Ketyl-type radicals from cyclic and acyclic esters are stabilized by SmI2(H2O)n: the role of SmI2(H 2O)n in post-electron transfer steps

Article abstract of DOI:10.1021/ja503494b

Mechanistic details pertaining to the SmI₂-H₂O- mediated reduction and reductive coupling of 6-membered lactones, the first class of simple unactivated carboxylic acid derivatives that had long been thought to lie outside the reducing range of SmI₂, have been elucidated. Our results provide new experimental evidence that water enables the productive electron transfer from Sm(II) by stabilization of the radical anion intermediate rather than by solely promoting the first electron transfer as originally proposed. Notably, these studies suggest that all reactions involving the generation of ketyl-type radicals with SmI₂ occur under a unified mechanism based on the thermodynamic control of the second electron transfer step, thus providing a blueprint for the development of a broad range of novel chemoselective transformations via open-shell electron pathways.

Full text of DOI:10.1021/ja503494b

Article
pubs.acs.org/JACS
Ketyl-Type Radicals from Cyclic and Acyclic Esters are Stabilized by
SmI2(H2O)n: The Role of SmI2(H2O)n in Post-Electron Transfer Steps
Michal Szostak,* Malcolm Spain, and David J. Procter*
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL United Kingdom
S
* Supporting Information
ABSTRACT: Mechanistic details pertaining to the SmI2−
H2O-mediated reduction and reductive coupling of 6-
membered lactones, the first class of simple unactivated
carboxylic acid derivatives that had long been thought to lie
outside the reducing range of SmI2, have been elucidated. Our
results provide new experimental evidence that water enables
the productive electron transfer from Sm(II) by stabilization of
the radical anion intermediate rather than by solely promoting
the first electron transfer as originally proposed. Notably, these
studies suggest that all reactions involving the generation of ketyl-type radicals with SmI2 occur under a unified mechanism based
on the thermodynamic control of the second electron transfer step, thus providing a blueprint for the development of a broad
range of novel chemoselective transformations via open-shell electron pathways.
ment,6c and efficient protonation of radical anions7 might play a
INTRODUCTION
■
crucial role in some of these transformations.8 Although
Water is a critical additive used to activate SmI2 toward
extensive empirical synthetic studies have shown that water is
numerous fully chemoselective reductions and reductive
instrumental in enabling a broad range of valuable Sm(II)-
cyclizations involving ketyl-type radicals to furnish primary
mediated reactions,9 the mechanistic details of the role of the
alcohols and complex carbocyclic ring systems with myriad
water additive on the stabilization of the formed ketyl radicals,10
applications in organic synthesis and selectivity unattainable
a fact which determines the facility of electron transfer steps
using other reagents operating via either one- or two-electron
and dictates the reaction pathways,11 are poorly understood.
Moreover, there are contradicting reports regarding the
mechanism of Sm(II)-mediated reactions of carbonyl groups,2
which prevents a generalization of mechanism for the formation
and reactivity of ketyl-type radicals using divalent lanthanides12
and hampers the rational development of novel transformations
mediated by the extremely useful SmI2 reagent.13
pathways (Figure 1).1−3 Historically, water has been used as a
proton donor to enhance the regio-, chemo-, and diaster-
eoselectivity of the reductive transformations mediated by
Sm(II).4 The seminal mechanistic reports by Curran,5
Flowers,6 and Hoz7 suggested that coordination of water to
Sm(II),5 increase of the redox potential,6b ligand displace-
To understand the role of water in Sm(II)-mediated
reductions, we examined in detail the mechanism of the
reduction and cyclization of 6-membered lactones,14 substrates
which had long been thought to lie outside the reducing range
15
of SmI2 and have been shown to react with SmI2 only upon
activation of the reagent with H2O16 (Scheme 1A). As a result
of these studies, we report herein experimental evidence
showing that (1) water enables the productive electron transfer
from Sm(II) by enhancing the stabilization of the intermediate
radical anion rather than solely promoting the first electron
transfer step as we originally proposed;14a,b (2) there is a direct
and nonlinear correlation between the rate of lactone reduction
and the concentration of water, in contrast to what we
originally proposed;14b (3) proton transfer is not involved in
the rate-determining step of the reduction of lactones, and the
same is also true for the reduction of simple ketones and
Figure 1. (a) Proposed mechanism for SmI2-mediated electron
transfer to aldehydes and ketones. (b) This study: mechanism of
chemoselective electron transfer to esters using the SmI2−H2O
reagent.
