Revisiting the reaction of hydroxyl radicals with vicinal diols in water

Article abstract of DOI:10.1039/c1ob06538f

The carbonyl products of the reactions of hydroxyl radicals with three vicinal diols (ethane-1,2-diol, propane-1,2-diol and butane-2,3-diol) have been identified and quantified. Hydroxyl radicals were produced by γ-radiolysis of N₂O-saturated aqueous solutions. The reactions result in the formation of alkoxyl radicals (～15%) followed by β-fragmentation, and α-hydroxyl alkyl radicals that undergo H₂O elimination. The latter process is part of a radical chain reaction at higher diol concentrations.

Full text of DOI:10.1039/c1ob06538f

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Organic &
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PAPER
Revisiting the reaction of hydroxyl radicals with vicinal diols in water†
a
b
a
b
Dong Jiang, Sebasti a´ n Barata-Vallejo,‡ Bernard T. Golding,* Carla Ferreri and
b
Chryssostomos Chatgilialoglu*
Received 7th September 2011, Accepted 26th October 2011
DOI: 10.1039/c1ob06538f
The carbonyl products of the reactions of hydroxyl radicals with three vicinal diols (ethane-1,2-diol,
propane-1,2-diol and butane-2,3-diol) have been identified and quantified. Hydroxyl radicals were
produced by g-radiolysis of N O-saturated aqueous solutions. The reactions result in the formation of
2
alkoxyl radicals (~15%) followed by b-fragmentation, and a-hydroxyl alkyl radicals that undergo H O
2
elimination. The latter process is part of a radical chain reaction at higher diol concentrations.
∑
Introduction
deoxyadenosyl radical (Ado-CH
(
2
), derived from coenzyme B12
∑
5¢-deoxyadenosylcobalamin, AdoCbl) on the diol leading to S
-H). The conversion of S to P
was shown by O-labelling to exhibit the migration of a hydroxyl
The acid-catalyzed conversion of vicinal diols to aldehydes or
ketones exemplified by the ‘pinacol rearrangement’ has been
known since 1860 and exhibits well-established mechanisms
4
∑
∑
and 5¢-deoxyadenosine (Ado-CH
2
18
1
7
group from C-2 to C-1. Independent of these discoveries, it was
initiated by protonation of a hydroxyl group. For diols containing
tertiary alcohols (e.g. pinacol, 2,3-dihydroxy-2,3-dimethylbutane),
the classical mechanism entails formation of a tertiary carbocation
by loss of water from the protonated diol followed by migration of
revealed that reactions of simple 1,2-diols with hydroxyl radicals
led to the same radical (i.e. S ) proposed as an intermediate
∑
in the enzyme-catalyzed reactions and the ensuing chemistry
8,9
of this radical was similar. It was further shown that the
2
3
a methyl group from the adjacent carbon centre. The discovery
of enzyme-catalysed conversions of 1,2-diols to aldehydes in the
960s was an apparent biochemical addition to the chemical
armoury. However, it was soon established that the enzymatic
∑
S species underwent either acid- or base-catalyzed elimination
of a diol hydroxyl group (as water or hydroxide) to afford a
1
10
carbon radical stabilized by an adjacent carbonyl group (e.g.
the formylmethyl radical from ethane-1,2-diol, see Scheme 2). The
relevance of this radical chemistry to the catalytic mechanism of
4,5
mechanism was fundamentally different from that of the pinacol
rearrangement. In particular, it was decisively shown that the
key intermediates in the mechanism of the diol dehydratase-
catalysed conversion of propane-1,2-diol to propionaldehyde are
11
diol dehydratase was immediately pointed out. In this paper,
we describe product studies for the reactions of hydroxyl radicals
with three diols (ethane-1,2-diol, propane-1,2-diol and butane-2,3-
diol). This research serves to show the extraordinary selectivity
of diol dehydratase in its action on 1,2-diols and contributes
to the mechanistic understanding of both the chemistry and
biochemistry of carbon radicals from vicinal diols.
∑
a substrate-derived radical (S ) and a product-related radical
∑
6
(
P ) [see Scheme 1]. These species arise by attack of the 5¢-
a
School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1
7
RU, UK. E-mail: b.t.golding@newcastle.ac.uk; Fax: +44 (0)191 222 6929;
Tel: +44 (0)191 222 6647
Results and discussion
b
ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, I-40129
Bologna, Italy. E-mail: chrys@isof.cnr.it; Fax: +39 051 639 8349; Tel: +39
Radiolytic production of transients
0
51 639 8309
†
1
Electronic supplementary information (ESI) available. See DOI:
0.1039/c1ob06538f
Doctoral candidate at the Faculty of Pharmacy and Biochemistry,
Radiolysis of neutral water leads to the reactive species eaq-, HO∑
∑
+
and H , together with H and H
2
O
2
as shown in eqn (1). The values
‡
University of Buenos Aires, Argentina.
in parentheses represent the radiation chemical yields (G) in units
Scheme 1 Diol dehydratase-catalysed pathway for the conversion of propane-1,2-diol into propionaldehyde (mauve indicates isotopic labelling with
18
deuterium or tritium; red indicates labelling with O).
