Chelating alcohols accelerate the samarium diiodide mediated reduction of 3-heptanone

Article abstract of DOI:10.1016/S0040-4039(01)00958-3

Initial rate studies of samarium diiodide mediated reduction of 3-heptanone to 3-heptanol are reported. The reduction of 3-heptanone with the polydentate tri(ethylene glycol) methyl ether is 16 times faster than without a proton donor, and 4.3 times faster than methanol. The primary kinetic isotope effect (KIE) was measured as k^H/k^D ≈ 2, indicating a rate-determining proton transfer. Diols are superior to mono-alcohols as proton donors, the reduction of 3-heptanone is 255 times as fast with di(ethylene glycol) than in the absence of a proton donor. A mechanism of glycol accelerated samarium diiodide reduction is discussed.

Full text of DOI:10.1016/S0040-4039(01)00958-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5565–5569
Chelating alcohols accelerate the samarium diiodide mediated
reduction of 3-heptanone
Anders Dahle´n and Go¨ran Hilmersson*
Organic Chemistry, Department of Chemistry, Go¨teborg University, SE-412 96 Go¨teborg, Sweden
Received 20 April 2001; accepted 1 June 2001
Abstract—Initial rate studies of samarium diiodide mediated reduction of 3-heptanone to 3-heptanol are reported. The reduction
of 3-heptanone with the polydentate tri(ethylene glycol) methyl ether is 16 times faster than without a proton donor, and 4.3 times
faster than methanol. The primary kinetic isotope effect (KIE) was measured as kH/kD:2, indicating a rate-determining proton
transfer. Diols are superior to mono-alcohols as proton donors, the reduction of 3-heptanone is 255 times as fast with di(ethylene
glycol) than in the absence of a proton donor. A mechanism of glycol accelerated samarium diiodide reduction is discussed.
© 2001 Elsevier Science Ltd. All rights reserved.
Samarium diiodide (SmI2) is rapidly becoming an
important reagent in synthetic organic chemistry for its
versatility in single and two electron transfer reactions.
Samarium diiodide promotes reduction of halides, alde-
hydes, ketones, carboxylic acids, reductive eliminations,
deoxygenations and many other reactions.1 SmI2-cata-
lyzed reactions are known to be group selective, and the
development of SmI2 for asymmetric synthesis is under
exploration.2 However, the lack of detailed mechanistic
knowledge prevents the full use of this promising
reagent.3
to crystallize from a THF solution.4 The cis and trans
isomers of 8-coordinated samarium have been reported
by Sen et al. for the dimethoxyethane (glyme) complex
of SmI2, {SmI2(diglyme)2}.5 Recently we crystallized
the chiral 8-coordinated complexes {D− and L-
SmI2(glyme)3}.6
We now report on the kinetics of SmI2 reduction of
3-heptanone using various alcohols as proton sources.
The first studies of SmI2 reductions of aldehydes and
ketones showed that a proton source should be present
to obtain high yields of alcohol,1,3 but the actual role of
the alcohol has not been investigated in detail. We have
determined the role of the proton source or alcohol in
the reduction of ketones by investigating the kinetics of
simple alcohols, glycols and other chelating alcohols.
Despite the extensive use of SmI2 in THF, little is
known about the structure of SmI2 in other ethereal
solvents and chelating groups. The seven coordinate
solvate {SmI2(THF)5} has been shown by Evans et al.
Figure 1. Initial rates of reduction of 3-heptanone with SmI2 (0.1 M in THF) with various alcohols as proton sources.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00958-3