Received: April 11, 2014
Published: May 8, 2014
© 2014 American Chemical Society
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Scheme 1. Previous Studies on the Reduction and Reductive
Cyclization of Lactones using SmI2−H2O
Scheme 2. Proposed Mechanism of the Reduction of
Lactones Using SmI2−H2O
Sm(II) reduction conditions available for this substrate.14b We
started our investigation by monitoring the reduction of 1 with
increasing concentrations of water (Figure 2). Previously, we
aldehydes, in contrast to what has been previously propose-
d;6a,8e (4) the rate of radical cyclizations mediated by Sm(II)−
H2O is directly related to the concentration of water; (5)
second electron transfer is the rate-determining step in
reductions and reductive cyclizations mediated by SmI2−
H2O. Moreover, we reveal a novel mode of reactivity of cyclic
esters involving a radical C−O bond scission mechanism.
Overall, these results demonstrate that the concentration of
water is instrumental for achieving high chemoselectivity in
reductive processes mediated by the SmI2−H2O system and
strongly imply that reactions involving generation of ketyl
radicals under Sm(II) conditions occur under a unified
mechanism based on thermodynamic control of the second
electron transfer step. Most importantly, this study sets the
stage for application of SmI2−H2O complexes to rationally
design and exploit ketyl-type radicals formed from an array of
carbonyl group precursors.
Figure 2. Plot of concentration of H2O versus kobs for the reduction of
1. [H2O] = 0−10 M (0−800 equiv). M = mol/L. The inset
(independent runs) shows the same up to [H2O] = 2 M. SmI2 = (6
equiv), ester = (1 equiv), T = 23 °C.
have shown that the reduction of 5-decanolide with SmI2−H2O
is zero order in water within the concentration range of 100−
180 equiv of water with respect to [SmI2].14b Previous studies
have determined that water exhibits an unusual high affinity for
SmI2 and displaces THF from the lanthanide(II) coordination
sphere at low concentrations.8g,6b This range of concentrations
was found to activate Sm(II) toward the lactone reduction,
which is in agreement with the thermodynamic increase of the
redox potential of Sm(II) in the ground state by the
coordination of water (SmI2: −1.5 V vs Ag/AgNO3 in THF;
SmI2(H2O)n: −1.9 V vs Ag/AgNO3, n = 500 equiv, THF).6b In
an extended study, we now found a nonlinear rate dependence
on H2O within the concentration range of 0−100 equiv with
respect to [SmI2] in the reduction of 1 (Figure 2). At lower
concentrations (up to 25 equiv, 1.5 M) the rate was found to
increase linearly with a slope, which is consistent with
saturation of Sm(II) (15−25 equiv, 0.9−1.5 M). However, at
higher concentrations (50 equiv, 3.0 M) the rate decreased
dramatically (>10-fold decrease in rate; 4-fold change in
[H2O]), consistent with substrate dissociation from the inner
coordination sphere of Sm(II). From a practical point of view,
it is important to note that SmI2 has been shown to be stable at
high concentration of water for periods in the order of
days,5,6,14 whereas the oxidation of SmI2 to Sm(III) in the
RESULTS AND DISCUSSION
■
Recently, we reported that H2O activates Sm(II) to allow the
first reduction of unactivated 6-membered lactones thus
enabling fully chemoselective electron transfer processes,14
including reductive cyclizations14b and reductive cascades14c
proceeding via unusual ketyl-radical intermediates generated
directly from the lactone carbonyl groups (Scheme 1A−D).
