Hydrogen Sulfide: A Reagent for pH-Driven Bioinspired 1,2-Diol Mono-deoxygenation and Carbonyl Reduction in Water

Article abstract of DOI:10.1021/acs.orglett.8b01713

Hydrogen sulfide (H₂S) was evaluated for its peculiar sulfur radical species generated at different pHs and was used under photolytical conditions in aqueous medium for the reduction of 1,2-diols to alcohols. The conversion steps of 1,2-cyclopentanediol to cyclopentanol via cyclopentanone were analyzed, and it was proven that the reaction proceeds via a dual catalytic/radical chain mechanism. This approach was successfully adapted to the reduction of a variety of carbonyl compounds using H₂S at pH 9 in water. This work opens up the field of environmental friendly synthetic processes using the pH-driven modulation of reactivity of this simple reagent in water.

Full text of DOI:10.1021/acs.orglett.8b01713

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Hydrogen Sulfide: A Reagent for pH-Driven Bioinspired 1,2-Diol
Mono-deoxygenation and Carbonyl Reduction in Water
†,‡
Sebastian Barata-Vallejo, Carla Ferreri,† Bernard T. Golding,§ and Chryssostomos Chatgilialoglu*,†
́
†ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy
§School of Natural & Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
S
* Supporting Information
ABSTRACT: Hydrogen sulfide (H2S) was evaluated for its peculiar sulfur
radical species generated at different pHs and was used under photolytical
conditions in aqueous medium for the reduction of 1,2-diols to alcohols.
The conversion steps of 1,2-cyclopentanediol to cyclopentanol via
cyclopentanone were analyzed, and it was proven that the reaction proceeds
via a dual catalytic/radical chain mechanism. This approach was successfully
adapted to the reduction of a variety of carbonyl compounds using H2S at
pH 9 in water. This work opens up the field of environmental friendly
synthetic processes using the pH-driven modulation of reactivity of this
simple reagent in water.
he selective deoxygenation of a 1,2-diol to an alcohol is a
difficult chemical conversion that has a myriad of
residues provide the electrons via a disulfide radical anion to
reduce the intermediate ketone to an alcohol.
T
The dehydration of simple 1,2-diols initiated by HO•
radicals with formation of the corresponding aldehyde or
ketone has been extensively studied, principally as a model
system for carbohydrate substrates,8 and in connection with
the mechanism of diol dehydratase.9,10 The 1,2-dihydroxyalkyl
radicals that are intermediates in this reaction readily undergo
either acid- or base-catalyzed elimination of water to afford a
carbon-centered radical stabilized by an adjacent carbonyl
group.11 The intermediate carbonyl compound formation has a
very large industrial utilization for natural products and polyol
conversions, and efforts have been carried out in this field
toward environmental friendly approaches in water.12,13
The enzymatic mechanisms operating in Figure 1 can be
taken as inspiration for using sulfur radical chemistry in the
1,2-diol transformation to monoalcohols and the reduction of
carbonyl compounds. Indeed, bioinspired chemical conver-
sions are quite interesting since they open up perspectives for
new catalytic processes as well as for green methodologies.14
The simplest thiol H2S in the past decade has attracted
increasing interest in a multidisciplinary context from
chemistry to biology.15,16 Research has highlighted the strong
versatility of this molecule due to a variety of oxidation
states17,18 and the peculiar reactivity of its sulfhydryl and
disulfide radical species driven by different pHs in aqueous
systems. Some of us previously investigated the pH-sensitive
biomimetic cis−trans isomerization process involving unsatu-
rated fatty acids in liposomes with sulfhydryl radical (HS•)
derived from protein modifications or H2S.19,20 This simple
molecule, present among the other gases in primordial
potential synthetic applications and is fundamental to the
origin of life. In principle, this conversion can be accomplished
by dehydration of a 1,2-diol to an aldehyde or ketone followed
by a reduction. The foremost known pathways for the
reduction or dehydration of 1,2-diols proceed via intermediate
radicals. The Barton−McCombie reaction is, for example, a
multistep approach that is applicable to sugar substrates and
involves protection and derivatization to an intermediate that
undergoes a radical-mediated deoxygenation reaction.1,2
The monodeoxygenation of a 1,2-diol is performed in nature
by ribonucleotide reductases that employ thiyl radical based
chemistry (Figure 1). The ribose unit of ribonucleotide
Figure 1. Transformation of ribonucleotides to 2′-deoxy-ribonucleo-
tides.