1
102 | Org. Biomol. Chem., 2012, 10, 1102–1107
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Scheme 2 Conversion of ethane-1,2-diol to the 1,2-dihydroxyethyl radical
induced by the hydroxyl radical.
-
1
12,13
O), eaq-
of mmol J .
In a N
2
O-saturated solution (~0.02 M of N
2
∑
is transformed into a HO radical with a rate constant k
2
= 9.1 ¥
9
-1 -1
∑
-1
∑
1
0 M s (eqn (2)), affording G(HO ) = 0.55 mmol J , i.e., HO
∑
radicals and H atoms account for 90% and 10%, respectively, of
the reactive species.
g
-
⋅
⋅
+
H O ⎯ ⎯→ e (0.27), HO (0.28), H (0.06), H (0.27), H O (0.07)
2
aq
2
2
(
1)
-
∑
+ HO-
e
aq + N
2
O + H
2
O → HO + N
2
(2)
Fig. 1 HPLC analyses of g-irradiation of N
2
O-saturated unbuffered
When a vicinal diol is added to the solution, this acts as
a scavenger of HO radicals and H atoms, to generate mainly
solutions of 0.2 M (upper) and 2.0 M (lower) ethane-1,2-diol at various
∑
-1
doses (dose rate = 5.9 Gy min ) after 2,4-DNP derivatisation of the
a-hydroxyalkyl radicals. In Table 1, the rate constants for the
carbonyl-containing compounds. The black and blue peaks correspond
to formaldehyde and acetaldehyde, respectively.
reactions of the vicinal diols used in this work with hydroxyl
12,13
radicals and hydrogen atoms are shown.
It is worth mentioning
-
1
2
.31 mmol J when the lines are extrapolated to zero dose for 2 M
that hydroxyl radicals react with all three substrates with similar
∑
solutions (Fig. 2, lower). The data obtained from the analogous
rate constants, whereas the rate constants for H are expected to
experiment with 0.2 M solutions gave G(HCHO) = 0.16 and
increase with increasing methyl substitution.
-
1
G(CH CHO) = 0.43 mmol J when the lines are extrapolated to
3
Ethane-1,2-diol
zero dose (Fig. 2, upper).
Sample solutions (0.2 or 2 M) of ethane-1,2-diol (1) in unbuffered
H
2
O were saturated by N
2
O prior to irradiation. Irradiation
doses were up to 300 Gy and to 3000 Gy for 0.2 and 2.0 M
-
1
solutions, respectively, using a dose rate of ca. 5.9 Gy min .
,4-Dinitrophenylhydrazine (2,4-DNP) was added to convert the
2
carbonyl-containing products to 2,4-DNP derivatives. HPLC
analysis of the mixture of 2,4-DNPs indicated the formation of
formaldehyde and acetaldehyde (Fig. 1). For recognition and
quantification of the 2,4-DNPs of the carbonyl compounds, a
14
published protocol was employed. The comparison was obtained
from the same derivatisation procedure performed with the
commercially available compounds followed by HPLC analysis.
From the concentration values of formaldehyde and acetalde-
hyde derived from Fig. 1, the radiation chemical yields (G) can be
-
1
calculated by dividing the formation of the products (mol kg ) by
-
1
the absorbed dose (1 Gy = 1 J kg ). Analysis of the data in terms of
radiation chemical yield gave G(HCHO) = 0.20 and G(CH
3
CHO) =
∑
∑
Table 1 Rate constants for the reactions of HO radicals and H atoms
with vicinal diols
k(HO ), /M s-1
∑
a
-1
k(H ), /M s-1
∑
a
-1
Diol
9
7
Ethane-1,2-diol
Propane-1,2-diol
Butane-2,3-diol
1.8 ¥ 10
1.4 ¥ 10
9
1.7 ¥ 10
9
1.3 ¥ 10
3
Fig. 2 Radiation chemical yields (G) of HCHO (᭹) and CH CHO ( )
a
vs. dose from the experiments with 0.2 M (upper) and 2.0 M (lower)
ethane-1,2-diol (cf. Fig. 1).