Although we originally proposed a mechanism that involved
activation of the Sm(II) reagent by water to enable the rate
determining initial electron transfer to the lactone carbonyl
group (Scheme 2) aided by anomeric stabilization of the ketyl
radical 1a and featuring zero order dependence on water
concentration,14a,b after continuous probing of the reaction
pathway, several observations suggested that an alternative
mechanism might be operative.
To elucidate the role of water in the SmI2-mediated
reduction of 6-membered lactones, a series of kinetic rate
studies were performed. 5-Decanolide was selected as a model
substrate because its rate of reduction is in a convenient range
for kinetic studies and there is ample literature precedent for
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related but more reducing SmI2, water, amine systems has been
determined to occur in hours at room temperature.4,8e−j Note,
although SmI2−H2O−amine systems are strongly reducing,4a,b
issues of chemoselectivity can arise in electron transfer to
carbonyl groups.8e−j,16b,e,f
To probe the role of each reactant in the reduction of 1, the
rate orders for reaction components were determined at 15−25
equiv (with respect to [SmI2]) concentration of water (Table
1). The rate orders obtained in the previous study (100 equiv
the reduction of an acyclic, unactivated pfp ester (penta-
fluorophenyl 3-phenylpropanoate) under identical SmI2−H2O
reaction conditions (see the SI for detailed reaction profiles),
thus suggesting that the observed effect is general. Overall,
these results indicate that synthetically useful changes in the
rate of electron transfer steps can be achieved by simply
modifying the concentration of water additive.18
To further test the impact of water on the rate of reduction
of ketyl radicals, we exposed the 6-membered lactone 3 bearing
a tethered olefin to the SmI2−H2O conditions under a range of
water concentrations (Table 2, Figure 3).19 The bimolecular
Table 1. Reaction Orders for the Reduction of 1 Using the
SmI2−H2O System
Table 2. Effect of Concentration of Water on the Rate of
a
Reduction of Acyl-Type Radicals Derived from Lactone 3
rate order
a
b
c
entry H2O (equiv)
substrate
SmI2
H2O
kH/kD
1
2
15−25
>100
2.2 0.1
1.1 0.1
1.1 0.1
1.3 0.1
2.1 0.1
0
1.33
1.5
entry H2O (equiv)
4:5
[SmI2] [H2O] rate [107 × M−1 s−1
]
1
2
0
>98:2
>98:2
>98:2
>98:2
97:3
0.053
0.053
0.053
0.053
0.052
0.050
0.048
0.042
0.035
0.026
0.025
0.015
>21.3
>21.3
>21.3
>21.3
14.30
7.21
a
[SmI2] = 70 mM, [H2O] = 15 equiv, [ester] = 0.05−0.15 mmol;
b
25
0.22
0.44
0.88
1.73
3.33
6.40
11.20
18.67
27.75
3.33
2.00
[SmI2] = 10 mM, [H2O] = 150 equiv, [ester] = 45−70 equiv. [SmI2]
= 50−70 mM, [H2O] = 15 equiv, [ester] = 1 equiv; [SmI2] = 5−10
3
50
c
4
100
200
400
800
1600
3200
6400
800
800
mM, [H2O] = 150 equiv, [ester] = 5 mM. [SmI2] = 70 mM, [H2O] =
5
15−25 equiv, [ester] = 1 equiv; [SmI2] = 10 mM, [H2O] = 100−180
equiv, [ester] = 650 mM. Values for entry 1 are listed first.
6
94:6
7
77:23
42:58
30:70
22:78
81:19
86:14
1.60
with respect to [SmI2])14b are depicted in Table 1 for
comparison purposes. Within experimental error, the reduction
of 1 with SmI2−H2O was found to be second order in lactone,
first order in SmI2, and second order in H2O at lower
concentration of water. The rate order of two for the lactone
most likely results from the formation of a dimeric SmI2-lactone
complex with the substrate serving as one of the Sm(II)
ligands.16d The rate order of one for SmI2 and of two for water,
indicates that the mechanism of the reduction changes with
increasing concentration of water (Table 1); that is, at low
concentration, H2O is involved in the rate-determining step of
the reaction; at high concentration water promotes the reaction
only by the formation of a thermodynamically stronger
reductant by activating SmI2 toward the electron transfer (eq
1: reduction of 1 at high concentration of water;14a,b eq 2:
reduction of 1 at low concentration of water).