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A. Dahle´n, G. Hilmersson / Tetrahedron Letters 42 (2001) 5565–5569
We observed that there is a significant increase in rate
upon introducing chelating ether function(s) into the
alcohol. The initial rate is almost 2 times larger with
methoxyethanol (the initial rate is 2.7×10−4 M h−1) than
with methanol. With di- and tri(ethylene glycol) methyl
ether the initial rates are 3.3 and 4.5 times as large as
with methanol, respectively. The initial rate of reduc-
The results from mono-alcohols were also compared
with those of the corresponding diols. We have studied
the reduction of 3-heptanone in THF in the presence of
various proton sources. An excess of SmI2 and the
proton source were used in order to keep the concentra-
tion of reactants approximately constant over the time
for initial rate determinations. The progress of the
reduction was followed by GC.7
tion with tri(ethylene glycol) methyl ether is 6.0×10−4
M
h−1, or 16 times that without a proton source.
We also performed the reduction with half an equiva-
lent of di(ethylene glycol) methyl ether versus SmI2.
However, the initial rate decreased by less than 20%,
and doubling the amount of proton source resulted in
less than a 10% increase in the initial rate. This small
initial rate dependence on concentration indicates satu-
ration kinetics. This could be the result of the forma-
tion of a complex between the SmI2 and the chelating
alcohol.
The most commonly used proton sources (H+) in SmI2-
mediated reactions are methanol and t-butanol. We
found by IR studies that the alcohols (MeOH and
t-BuOH) do not coordinate strongly to samarium, and
therefore the stability of SmI2 in THF is high, resulting
in slow decomposition. The initial rates of the reduction
with and without simple alcohols are shown in Fig. 1.
The initial rate of reduction without a proton source
appears very slow (0.3×10−4 M h−1). Clearly there is an
increase in rate observed when a proton source such as
methanol, t-butanol or water is added to the THF
solution of SmI2 and 3-heptanone. The initial rate with
methanol is 1.4×10−4 M h−1 or about 3.5 times the value
without an added proton source. It is important to
notice that in the absence of a proton source, the
pinacol product is favored, especially in the case of
phenyl substituted ketones.4 The reactions involving
methanol were rather slow and after 3 days at room
temperature, only a 20% yield of heptanol was detected
by GC. Prolonged reaction time, up to 3 weeks, did not
improve the chemical yield. This is likely to be due to a
slow reaction between the samarium diiodide and either
THF or the alcohol.
Furthermore, with the glycol methyl ethers the reac-
tions did not stop at low conversion, as was the case
with for example methanol. Instead, we observed yields
above 90% after a reaction time of one week. Clearly
the possibility of forming chelates between the alcohol
and SmI2 are crucial for the success of this reaction. We
also added methanol to a SmI2–THF solution contain-
ing one equivalent of triglyme. The initial rate of reduc-
tion of 3-heptanone using this mixture is much slower
than that with only methanol. This result clearly shows
that the rate of reduction increases significantly with
alcohols that coordinate to the electron source, i.e.
samarium diiodide.
Kinetic isotope effect
The large increase in rate upon addition of chelating
glycols encouraged us to look for a primary kinetic
isotope effect. The alcohols were deuterated by treat-
ment with NaH followed by immediately quenching the
alkoxide with D2O.
We introduced additional chelating or coordinating
group(s) in the alcohol, i.e. methoxyethanol and the di-
and tri(ethylene glycol) methyl ethers. Alcohols with
two, three or four available oxygens that can form
chelates with samarium are better candidates at com-
peting with THF due to entropy.
The reduction performed with the deuterated alcohols
proceeded at a significantly slower rate. From the initial
Figure 2. Initial rates of the reduction of 3-heptanone (0.014 M) with SmI2 (0.1 M in THF) with [1-H]di(ethylene glycol) methyl
ether and [1-D]di(ethylene glycol) methyl ether.

