On the role of pre- and post-electron-transfer steps in the SmI 2/Amine/H2O-mediated reduction of esters: New mechanistic insights and kinetic studies

Article abstract of DOI:10.1002/chem.201400295

The mechanism of the SmI₂-mediated reduction of unactivated esters has been studied using a combination of kinetic, radical clocks and reactivity experiments. The kinetic data indicate that all reaction components (SmI₂, amine, H₂O) are involved in the rate equation and that electron transfer is facilitated by Bronsted base assisted deprotonation of water in the transition state. The use of validated cyclopropyl-containing radical clocks demonstrates that the reaction occurs via fast, reversible first electron transfer, and that the electron transfer from simple Sm(II) complexes to aliphatic esters is rapid. Notably, the mechanistic details presented herein indicate that complexation between SmI₂, H₂O and amines affords a new class of structurally diverse, thermodynamically powerful reductants for efficient electron transfer to carboxylic acid derivatives as an attractive alternative to the classical hydride-mediated reductions and as a source of acyl-radical equivalents for C-C bond forming processes. Electron donors: The mechanism of the SmI ₂-mediated reduction of unactivated esters has been studied by using a combination of kinetic, radical clock, and reactivity experiments. Notably, the mechanistic details presented herein indicate that complexation between SmI₂, H₂O, and amines gives a new class of structurally diverse, thermodynamically powerful reductants for efficient electron transfer to carboxylic acid derivatives as an attractive alternative to the classical hydride-mediated reductions and as a source of acyl-radical equivalents for C-C bond-forming processes (see scheme).

Full text of DOI:10.1002/chem.201400295

DOI: 10.1002/chem.201400295
Communication
&
Radical Reactions
On the Role of Pre- and Post-Electron-Transfer Steps in the SmI2/
Amine/H2O-Mediated Reduction of Esters: New Mechanistic
Insights and Kinetic Studies
Michal Szostak,* Malcolm Spain, and David J. Procter*[a]
Abstract: The mechanism of the SmI2-mediated reduction
of unactivated esters has been studied using a combina-
tion of kinetic, radical clocks and reactivity experiments.
The kinetic data indicate that all reaction components
(SmI2, amine, H2O) are involved in the rate equation and
that electron transfer is facilitated by Brønsted base assist-
ed deprotonation of water in the transition state. The use
of validated cyclopropyl-containing radical clocks demon-
strates that the reaction occurs via fast, reversible first
Figure 1. Accepted and proposed mechanism of SmI2-mediated electron
transfer to aldehydes, ketones, and carboxylic acid derivatives; rds=rate-de-
termining step.
electron transfer, and that the electron transfer from
simple Sm(II) complexes to aliphatic esters is rapid. Nota-
bly, the mechanistic details presented herein indicate that
complexation between SmI2, H2O and amines affords
hydes.[6] However, the mechanistic details of this process, in-
a new class of structurally diverse, thermodynamically
powerful reductants for efficient electron transfer to car-
boxylic acid derivatives as an attractive alternative to the
classical hydride-mediated reductions and as a source of
acyl-radical equivalents for CÀC bond forming processes.
cluding the critical role of amine and H2O additives, remained
unclear.[6,7] As a better mechanistic understanding of the role
of these additives could afford key insights for the develop-
ment of new reductive processes, including chemoselective re-
duction of less reactive functional groups, such as nitriles,
amides and amino acids, as well as the development of new
CÀC bond-forming reactions,[8] we initiated a mechanistic in-
vestigation into the reduction of unactivated esters using
SmI2/amine/H2O. The data described herein show two impor-
tant features: 1) all reaction components (SmI2, amine, H2O) are
involved in the rate equation, and there is a direct correlation
between the rate of ester reduction and pKBH+ of amines;
2) the reaction occurs via fast, reversible first electron transfer,
and the electron transfer from simple SmII complexes to ali-
phatic esters is rapid. Importantly, this study sets the stage for
the use of SmI2/amine/H2O complexes to generate acyl-type
radicals from a plethora of carboxylic acid derivatives.
Samarium(II)-mediated generation of ketyl radicals has been
the focus of intense research for more than three decades,[1]
and the SmI2-promoted reductions, which enable the synthesis
of alcohols under conditions orthogonal to other reagents op-
erating through single- and two-electron pathways,[2,3] are
a prominent class of these processes (Figure 1). Until recently,
it had been thought that unactivated carboxylic acid deriva-
tives were outside the reducing range of SmI2,[4] which pre-
vented progression of the rich carbonyl chemistry of SmI2 (e.g.,
reduction, cross-coupling, tandem bond-forming events) to
acyl-type radicals generated from carboxylic acid derivatives
under mild and chemoselective reaction conditions (Figure 1).