8
0.39
9
0.28
10
11
12
0.25
3.92
9.41
a
Conditions: SmI2 (6 equiv), THF, H2O, 23 °C. [SmI2] = 0.015−
0.053 M. [H2O] = 0.22−27.75 M. See SI for full experimental details.
rate constant for the reduction of the ketyl-type radical was
obtained by using an approximated unimolecular rate constant
k5‑exo = ca. 2.3 × 105 s−1 for the validated 5-exo alkyl radical
clock.19,20 As expected no reaction occurred in the absence of
water.14a Remarkably, the rate of reduction of the ketyl-type
−d[SmI2 − H2O]/dt = k[SmI2 − H2O]1[5‐decanolide]1
(1)
d[2]/dt = k[SmI2]1[H2O]2[5‐decanolide]2
(2)
Moreover, the kinetic isotope effect was measured for the
reduction of 1 at the same concentration of water (Table 1).
The obtained value kH/kD of 1.33, parallel runs, indicates that
proton transfer is not involved in the rate-determining step of
the reaction.17
Importantly, the nonlinear dependence on water concen-
tration in the reduction of 1 was further confirmed by
monitoring the reduction of 1 with SmI2−H2O under the
standard experimental reaction conditions utilizing preformed
solutions of SmI2 and SmI2 powder, which validates that the
observed dependence is not related to the heterogeneous
nature of SmI2 stock solutions1c,d (see the Supporting
Information (SI) for detailed reaction profiles). Moreover, a
nonlinear dependence on water concentration was observed in
Figure 3. Cyclization of acyl-type radical derived from 3 as a function
of concentration of water. The inset shows the same for a pfp ester
(pentafluorophenyl 2-benzylhex-5-enoate). SmI2 (6 equiv), H2O (0−
6400 equiv), T = 23 °C. See SI for full experimental details.
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radical obtained from 3 to give 4 was found to decrease linearly
with increasing concentration of water, in contrast to the rates
expected from the thermodynamic redox potentials determined
for Sm(II)−H2O complexes in the ground state.6b Control
experiments at different concentrations of SmI2 with a constant
amount of water show that the rate of reduction increases at
lower concentration of SmI2.19b Furthermore, the study of the
role of water on the reduction of a ketyl-radical derived from an
unactivated acyclic pfp ester bearing a tethered olefin poised for
the 5-exo cyclization (pentafluorophenyl 2-benzylhex-5-enoate,
see SI for details) demonstrates that the rate of the reduction
decreases linearly with increasing concentration of water. Based
on these results, complete chemoselectivity for the 5-exo
cyclization or reduction can be achieved by simply modifying
the concentration of water additive (see SI for additional
discussion).
the Sm(II) coordination sphere.6c Notably, high concentration
of water favors reductive cyclizations due to the competing
coordination of water to the Sm(II), despite a much higher
thermodynamic redox potential of the SmI2−H2O reagent in a
process that is formally analogous to an outer-sphere electron
transfer.23,9n,o
With a working mechanism in place, we sought to further
elucidate the impact of water on the electron transfer steps. In
particular, we recognized that providing an alternative reaction
pathway to the straight reduction/cyclization should allow
validation of the findings obtained from the 5-exo radical
clocks. Specifically, we hypothesized that lactones bearing a
radical-stabilizing group at the 5-position could undergo C−O
bond scission24 depending on the reaction conditions, thus
providing further insight into the role of water in the
stabilization of ketyl-type radical intermediates.