Ref. 12 and 13.
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-1
The experiment with
2
M
ethane-1,2-diol produced
CHO) = 2.31 mmol J , which is 4–5 times more than G(2) =
.53. This result indicated a chain reaction for the formation of
Table 2 Radiation chemical yields (G, mmol J ) for the reaction of
∑
∑
-
1
HO /H with propane-1,2-diol (5)
G(CH
3
0
a
b
b
Products
G from 0.2 M 5,
G from 2 M 5,
10
CH
3
CHO. Scheme 3 illustrates our proposal, which involves H O
2
elimination from the nucleophilic radical 2 with formation of the
electrophilic radical 4 and the subsequent hydrogen abstraction
from the starting material that completes the chain.
HCHO
0.10
0.11
1.55
0.05
0.08
0.17
3.05
0.09
CH
3
CHO
Acetone
CH CH CHO
3 2
a
b
All compounds quantified by the 2,4-DNP procedure. Values are
extrapolated to zero dose (see ESI†).
relative low energy of activation, because O–O antibonding is low
as a result of the weak O–O bond.
Propane-1,2-diol
Sample solutions (0.2 or 2 M) of propane-1,2-diol in unbuffered
H
2
O were saturated by N O prior to irradiation. Various irra-
2
diation doses up to 300 Gy and 2500 Gy for 0.2 and 2.0 M
solutions, respectively, were employed. Derivatisation to a 2,4-
DNP mixture and HPLC analysis indicated the formation of
formaldehyde, acetaldehyde, acetone and propionaldehyde (Fig.
3) on comparison with authentic compounds. Analysis of the data
in terms of radiation chemical yields is reported in Table 2.
∑
∑
Scheme 3 Proposed mechanism for the reaction of HO /H with
ethane-1,2-diol (1). The compounds quantified by the 2,4-DNP procedures
(
Fig. 1) are shown in red.
The above findings need further comments. Asmus and co-
∑
workers some time ago investigated the site of HO attack on
15
aliphatic alcohols in aqueous solution using pulse radiolysis.
The formation of reducing and oxidising radicals were identified
-
by their reaction with C(NO
2
)
4
and I , respectively. Thus, it was
∑
estimated that the reaction of HO with CH
the CH group and 7% from the OH site. On the other hand,
the reaction of HO with ethane-1,2-diol was assigned 100% to
occur from the CH moieties, because no oxidising species were
obtained in the presence of 5 ¥ 10 M I . The findings that the
formation of HCHO occurs in substantial quantities, suggests
another scenario. On the basis of G(HCHO) = 0.16 and assuming
3
OH occurs 93% from
3
∑
2
-
4
-
-
1
that G(HCHO) = 2 ¥ G(3), we calculated a G(3) = 0.08 mmol J
-
1
and consequently a G(2) = 0.53 mmol J (cf. eqn (1) and (2)). Since
H-atoms are expected to produce only radical 2, a G(3) = 0.08
∑
indicates that 14–15% of generated HO radicals react with one of
the two HO-groups of ethane-1,2-diol. This is in good agreement
with the site of attack on CH
3
OH discussed above. We also suggest
that the fragmentation of 3 (oxidising species) to give HCHO and
∑
HOCH
2
(reducing species) is fast enough in aqueous solution to
compete with the bimolecular oxidation of iodide ions, so that the
15
Fig. 3 HPLC analyses of g-irradiation of N
2
O-saturated unbuffered solu-
product radicals are only reducing species. It is well-known that
alkoxyl radicals undergo facile b-fragmentation and 1,2-H-shift.
For example, the b-fragmentation of the tert-butoxyl radical is
tions of 0.2 M (upper) and 2.0 M (lower) propane-1,2-diol at various doses
-1
(
dose rate = 5.9 Gy min ) after 2,4-DNP derivatisation of the carbonyl
compounds. The black and blue peaks correspond to formaldehyde and
acetaldehyde, whereas the red and green peaks correspond to acetone and
propionaldehyde, respectively.