We started our investigation by conducting a range of kinet-
ic studies (Table 1). tert-Butyl 3-phenylpropanoate (1) was se-
lected as a model substrate, because its rate of reduction is in
a convenient range for kinetic studies, and there is ample liter-
ature precedent for SmII reduction conditions available for this
substrate.[5] Within experimental error, the reduction of 1 in
the presence of SmI2/Et3N/H2O was found to be first order in
all components of the reaction (Table 1). The rate constant of
1.4Æ0.1ꢀ10mÀ3 sÀ1 was determined for the reduction of
1 under these reaction conditions. Taken together, these re-
sults suggest that all reaction components are involved in the
rate equation, and that the reduction of 1 is a fast process.
To further explore the impact of H2O, the reduction rate of
1 was monitored over a 20-fold concentration range as depict-
In 2011, we reported that the SmII reagent produced from
SmI2, amine and H2O is capable of reducing unactivated esters
via radical intermediates,[5] thus for the first time expanding
the carbonyl chemistry of SmI2 beyond ketones and alde-
[a] Dr. M. Szostak, M. Spain, Prof. Dr. D. J. Procter
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (UK)
Fax: (+44)161-275-4939
E-mail: michal.szostak@manchester.ac.uk
david.j.procter@manchester.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400295.
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Table 1. Rate constant and reaction orders for the reduction of 1 using
the SmI2/Et3N/H2O system.[a]
Table 2. Determined initial rate in the reduction of 1 using SmI2/amine/
H2O versus pKBH+.
[a]
[b]
Entry
Amine
vinitial [mMsÀ1
]
pKBH+
1
2
3
4
5
morpholine
nBu3N
Et3N
nBuNH2
pyrrolidine
2.4ꢀ10À4
3.9ꢀ10À5
5.0ꢀ10À4
6.8ꢀ10À3
8.8ꢀ10À3
9.0Æ0.2
10.0Æ0.5
10.6Æ0.3
10.7Æ0.1
11.3Æ0.2
Rate order
[b]
k[a][mÀ3 sÀ1
]
Substrate[a]
SmI2
Et3N[c]
H2O[d]
1.4ꢀ10
0.96Æ0.10
1.09Æ0.10
1.18Æ0.10
0.92Æ0.10
[a] [SmI2]=75 mm; [H2O]=250 mm; [ester]=12.5 mm; [amine]=150 mm;
T=238C. [b] Determined from ACD lab prediction algorithm.
[a] [SmI2]=75 mm; [H2O]=250 mm; [Et3N]=150 mm; [ester]=5–20 mm.
[b] [SmI2]=50–100 mm; [H2O]=250 mm; [Et3N]=150 mm; [ester]=
12.5 mm. [c] [SmI2]=75 mm; [H2O]=250 mm; [Et3N]=75–250 mm;
[ester]=12.5 mm. [d] [SmI2]=75 mm; [H2O]=75–300 mm; [Et3N]=
150 mm; [ester]=12.5 mm. T=238C. See the Supporting Information.
tained.[11] By plotting log(kobs) versus pKBH+, a linear correlation
was found with a slope corresponding to 0.79, which corre-
sponds very well to the value obtained in the reduction of
alkyl halides via an outer-sphere mechanism using SmI2/amine/
H2O reported by Hilmersson (0.76; for a detailed comparison,
see the Supporting Information).[7e] This result strongly sug-
gests that the role of the amine component is independent of
the mechanistic pathway (inner- vs. outer-sphere electron
transfer) and the relative redox potentials of both classes of
substrates. Considering steric properties exerted by these
amines, our findings bode well for the chemoselective fine
tuning of SmII/amine reductants to specific functional groups.
Several additional studies give insight into the electron-
transfer steps. 1) The reduction with SmI2/amine/D2O gives the
alcohol with >95% [D]2 incorporation suggesting that anions
are protonated in a series of electron transfers. 2) The kinetic
isotope effect in the reduction of isopropyl 3-phenylpropa-
noate using SmI2/Et3N/H2O of 1.5Æ0.1, parallel runs, and 1.4Æ
0.1, intramolecular competition,[5] indicate that proton transfer
is not involved in the rate-determining step.[12] 3) UV/Vis spec-
trophotometric studies carried out on various SmI2/amine/H2O
systems show isosbestic points and absorbance changes upon
addition of amines and H2O to SmI2,[7d] which is consistent with
the formation of distinct SmII reductants.
ed in Figure 2. In this study, a nonlinear rate dependence on
H2O was found. At lower concentrations (up to 300 mm), the
rate was found to increase linearly with a slope corresponding
to the rate order of one, consistent with saturation behavior
Figure 2. Plot of kobs versus concentration of H2O for the reduction of 1.