diphosphates is converted into 2-deoxyribose units required
as building blocks for the de novo synthesis of DNA.3,4 In this
mechanism,5,6 one of the cysteine residues at the active site
generates a thiyl radical CyS• which effects H-abstraction from
C-3′. There follows elimination of the OH group in C-2′ with
translocation of the radical center to C-2′, quenching of the
newly formed C-2′ radical and reduction of the C-3′ carbonyl
group. Essentially, a (3′,2′)-spin center shift occurs, eliciting a
β-C−O scission and elimination of water.7 A pair of cysteine
Received: May 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01713
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
atmosphere,21 attracts interest in prebiotic reactions in
connection with the origin of life.22,23
Here, we report the direct conversion of 1,2-cyclopentane
diol to cyclopentanol, starting from the photolysis of H2S at
different pH values in aqueous medium with a complete
mechanistic picture. In particular, based on the properties of
the HS• radical and inspired by the biological mechanism of
ribonucleotide reductases, we developed a dual catalytic/
radical chain system capable of unprecedented organic
transformations using H2S radical chemistry.
Thus, Na2S was used as source of H2S in aqueous solution
for the reduction of cis-1,2-cyclopentanediol (1) under
photolytical conditions in the absence of oxygen. Photolysis
(low-pressure Hg lamp, 5.5 W) of N2-saturated aqueous
solutions of 1 (8.3 mM) containing Na2S·9H2O (16.6 mM)
was monitored for up to 60 min and at various pH values (2,
4.5, 7 and 9). In all experiments, cyclopentanone (2) and
cyclopentanol (3) were the only products. The extent of
formation of these products under various conditions is
summarized in Table 1 (see also Figures S2−S5). Figure 2a
Figure 2. (a) Monodeoxygenation of cis-1,2-cyclopentanediol;
Table 1. Photolysis (low pressure Hg lamp, 5.5 W) of N2-
Saturated Aqueous Solutions of cis-1,2-Cyclopentanediol (1,
8.3 mM) Containing Na2S·9H2O (16.6 mM) with
□
■
○ ●
△
▲
) vs irradiation
concentration of 1 ( , ), 2 ( , ), and 3 (
,
time at pH 4.5 (dashed lines) and pH 7 (full lines) for the photolysis
of N2-saturated cis-1,2-cyclopentanediol (1) aqueous solutions (8.3
mM) containing Na2S·9H2O (16.6 mM). (b) Formation of 3 vs
irradiation time for the photolysis of N2-saturated cyclopentanone (2)
aqueous solutions (8.3 mM) containing Na2S·9H2O (16.6 mM),
Formation of Cyclopentanone (2) and Cyclopentanol (3) at
a
Different Irradiation Times and pH
pH
2
time (min)
1 (mM)
2 (mM)
3 (mM)
□
○
△
different irradiation times, and pH values: ,pH 2; , pH 4.5; pH
7; , pH 9.
20
40
60
20
40
60
20
40
60
30
40
6.7
5.3
4.7
6.5
5.2
4.6
5.9
4.6
3.9
7.8
7.3
6.2
1.5
2.7
3.1
1.3
2.1
2.4
0.5
0.9
0.1
0.3
0.5
0.5
1.0
1.3
1.9
2.8
3.2
0.5
1.0
2.1
◊
To evaluate the versatile behavior of H2S, its properties must
be considered: its weak acidity (pKa 6.98 at 25 °C, 6.76 at 37
°C24); one-electron reduction and hydrogen abstraction from
both H2S and HS− under photolytic conditions (Figure 3a).
The sulfhydryl radical (HS•/S•−) has a pKa value (∼4) three
units lower than that of H2S.20,25 The HS• radical adds
reversibly to HS− to form the dimer radical HSSH•− (pKa
4.5
7
1.2
c
9
unknown). The S•− adds reversibly to HS− to give HSS•2−
,
c
c
with forward and reverse rate constants of 4.0 × 109 M−1 s−1
and 5.1 × 105 s−1, respectively, with the equilibrium constant
Keq being 8,000 M−1.25 The bond dissociation enthalpy of H2S,
DH298(HS−H) is 91.2 0.1 kcal/mol, which is 3.8 kcal/mol
stronger than methanethiol [DH298(CH3S−H) = 87.4 0.5].