6
-1
16
∑
1
2
.2 ¥ 10 s in water and the 1,2-H-shift in CH
3
CH
2
O is (5 ±
6
-1
17
) ¥ 10 s in water. The b-fragmentation of radical 3 is expected
to be much faster than tert-butoxyl radical due to the formation
∑
∑
of the stabilized HOCH
2
radical versus the CH
3
radical. The high
Scheme 4 shows the mechanism we conceived for the reaction
∑
∑
∑
reactivity of HO radicals towards the OH moiety of ethane-1,2-
diol is unsurprising. We have shown that for X–H + Y to give X
H–Y, a major factor affecting the energy of activation is X–Y
antibonding at the TS in addition to the enthalpy of reaction.
of HO /H with propane-1,2-diol, taking into consideration the
mechanism for ethane-1,2-diol discussed above (Scheme 3). H-
atoms are expected to produce only radicals 6 and 7, whereas
∑
∑
+
18
∑
HO radicals abstract hydrogen atoms from all possible sites to
It was suggested that abstraction from a OH moiety will have a
give radicals 6–10. The fact that G(acetone) increases from 1.55
1
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∑
∑
Scheme 4 Proposed mechanism for the reaction of HO /H with propane-1,2-diol (5). The compounds quantified by the 2,4-DNP procedures (Fig. 3)
are shown in red.
to 3.05 by increasing the concentration of starting material from
0.2 to 2 M, clearly indicates a chain reaction. Both radicals 6 and
7
undergo H O elimination to give the electrophilic radicals 11
2
and 12, respectively, and their reaction with 5 gives mainly the
most stable radical 7. The remaining radicals 8, 9, and 10 are
expected to afford the same products by b-fragmentation. This
unimolecular process for 8 should be much slower than that for
1
5
9
and 10. Asmus and co-workers reported that the reaction of
∑
HO with propane-1,2-diol occurs 79.2% by abstraction of an H
atom from the a position of the HO-group, and the remaining
2
0.7% from the methyl site. By analogy with the ethane-1,2-diol
case, we suggest that 79.2% of the reducing species contain also the
hydrogen abstraction from the OH site, because the fragmentation
of 9 and 10 (oxidizing species) is fast enough in aqueous solution
to compete with the bimolecular oxidation of iodide ions.
Butane-2,3-diol
Sample solutions (0.2 or 2 M) of butane-2,3-diol in unbuffered
H
2
O were saturated by N O prior to irradiation. Various irra-
2
diation doses up to 300 Gy and 1500 Gy for the 0.2 and 2.0
M solutions, respectively, were used. Derivatisation to a 2,4-
DNP mixture and HPLC analysis indicated the formation of
acetaldehyde, 3-hydroxybutan-2-one and 2-butanone (Fig. 4) by
comparison with authentic compounds. Analysis of the data in
terms of radiation chemical yields is reported in Table 3.
Fig. 4 HPLC analyses of g-irradiation of N O-saturated unbuffered
2
Scheme 5 shows the mechanism we conceived for the reaction
of HO /H with butane-2,3-diol, taking into consideration the
mechanisms for ethane-1,2-diol and propane-1,2-diol reported
solutions of 0.2 M at 300 Gy (upper) and 2.0 M at various doses (lower)
of butane-2,3-diol (dose rate = 5.9 Gy min ) after 2,4-DNP derivatisation
of the carbonyl compounds. The yellow and blue peaks correspond to
∑
∑
-1
3
-hydroxybutan-2-one (18) and acetaldehyde, whereas the magenta and
above (Scheme 1). H-atoms are expected to produce only radicals
∑
grey peaks correspond to 2-butanone and the unknown carbonyl product,
respectively.
1
4 and 15, whereas HO radicals abstract hydrogen atoms from all
possible sites to give radicals 14–16. The fact that G(CH CHO) and
3
G(butan-2-one) are nearly doubled by increasing the concentration
of starting material from 0.2 to 2 M, suggests that radical 14
-
1
Table 3 Radiation chemical yields (G, mmol J ) for the reaction of
∑
∑
HO /H with butane-2,3-diol (13)
undergoes H
its reaction with 2,3-diol 13 gives butan-2-one and both radicals
4 and 15. The radicals 15 and 16 are expected to afford the same
2
O elimination to give the electrophilic radical 17, and
a
b
b
Products
G from 0.2 M 13,
G from 2 M 13,
1
CH
Butan-2-one
-Hydroxybutan-2-one
3
CHO
0.13
0.16
0.08
0.03
0.27
0.25
0.08
0.04
products by b-fragmentation, whereas 3-hydroxybutan-2-one (18)
should result from the disproportionation of radical 15 followed
by tautomerism. However, the presence of an unknown carbonyl
derivative suggests an even more complex reaction scheme. Asmus
3
Unknown carbonyl
a
b
All compounds quantified by the 2,4-DNP procedure. Values are
extrapolated to zero dose (see ESI†).
15
∑
and co-workers reported that the reaction of HO with butane-
2
,3-diol occurs 71% by abstraction of an H atom from the a
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Experimental
Materials
Commercially available starting materials were obtained from
Sigma-Aldrich Co. and used as received. Solvents were purchased
from Merck (HPLC grade) and used without further purification.