[H2O]=0.075–1.2m; [SmI2]=75 mm; [Et3N]=150 mm; [ester]=12.5 mm;
T=238C.
Next, we utilized intermolecular competition studies to eluci-
date the actual productivity difference in the SmI2/amine/H2O-
mediated reduction of esters (Table 3). In these experiments,
an equimolar amount of two esters was reacted with limiting
SmI2 (typically, less than 2 equiv). The relative reactivity values
were determined from the product distribution. This method
allows to accurately measure the relative reactivity values of
SmII-mediated reactions provided that the studied substrates
do not participate in alternative reaction pathways.[13] Methyl
decanoate was chosen as an arbitrary standard. Remarkably, in
the series of eight methyl esters, a reactivity range of over
three orders of magnitude was observed, depending on the
steric and electronic properties of the a-carbon substituent at
the ester group undergoing the reduction (Table 3, entries 1–
8). This effect is consistent with both electronic stabilization of
ketyl-type radicals (Table 3, entries 1–4) and steric inhibition of
coordination to SmII (entries 4–8). Moreover, several substrates
with enhanced leaving-group ability compared to the methyl
ester were examined (Table 3, entries 9–12). These results fur-
ther support the importance of electronic effects for the stabili-
zation of the ketyl-type radical intermediates and determining
(300 mm). However, at higher concentrations (300–1200 mm),
the rate decreased dramatically, consistent with substrate dis-
placement from the inner coordination sphere of SmII. In con-
trast, a linear rate dependence on amine at these concentra-
tions was found. In agreement with previous studies, H2O is ex-
pected to show high affinity for SmII and compete for coordi-
nation to SmII with the ester substrate.[9] Interestingly, the con-
centration of H2O at which the decrease in the reaction rate
was observed correlates with iodide displacement from the
SmII coordination sphere.[10]
To further elucidate the role of the amine component, the
reduction rate of 1 was measured in the presence of a wide
range of amines with varying steric and electronic properties
(Table 2). Remarkably, a dramatic change in the reaction rate of
over two orders of magnitude was found by simply using dif-
ferent amines for the reduction. Moreover, a good correlation
between the reaction rate and basicity of amines was ob-
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Table 3. Steric and electronic influence on the relative rates for the re-
duction of esters.
Entry
RV[a]
1
2
3
4
>100
9.14
4.29
1.00
5
0.41
Scheme 1. Studies designed to investigate the mechanism of reduction of
unactivated esters using SmI2/Et3N/H2O.
6
7
8
0.26
0.91
0.05
clopropylcarbinol 6 was not detected in the reaction. Several
control experiments were performed (see the Supporting Infor-
mation). 1) The reaction of 3 with SmI2/H2O (8 equiv, RT, 2 h) re-
sulted in a facile opening to ester 4, with no over-reduction to
5 or 6 observed. 2) The reduction of the methyl ester of cyclo-
propanecarboxylic acid (approximated unimolecular rate con-
stant kfrag ꢀ9.4ꢀ107 sÀ1 at 258C)[20] with excess SmI2/amine/H2O
afforded the corresponding acyclic alcohol and cyclopropylcar-
binol in 96:4 ratio. This allows to estimate the rate of reduction
of ketyl-type radicals with SmII to be comparable to a unimolec-
Entry
RV[a]
9
R=OMe
R=OPh
R =Opfp
R=SEt
1.00
6.88
9.15
5.78
10
11
12
[a] Relative reactivity values (RV) determined from product distribution by
1H NMR and/or GC analyses of crude reaction mixtures. All data represent
the average of at least two experiments. pfp=pentafluorophenyl.
ular reaction with k of about 108 sÀ1 [21]
3) The reductive open-
.
ing of radical clock 3 was not observed with other SmII re-
agents, including systems with higher redox potential (SmI2/
MeOH, SmI2/LiCl, SmI2/HMPA (HMPA=hexamethylphosphor-
amide), and SmI2/Et3N).[4b] Finally, experiments utilizing chiral
probe 7 (Scheme 1) were carried out and demonstrate that
enolization did not occur in the process despite basic reaction
conditions, whereas control experiments using H218O
(Scheme 1 and the Supporting Information) show that the re-
duction did not proceed via a sequential ester hydrolysis/acid
reduction mechanism. Overall, these findings strongly suggest
that the reduction of unactivated esters with SmI2/amine/H2O
occurs through fast, reversible electron transfer, and, in contra-
ry to the current paradigm,[1,2] show that electron transfer from
simple SmI2/H2O complexes to aliphatic esters is rapid.[22]
the redox potential of the substrates.[14] Importantly, the data
presented in Table 3 indicate high levels of chemoselectivity in
the reduction of esters with SmI2/Et3N/H2O.