H2S reactivity is therefore analogous to that of thiols with
respect to H atom donation and H atom abstraction by the
HS• radical (Figure 3a).26 The reduction potential of the
dimeric radical, E(HSS•2−, H+/2HS−) was determined to be
0.69 V vs NHE at pH 7,25 whereas the reduction
potential E(HSS−/HSS•2−) is estimated to be −1.13 V.27
Therefore, the dimeric radical is a good reducing agent for a
variety of organic molecules.
b
60
a
b
Reaction temperature was constant at 42 1 °C. pH = 7.5, after 60
c
min irradiation. Undetectable.
shows the irradiation time profile of the disappearance of 1
(□, ■) and the formation of 2 (○, ●) and 3 (△, ▲) at pH
4.5 (dashed lines) and 7 (full lines), respectively. The
percentage of starting material conversion was similar, i.e.,
after 60 min, a 45% conversion was obtained at pH 4.5 (□)
and 52% (■) at pH 7, whereas in the product distribution
cyclopentanone predominated at pH 4.5 (○) and cyclo-
pentanol at pH 7 (▲). The ratio of the two products was
strongly influenced by the pH conditions and also by the
reaction time, indicating the intermediacy of 2 in the formation
of product 3.
trans-1,2-Cyclopentanediol behaves exactly like the cis-
isomer, giving the same conversion and the same trend in
the product formation for 2 and 3 (see Figure S6). Further
support for the intermediate reduction step 2 → 3 was
obtained by observing the direct reduction of cyclopentanone
(2) under identical experimental conditions. Figure 2b shows
the irradiation time profile for the formation of 3 at various
pHs (see Figure S7). Interestingly, reduction efficiency
increases with pH, becoming very effective at pH 9.
These observations suggest the mechanism depicted in
Figure 3b: the HS•/S•− radical couple generated by photolysis
of H2S/HS− in aqueous environment abstracts a H atom from
1 to give the radical 4. This species undergoes a β-C−O
scission and elimination of H2O, with the shift of the radical
center to give 5, which completes the catalytic cycle by reacting
with H2S/HS− regenerating HS•/S•−. The so-formed cyclo-
pentanone (2) is reduced to the radical anion 6 by the dimeric
radical species HSSH•−/HSS•2−. Subsequent protonation (7)
and H atom abstraction from H2S/HS− affords the product 3
completing the radical chain. The reversible addition of HS•/
S•− radical to H2S/HS− is the key step that plays a role in the
B
DOI: 10.1021/acs.orglett.8b01713
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 3. (a) Hydrogen sulfide (H2S/HS−) affords the sulfhydryl radical (HS•/S•−) that adds reversibly to the parent compound to form the
dimeric radical species. (b) Dual catalytic/radical chain mechanism for the deoxygenation of cis-1,2-cyclopentanediol (1) to cyclopentanol (3) via
cyclopentanone (2).
efficacy of this conversion. Interplay of the various pKa values
(known and still unknown) ensures that the dimeric radical
species is present across the pH range (2−9) used.
Figure 4a shows representative GC analyses. Figure 4b displays
a graph with the disappearance of 8 (⧫) and the formation of
9 (●) and 10 (▲) as a function of the reaction time, showing
clearly that the reaction 8 → 10 occurs stepwise. The loss of 8
was matched by the formation of 9 and 10, with 2%, 21% and
77%, respectively after 60 min. The reaction also occurs at pH
The reduction 1 → 2 in aqueous solution has no precedent
in the literature. The reaction of HS•/S•− radical with 1 is
endothermic (∼3 kcal/mol), although polar effects should
stabilize the transition state based on DH[Me2(HO)C−H].28
In the reaction of cis-1,2-cyclopentanediol, no trace of trans-
isomer was observed, and vice versa for the reaction with trans-
1,2-cyclopentanediol, suggesting that the reverse reaction 4 →
1 is much slower than water elimination. On the other hand,
the reaction of radical 5 with H2S/HS− is thermoneutral based
on DH[MeC(O)CH(−H)Me].26 The water elimination step
(4 → 5) is a general feature in carbohydrate free-radical
chemistry.8
Examining the data in Table 1, two features of the
experiments at pH 9 are notable: (i) cyclopentanone was
undetectable and (ii) there was less conversion of the starting
material (25% after 60 min of reaction time) compared to
other pHs. These data indicated the low availability of
sulfhydryl radicals (HS•/S•−) at alkaline pH, but the fast
reduction of carbonyl moiety to 3 as described above. On the
other hand, the reduction of the carbonyl moiety at pH 2 is
limited due to the very low concentration of the necessary
radical species (HSSH•−/HSS•2−).