We likewise investigated the effect of water on the rate of
reduction of lactones 6 bearing a tethered olefin at the 5-
position (Table 3). Positioning an alkene tether alpha to the
To this end, phenyl bearing lactones 9 were prepared and
subjected to the SmI2−H2O reaction conditions at a range of
water concentrations (Table 4). In the original studies14a,b we
Table 3. Effect of Concentration of Water on the Rate of
Reduction of Acyl-Type Radicals Derived from Lactones 6
Table 4. Effect of Concentration of Water on the Stability of
Acyl-Type Radicals Derived from Lactones 9
a
a
rate [105 × M−1 s−1
]
entry
n
H2O (equiv) time (h)
10:11
conv. (%) [H2O]
entry
R
H2O (equiv)
7:8
[H2O]
1
2
3
4
5
6
0
0
1
1
2
2
200
800
200
800
200
800
5
5
5
5
5
5
41:59
77:23
34:66
72:28
96:4
35
1.93
6.99
1.93
6.99
1.93
6.99
1
2
H
H
200
800
2200
200
800
66:34
91:9
95:5
93:7
99:1
2.02
7.36
20.07
2.54
8.95
19.42
4.14
2.30
2.27
0.35
b
9
b
96
92
3
H
4
5
Ph
Ph
>98
>98
a
99:1
Conditions: SmI2 (6 equiv), THF, H2O, 23 °C; [SmI2] = 0.063−
0.080 M. Ref 14c. All entries, >85% yield based on recovered
substrate. See SI for full experimental details.
a
b
Conditions: SmI2 (8 equiv), THF, H2O, 23 °C, 5 h; [SmI2] = 0.070−
b
0.077 M. 92% yield, 10:11 = 79:21, using a SmI2−MeOH−amine
system. All entries, >95% yield based on recovered substrate. See SI for
full experimental details.
oxygen atom on the lactone scaffold allows access to seven-
membered polyoxygenated carbocycles by cyclizations of the
radical anion intermediates derived from the SmI2−H2O
reduction.14c The results in Table 3 clearly indicate that a
significant effect of water concentration on the rate of reduction
of the radical derived from 6 is observed. Importantly, the same
order of the water effect as in the case of 2-tethered lactones is
observed (i.e., faster reduction rate at lower concentration).
Remarkably, the rate of reduction of the acyl-type radical is
directly related to the electronic properties of the olefin π-
acceptor,21 thus providing strong indication that the first
electron transfer to the lactone carbonyls is reversible in these
systems and that the reductive coupling occurs via a late
transition state.22 As expected from the relative rates of radical
cyclizations,19a the reduction of lactones 6 is slower than the
corresponding 2-tethered analogues under the same concen-
tration of water.
Taken together, the results outlined in Tables 1−3 strongly
suggest that the reduction of acyl-type radicals by SmI2−H2O is
favored by a concentration of water at which Sm(II) is activated
toward the reduction;6a,b however, the coordination sphere of
Sm(II) cannot be saturated with the water additive.6c The
concentration of H2O at which the maximum rate of the
reduction is observed correlates with iodide displacement from
found that similarly alkyl substituted 5- and 7-membered
lactones could not be reduced to diols by SmI2−H2O, which we
ascribed to the slower rate of the initial electron transfer to the
lactone carbonyl groups. Remarkably, we now determined that
5-, 6-, and 7-membered lactones 9 decorated with a radical
stabilizing group undergo efficient electron transfer from SmI2−
H2O to give, depending on ring-size and concentration of
water, the C−O fragmentation products in good to high
selectivity and yields. At lower concentration of water (Table 4,
entries 1, 3, and 5) the radicals were found to undergo fast
reduction, leading to a decreased C−O scission selectivity,
which mirrors the effect of the concentration of water outlined
above in the 5-exo cyclization reactions. In contrast, at high
concentration of water (Table 4, entries 2, 4, and 6), C−O
fragmentation is the predominant reaction pathway. Crucially,
by providing an alternative reaction pathway to the reduction of
simple alkyl analogues (i.e., fragmentation), it is clear that other
ring sizes of lactones than 6-membered serve as viable
precursors to unusual acyl-type radicals. We note that this
finding significantly expands the utility of SmI2−H2O to effect
electron transfer to traditionally unreactive substrates. More-
over, the results presented in Table 4 provide yet another
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indication of the fast reversible electron transfer to the lactone
carbonyl groups in these systems.