Water was purified with a Millipore system.
Continuous radiolysis
Solutions were freshly prepared by using water purified with a
Millipore (Milli-Q) system. Sample solutions (0.2 and 2 M) of
the compounds were saturated with N O prior to irradiation.
2
Continuous radiolyses were performed at room temperature (22 ±
∑
∑
◦
6
0
Scheme 5 Proposed mechanism for the reaction of HO /H with bu-
tane-2,3-diol (13). The compounds quantified by the 2,4-DNP procedures
2
C) on 250 mL samples using a Co-Gammacell, with dose
-1
rates ca. 6 Gy min . The absorbed radiation dose was determined
(
Fig. 4) are shown in red.
3+
with the Fricke chemical dosimeter, by taking G(Fe ) = 1.56 mmol
-
1 24
J . HPLC analyses were recorded on an Agilent 1100 Liquid
Chromatograph, equipped with a quaternary pump delivery
system, a column thermostat and a variable-wavelength detector.
position of the HO-group, and the remaining 29% from the methyl
site. In analogy with the ethane-1,2-diol case, we suggest that 71%
of the reducing species also partly result from hydrogen abstraction
from the OH site, because the fragmentation of 16 (oxidising
species) is fast enough in aqueous solution to compete with the
Quantification and identification of the carbonyl compounds
19
bimolecular oxidation of iodide ions.
The quantification of the carbonyl compounds was performed
via the corresponding 2,4-dinitrophenylhydrazone derivatives,
14
following a published protocol adapted to our case. 1 mL
of an irradiated sample was diluted with 500 mL 0.4% v/v
Conclusions
conc. H
3
PO (in 9 : 1, acetonitrile : water, v/v). 500 mL of 2,4-
4
The results of the experiments described herein emphasise the
extraordinary selectively of the enzymatic reactions catalysed by
diol dehydratase and the related enzymes glycerol dehydratase
dinitrophenylhydrazine (2,3-DNP) 40 mM in acetonitrile was
added and the resulting solution was vortexed for 12 h. Af-
ter derivatisation, the reaction mixture was diluted to 1 : 10
acetonitrile : water, (1 : 1, v/v) and 20 mL was injected for HPLC
and ribonucleotide reductase (coenzyme B12-dependent and B12
-
5
independent) acting on their substrate vicinal diols compared
to the chemical reactions of diols with hydroxyl radicals described
herein, despite similarities of mechanism. For the diol dehydratase-
catalysed reaction with propane-1,2-diol, selectivity with respect
to H atom abstraction is achieved by tight binding of the diol by
analysis using a GraceSmart RP 18 5 mm column (150 mm ¥
◦
4
.6 mm), at 30 C, with detection at l = 338 nm. Mobile phase A
was 0.1% trifluoroacetic acid in water and mobile phase B was 0.1%
trifluoroacetic acid in acetonitrile. The separation was obtained at
-
1
2
+
a flow rate of 1 mL min with a gradient program as follows:
0 min 40% B, followed by a 25 min step to increase eluent B
four amino acid residues aided by a Ca ion with the placement
1
of the 5¢-deoxyadenosyl radical close to a specific hydrogen at C-1
20
to 100%. Washing was carried out at 100% B and equilibration
at 40% B. Total time of analysis was 35 min. The identification
of the carbonyl compounds was performed by derivatisation of
commercially available compounds followed by HPLC analysis
and spike experiments.
of the diol. A special feature of the conversion of the substrate
7
to the product radical is a 1,2-hydroxyl shift that may occur by
a ‘push-pull’ mechanism via an oxirane-like species, which can
be qualitatively described as a complex of water with an alkene
4,5
radical cation. Our ongoing studies are exploring how far the
model chemistry and enzymatic chemistry correspond with respect
to the substrate radical to product radical conversion.
Acknowledgements
Some general considerations can be drawn from the radiation
chemistry of this study, which affords a deeper insight into the
reactivity of vicinal diols with radical species. The findings may
be relevant to the multiple uses of diols, such as the applications
of propane-1,2-diol, which are generally deemed safe, as a food
and pharmaceutical additive (E1520), anti-freeze component and
The support and sponsorship of COST Action CM0603 on
‘Free Radicals in Chemical Biology (CHEMBIORADICAL)’ are
gratefully acknowledged.
21
antiseptic substance. However, studies of ethanol-induced free
radical generation in animals have shown that the derived a-
hydroxyethyl radical and acetaldehyde may be responsible for
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