To determine the efficiency of the dimeric radical species
(HSSH•−/HSS•2−) for one-electron transfer to a carbonyl
group, the reduction of 2-hydroxycyclohexanone (8) at pH 9
was examined. Photolysis (low-pressure Hg lamp, 5.5 W) of
N2-saturated aqueous solutions of 8 (8.3 mM) containing
Na2S.9H2O (16.6 mM) was carried out for different times (up
to 60 min) at pH 9. In all experiments, cyclohexanone (9) and
cyclohexanol (10) were formed as the only products (eq 1).
Figure 4. (a) GC analyses after photolysis of N2-saturated 2-
hydroxycyclohexanone (8) aqueous solutions (8.3 mM) containing
Na2S.9H2O (16.6 mM), pH adjusted to 9.0, at 42
1 °C and
⧫
●
different irradiation times. (b) Concentration of 8 ( ), 9 ( ), and 10
▲
(
) vs irradiation time at pH 9 and at a constant temperature of 42
°C.
C
DOI: 10.1021/acs.orglett.8b01713
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7, in a similar way, but much slower, e.g., after 20 min, the
conversion of 8 was 73% at pH 9 and 37% at pH 7 (see Figures
S8 and S9). Therefore, the overall reaction 1 proceeds via a
dual radical chain mechanism (see also Figure S10).
Considering the efficiencies of the cyclopentanone (2) and
cyclohexanone (9) reductions, the scope of the methodology
for the reduction of carbonyl compounds to the corresponding
alcohols was further explored. Thus, under identical exper-
imental conditions, aldehydes 11 and 12 as well as ketones 13,
14, and 15 all gave exclusively the corresponding alcohols with
yield ≥90% (Figure 5a,b, see also Figures S11 and S12). The
this simple molecule present in the mixture of gases on Earth
and then substituted by cysteine and its disulfide in the actual
biological environment.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01713.
Experimental procedures and GC analyses of all
reactions Figures S1−S13 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chrys@isof.cnr.it.
ORCID
Chryssostomos Chatgilialoglu: 0000-0003-2626-2925
Present Address
‡(S.B.-V.) Visiting Scientist. Permanent address: Universidad
́
de Buenos Aires, Facultad de Farmacia y Bioquimica,
́
́
Departamento de Quimica Organica, Junin 954, CP 1113,
Buenos Aires, Argentina.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the EU COST Action CM1201
“Biomimetic Radical Chemistry”. S.B.V. acknowledges CONI-
CET (Argentina) for partially funding the visit to ISOF-CNR.
REFERENCES
■
(1) McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. Org. React.
2012, 77, 161−438.
(2) Chatgilialoglu, C.; Ferreri, C.; Landais, Y.; Timokhin, V. I. Chem.
Rev. 2018, DOI: 10.1021/acs.chemrev.8b00109.
Figure 5. Reduction of aldehydes (a) and ketones (b, c) to the
corresponding alcohols. N2-saturated aqueous solutions of carbonyl
compound (8.3 mM) containing Na2S·9H2O (16.6 mM), pH
̈
̊
(3) Eklund, H.; Uhlin, U.; Farnegardh, M.; Logan, D. T.; Nordlund,
P. Prog. Biophys. Mol. Biol. 2001, 77, 177−268.
(4) Minnihan, E. C.; Nocera, D. G.; Stubbe, J. Acc. Chem. Res. 2013,
46, 2524−2535.
(5) Licht, S.; Gerfen, G. J.; Stubbe, J. Science 1996, 271, 477−481.
(6) Greene, B. L.; Taguchi, A. T.; Stubbe, J.; Nocera, D. G. J. Am.
Chem. Soc. 2017, 139, 16657−16665.
(7) Jin, J.; MacMillan, D. W. C. Nature 2015, 525, 87−90.
(8) von Sonntag, C. Free-radical induced DNA damage and its repair:
A chemical perspective; Springer-Verlag: Berlin, 2006.
(9) Speranza, G.; Buckel, W.; Golding, B. T. J. Porphyrins
Phthalocyanines 2004, 8, 290−300.
adjusted to 9 at 42
1 °C, were irradiated for 60 min. Yields by
GC analysis based on products formation (see the SI for details).
stereochemical outcome of the reduction process was studied
using (−)-menthone (16) and (1R)-(+)-camphor (17). The
reduction of 16 led to a 2:1 mixture of (1R,2S,5R)-
(−)-menthol and (1S,2S,5R)-(+)-neomenthol in 83% yield,
while the reduction of 17 gave a 7:3 mixture of (+)-borneol
and isoborneol in close to quantitative yield (Figure 5c, see
also Figure S13). The method of reduction described is
attractive because it occurs under mild conditions and employs
inexpensive, easily removed reagents.