Several control experiments were conducted to gain
information on the stability of ketyl radical intermediates in
the C−O fragmentation substrates (Scheme 3 and see SI for
pentafluorophenyl 2-phenylcyclopropanecarboxylate resulted in
selective cyclopropyl opening (see SI). Taken together, these
results strongly suggest that the reduction of esters using
SmI2−H2O occurs via a fast reversible first electron transfer.
Moreover, the C−C bond fragmentation shows that the
stability of the resulting radicals is sufficient to allow follow-
up transformations in cyclic and acyclic esters other than six-
membered lactones, which considerably broadens the utility of
SmI2−H2O complexes for the generation of acyl-type radicals
from bench-stable carboxylic acid derivatives.
Scheme 3. Mechanistic Probes for the Fragmentation of
Acyl-Type Radicals Using SmI2−H2O
Finally, we recognized that the mechanism of the reduction
of lactones using SmI2 reductants as elucidated in the current
study is likely to be operative in other Sm(II)-mediated
electron transfer reactions involving carbonyl groups. Although
previously it has been correctly noted that the rate of the
reaction of ketones bearing tethered olefins under Sm(II)
conditions is fast relative to unsubstituted ketones,19c several
recent reports suggested that the rate-determining step in the
Sm(II)-mediated reduction of ketones might involve proto-
nation.6a,8e,17 In light of the evidence garnered in the current
study, we considered that a dramatic change of the reaction
pathway between esters and other carbonyl derivatives is
unlikely. To test the validity of this hypothesis, we measured
KIE for the reduction of several aldehydes, ketones, and other
carboxylic acid derivatives using Sm(II) (Table 5; see SI for
additional studies).
more details). In particular, we found that the conformationally
constrained lactone 12 bearing a fused aromatic ring and an
acyclic benzyl ester 15 do not undergo productive C−O bond
scission. These results are explained by the lack of electronic
overlap required for the fragmentation25 and lower stability of
the acyl-type radical intermediate in acyclic systems in which
radical stabilization from an anomeric effect26 cannot be
achieved, respectively. These control reactions further reveal
the unique chemoselectivity profile of SmI2−H2O reductants.
The viability of the mechanism involving fast reversible
electron transfer to lactone carbonyls was further probed using
validated cyclopropane radical clock substrates (Scheme 4).
Table 5. Kinetic Isotope Effects in the Reduction of
a
Carbonyl Derivatives Using SmI2−H2O
entry
substrate
SmI2 (equiv) H2O (equiv)
kH/kD
1
2
3
4
5
6
PhCH2CH2CHO
PhCH2CH2C(O)Me
PhCO2Me
3
3
6
6
3
3
100
100
200
200
100
100
1.4 0.1
1.5 0.1
1.4 0.1
1.4 0.1
1.8 0.1
2.0 0.1
Scheme 4. Radical Clock Experiments in the Reduction of
Cyclic Esters using SmI2−H2O
PhCO2H
PhC(O)Me
PhCHO
a
Conditions: SmI2 (3−6 equiv), THF, H2O, 23 °C. See SI for full
experimental details.
In most cases studied, a KIE between 1.4 and 1.5 was found,
which is consistent with proton transfer to carbon not being
involved in the rate-determining step of these reactions. The
impact of deuterium is likely to result from a solvent secondary
kinetic isotope effect due to the differential coordination of
D2O and H2O to Sm(II).27 Interestingly, in the case of
aromatic carbonyl derivatives, a higher KIE of 1.8−2.0 was
obtained.28 Although we cannot rule out that for this specific
group of substrates the KIE values indicate a rate determining
proton transfer to carbon, we suggest that these are secondary
KIEs resulting from a combination of a differential coordination
of D2O/H2O to Sm(II) (vide supra), the increased Lewis
acidity of Sm(III) and increased stability of aryl ketyl radicals.29
In reported examples of the hydrolysis of phenyl esters using
deuterium oxide a KIE of up to 1.8 was found as a result of the
secondary deuterium isotope effects.27 Moreover, it has been
well-established in numerous literature examples that aryl
ketones and aldehydes are subject to divergent reaction
pathways from their aliphatic counterparts upon exposure to
Sm(II) and other single electron transfer reductants (i.e., aryl
ketyls undergo predominantly pinacol or aryl cross-coupling
reactions).1−3 Overall, the examples documented above
highlight that to date the only type of Sm(II)-mediated
The reaction of 5- and 6-membered lactones 18 (approximated
unimolecular rate constant kfrag = ca. 3 × 1011 s−1 at 25 °C)19a,20
with a limiting amount of SmI2−H2O resulted in a rapid
cyclopropyl ring-opening to give the 2-phenethyl lactones 19.