Evidence for the electronic and steric stabilization of ketyl-
type radical intermediates was further substantiated by Ham-
mett and Taft correlation studies (see the Supporting Informa-
tion). The Hammett correlation study, employing methyl esters
of 4-substituted phenylacetic acids,[15] showed a large positive
1 value of 0.43 (R2 =0.98), which can be compared with the
1 value of 0.49 for ionization of phenylacetic acids in H2O at
258C.[16] The Taft correlation study,[17] obtained by plotting
log(kobs) versus ES in a series of aliphatic esters of hydrocin-
namic acid showed a large positive slope of 0.97 (R2 =0.97).
Overall, these results suggest that an anionic intermediate is
formed in the transition state of the reaction, and that a confor-
mational change similar in geometry to the ester hydrolysis,
tetrahedral intermediate, is taking place in the rate-determin-
ing step of the reaction.[18]
A mechanism that best fits the kinetic and reactivity studies
presented herein features the following steps (Scheme 2):[24]
1) Formation of the reactive complex between SmI2, H2O, and
amine, in which one or more molecules of H2O and amine are
coordinated to the SmII center.[23] Within this complex, one
molecule of amine participates in partial deprotonation of H2O,
resulting in a formal negative charge at oxygen and an overall
increase of the redox potential of the SmII reductant in the
transition state; 2) reversible ester coordination, protonation
and first electron transfer steps; 3) rate-limiting second elec-
tron-transfer step; 4) inner-sphere electron-transfer process
that is inhibited by large concentrations of H2O and facilitated
by Brønsted basic amines; and 5) rate-determining step that
can be fine-tuned by steric and electronic properties of the
ester substrate. The formation of a partial negative charge at
oxygen was further supported by our finding that under opti-
mized reaction conditions, SmI2/NaOH/H2O[25] reduces aliphatic
Finally, to gain independent evidence on the role of elec-
tron-transfer steps, we carried out several studies employing
mechanistic probes (Scheme 1 and the Supporting Informa-
tion). Most importantly, we recognized that implementation of
a suitable radical clock should allow the detection of reversible
reaction pathways.[19] To this end, the trans-cyclopropane-con-
taining radical clock 3 (approximated unimolecular rate con-
stant kfrag ꢀ3ꢀ1011 sÀ1 at 258C)[20] was selected and subjected
to the reaction conditions with a limiting amount of SmI2
(Scheme 1). The reaction resulted in rapid cyclopropyl-ring
opening to give acyclic ester 4 and alcohol 5 in 94:6 ratio. Cy-
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Scheme 2. A) Proposed mechanism. B) Final steps of the reduction of esters
using SmI2/Et3N/H2O.
esters in high yield. From a practical point of view,[26] the pKBH+
-dependent elongation of the hydrogen bond from H2O in
SmI2/amine/H2O complexes can have a profound impact on
the chemoselectivity of electron transfer to carboxylic acid de-
rivatives.
In summary, we have presented a series of kinetic and reac-
tivity experiments that probe the mechanism of the reduction
of unactivated esters by using SmI2/amine/H2O. Our data are
consistent with the formation of distinct SmII reductants by
complexation between SmII, amine, and H2O. The ester reduc-
tion appears to proceed after deprotonation of a molecule of
H2O by amine and to involve a reversible first electron-transfer
step. Most crucially, our results demonstrate that a set of new
SmII reductants that can be fine-tuned by the pKBH+ of the
amine component is now available for challenging electron-
transfer reactions to carboxylic acid derivatives. Equally impor-
tantly, this work shows that the major role of additives (e.g.,
H2O, amine/H2O) is to stabilize the ketyl intermediates. We fully
expect that these findings will serve as a foundation to enable
the development of new electron-transfer reactions. Work in
this direction using SmII systems is ongoing in our laboratories,
and these results will be reported shortly.
[5] M. Szostak, M. Spain, D. J. Procter, Chem. Commun. 2011, 47, 10254.
[6] Recent studies on chemoselective reductions using SmII: a) L. A. Duffy,
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Guazzelli, S. De Grazia, K. D. Collins, H. Matsubara, M. Spain, D. J. Procter,
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Acknowledgements
We acknowledge the EPSRC and GSK for financial support.
Keywords: electron donors · electron transfer · radicals ·
reduction · reductive coupling
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Received: January 24, 2014
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Published online on March 11, 2014
Chem. Eur. J. 2014, 20, 4222 – 4226
www.chemeurj.org
4226
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