360 to D. D. S.). S. R., Z. R. T. &
D. D. S. acknowledge the Harvard Origins of Life Initiative.
The authors thank Dr T. Rutherford for assistance with NMR
spectroscopy.
Conflicts of interest
Scheme 2 Proposed mechanisms for the photoredox cycling of iron(III)
3 iron(II) in the presence of Na2SO3.
There are no conflicts to declare.
Notes and references
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mechanisms involving cyanoferrate photoredox cycling are
proposed here (Scheme 2 and ESI 1.3†).
In conclusion, through sulfite (SO32À) and catalyzed, or
promoted by ferrocyanide ([FeII(CN)6]4À), SO2 can act as a more
efficient and globally available reductant than H2S in the
photochemically-driven homologation of HCN 1 to (precursors of)
biomolecules. Considering the ready availability of ferrous iron (FeII)
on early Earth, the ease with which atmospheric SO2 may be
concentrated into groundwater, and the numerous mechanisms
for supply of HCN, the sulfite-mediated, ferrocyanide-accelerated
photoreduction of cyanide offers a synthesis of sugars and
precursors of hydroxy acids and amino acids compatible with
a globally plausible geochemical scenario.
¨
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