The corresponding cyclopropyl diol and phenethyl diol were
not detected in these reactions. Furthermore, the reaction of 5-
and 6-membered lactones 18 using a more thermodynamically
powerful Sm(II) system containing amine as a Lewis basic
additive4,8e−j resulted in the selective formation of the
phenethyl diols 20 after less than 1 h reaction time. Hilmersson
determined that the system using Et3N as a Lewis basic additive
shows a half-life of approximately 24 h (vide supra).8i Control
reactions with the corresponding cyclopropyl diols under
Sm(II) conditions resulted in full recovery of the cyclopropyl
starting material (not shown, see SI). Moreover, the reaction of
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reactions that has been conclusively shown to proceed via a rate
determining protonation is the reduction of α,β-unsaturated
carbonyl acceptors (kH/kD of 6.0−7.6).7c Furthermore, care
needs to be taken when interpreting KIE results when using
Sm(II)−D2O reagent systems.17
From a practical perspective the finding that Sm(II)
mediated transformations of carbonyl compounds proceed
under one generalized mechanism can have a profound impact
on designing novel synthetically valuable reductive trans-
formations using Sm(II). In particular, these studies should
facilitate the development of reductive cascades using substrates
bearing multiple reactive sites,30 in which the selectivity is
tuned by simply adjusting the properties of a functional group/
intermediates to make them more thermodynamically acces-
sible for the reduction. We note that several examples of such
cascades have been published; however, a rationale for the
selectivity has been elusive.31
than by solely promoting the first electron transfer, and have
demonstrated that the reduction of simple carbonyl compounds
with Sm(II) is unlikely to involve a rate determining
protonation.
The two key conclusions obtained from this study are that
(1) the transformations involving generation of ketyl-type
radicals using SmI2−H2O are governed by thermodynamic
control of the second electron transfer step and (2) low
concentration of water facilitates the reduction of ketyl radicals,
which is in contrast to the thermodynamic potential of the
SmI2−H2O reductant in the ground state and results from an
outer-sphere electron transfer step at high concentration of
water. Notably, the results of our investigation suggest that a
wide range of novel precursors should become available for
Sm(II)-mediated reductive processes, including reductions,
cross-couplings, and cascade transformations. Moreover, we
have demonstrated that the generation of ketyl-type radicals
from lactones and acyclic esters with SmI2 occurs under a
unified mechanism, which should enable the rational design of
Sm(II)-mediated reactions of ketyl radicals. We hope that our
studies on the role of water as an additive for Sm(II) will
contribute to the discovery of new reactions involving the
generation of ketyl- and acyl-type radicals by this reagent.
Scheme 5 depicts a revised mechanism for lactone reduction.
As discussed above, we propose a pathway involving reversible
Scheme 5. Revised Mechanistic Pathways for the Reactivity
of Acyl-Type Radicals Generated from Lactones Using
SmI2−H2O
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization data and
details of kinetic studies. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
michal.szostak@manchester.ac.uk; david.j.procter@manchester.
ac.uk
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the EPSRC, GSK and The Leverhulme Trust
for financial support.
■
fast electron transfer and water-assisted stabilization of the
formed ketyl radicals as key features. The feasibility of this
mechanism is supported by the experiments outlined above.
Furthermore, based on the results reported herein we postulate
that a mechanism involving the rate determining second
electron transfer is operative in other Sm(II)-mediated
reactions of ketyl radicals. This mechanism is consistent with
numerous examples of single electron transfer reactions of
carbonyl groups,32 including reactions mediated by SmI2.33
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