In summary, we have described a highly efficient biomimetic
method in aqueous environment to reduce 1,2-diols and
carbonyl compounds to mono-ols with simple inexpensive
reagents inspired by the biological transformation of
ribonucleotides to deoxyribonucleotides. The method utilizes
radicals (HS•/S•− and HSSH•−/HSS•2−) derived from hydro-
gen sulfide. Application of the methodology reported herein is
in progress, and is being appropriately adapted for the
reduction of ribose and other carbohydrates. The mechanism
shown here can be also helpful for understanding other
chemical transformations evoked in prebiotic life,29,30 involving
(10) Jiang, D.; Barata-Vallejo, S.; Golding, B. T.; Ferreri, C.;
Chatgilialoglu, C. Org. Biomol. Chem. 2012, 10, 1102−1107.
(11) Steenken, S.; Davies, M. J.; Gilbert, B. C. J. Chem. Soc., Perkin
Trans. 2 1986, 1003−1010.
(12) Le Guenic, S.; Ceballos, C.; Len, C. Catal. Lett. 2015, 145,
1851−1855.
̈
̈
(13) Moller, M.; Schroder, U. RSC Adv. 2013, 3, 22253−22260.
(14) Chatgilialoglu, C.; Ferreri, C.; Matyjaszewski, K. ChemPlu-
sChem 2016, 81, 11−29.
(15) Fukuto, J. M.; Carrington, S.; Tantillo, D. J.; Harrison, J. G.;
Ignarro, L. J.; Freeman, B. A.; Chen, A.; Wink, D. A. Chem. Res.
Toxicol. 2012, 25, 769−793.
(16) Szabo, C. Biochem. Pharmacol. 2018, 149, 5−19.
(17) Mishanina, T. V.; Libiad, M.; Banerjee, R. Nat. Chem. Biol.
2015, 11, 457−464.
(18) Stein, A.; Bailey, S. M. Redox Biol. 2013, 1, 32−39.
D
DOI: 10.1021/acs.orglett.8b01713
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(19) Chatgilialoglu, C.; Ferreri, C.; Melchiorre, M.; Sansone, A.;
Torreggiani, A. Chem. Rev. 2014, 114, 255−284.
(20) Lykakis, I. N.; Ferreri, C.; Chatgilialoglu, C. Angew. Chem., Int.
Ed. 2007, 46, 1914−1916.
(21) Sutherland, J. D. Nat. Chem. Rev. 2017, 1, 0012.
(22) Parker, E. T.; Cleaves, H. J.; Dworkin, J. P.; Glavin, D. P.;
Callahan, M.; Aubrey, A.; Lazcano, A.; Bada, J. L. Proc. Natl. Acad. Sci.
U. S. A. 2011, 108, 5526−5531.
̌
́
́
̌
́
(23) Dragicevic, I.; Baric, D.; Kovacevic, B.; Golding, B. T.; Smith,
D. M. Chem. - Eur. J. 2015, 21, 6132−6143.
(24) Hughes, M. N.; Centelles, M. N.; Moore, K. P. Free Radical
Biol. Med. 2009, 47, 1346−1353.
(25) Das, T. N.; Huie, R. E.; Neta, P.; Padmaja, S. J. Phys. Chem. A
1999, 103, 5221−5226.
(26) Blanksby, S.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255−263.
(27) Koppenol, W. H.; Bounds, P. L. Arch. Biochem. Biophys. 2017,
617, 3−8.
(28) Zavistas, A. A. Thermochemistry and hydrogen transfer
kinetics. In Encyclopedia of Radical in Chemistry, Biology and Materials;
Chatgilialoglu, C., Studer, A., Eds.; Wiley: Chichester (UK), 2012;
Vol. 1, Chapter 4, pp 81−106.
(29) Olson, K. R.; Straub, K. D. Physiology 2016, 31, 60−72.
(30) Bonfio, C.; Valer, L.; Scintilla, S.; Shah, S.; Evans, D. J.; Jin, L.;
Szostak, J. W.; Sasselov, D. E.; Sutherland, J. D.; Mansy, S. S. Nat.
Chem. 2017, 9, 1229−1234.
E
DOI: 10.1021/acs.orglett.8b01713
Org. Lett. XXXX, XXX, XXX−XXX