A. Dahle´n, G. Hilmersson / Tetrahedron Letters 42 (2001) 5565–5569
5567
rates (see Fig. 2) we estimated a kinetic isotope effect
(KIE) kH/kD=2. This clearly indicates that the rate
limiting step in the SmI2 reduction, using di(ethylene
glycol) methyl ether as the proton source, involves a
proton transfer.
Mechanisms of diol accelerated SmI2 mediated reduc-
tion
SmI2 is a single electron transfer reagent and there-
fore the reduction reactions involve two SmI2
molecules and two proton donors. The relatively hard
Lewis base SmI2 is known to be complexed by ethers.
Hence, the addition of chelating ethers or ethereal
alcohols is expected to form complexes with SmI2.
Diols as proton sources
Encouraged by the observed large increase in rate by
introducing ethereal functions into the alcohols, we
were led to investigate the corresponding diols. The
first diol we studied was 1,2-ethanediol, or glycol,
with the oxygens separated by two methylene car-
bons. The initial rate of reduction with SmI2 in the
presence of one equivalent of 1,2-ethanediol was
determined to be 16×10−4 M h−1. Adding an ether
function between the two alcohols gives di(ethylene
glycol) (diglycol) (Fig. 3).
The samarium diiodide is likely to be complexed with
the glycol methyl ether in THF. To fulfil the coordi-
nation number of samarium(II), additional THF
molecules may be coordinated. The carbonyl group is
a strong dipole and competes with the ether function
of the glycol for complexation with the samarium.
Once the carbonyl is complexed to the samarium, an
inner sphere electron transfer occurs.
Today most researchers have accepted the House
mechanism with small variations or modifications.8
Kagan has already suggested that SmI2-mediated
reductions of ketones proceeds via such a mecha-
nism.3 However, this mechanism does not adequately
explain the large differences in the initial rates of
reduction observed with mono-alcohols and the diols
of the glymes. Either the rate determining step
involves several molecules of the alcohols, or more
likely another mechanism is dominating.
With diglycol we observed an initial rate of 97×10−4
M h−1. The initial rate of reduction exceeded by 20
times that of diglycol methyl ether. Thus, the reduc-
tion of 3-heptanone is increased 255 times when
diglycol is added to the THF–SmI2 solution.
Although the actual concentration of the proton
donor is twice that of SmI2, by itself, this does not
explain the large rate enhancement. With triglycol,
the initial rate was 36×10−4 M h−1. Tetraglycol gave a
comparably small rate enhancement, the initial rate
being only 2.6×10−4 M h−1. The number of ether oxy-
gens plays a central role, determining the efficiency of
the proton donor. The tetraglycol is probably too
large to allow the ketone to coordinate to SmI2.
There is a recent report on the low-valent lanthanide
mediated reduction of ketones, based on the isolation
of ketyls or radical anions of ketones. The ketyls
were found to be dimers in the solid state, with two
bridging alkoxide oxygens between two samarium(III)
cations.9 Based on this, we propose the following
mechanism involving a dimeric intermediate with two
alcohol groups bridging between two samarium(II)
diiodides, see Scheme 1. After electron transfer and
proton transfer, the resulting SmI2 alkoxide should be
We also performed the reduction with half an equiva-
lent of diglycol versus samarium diiodide. The initial
rate was determined to be approximately one sixth of
that with one equivalent. Thus, the initial rate of
reduction is strongly dependent on the concentration
of diglycol. This indicates that that there is more
than one molecule of diglycol involved in the rate
limiting step or that different mechanisms are
involved depending on the ratio of glycol versus
SmI2. Furthermore, the initial rate with 0.5 equiv.
diglycol is still 4 times as fast as with 1.0 equiv.
di(ethylene glycol) methyl ether (Table 1).
similar
to
the
known
isolated
structure
{YbI2·(OCH3)(CH3OCH2CH2OCH3)}2.10
Samarium(II) is oxidized to samarium(III) by the
electron transfer to the complexed ketone. Since there
are two samariums a two-electron transfer results in
the formation of the dianion of the ketone. Simulta-
Figure 3. Initial rates of the reduction of 3-heptanone (0.014 M) with SmI2 (0.1 M in THF) using various glycols.

5568
A. Dahle´n, G. Hilmersson / Tetrahedron Letters 42 (2001) 5565–5569
Table 1. Initial rates of SmI2 (0.1 M) mediated reduction of 3-heptanone (0.014 M) to 3-heptanol in THF at 20°C, with
various proton sources
Scheme 1. Proposed mechanism for the samarium diiodide/diglycol mediated reduction of a ketone.

A. Dahle´n, G. Hilmersson / Tetrahedron Letters 42 (2001) 5565–5569
5569
Acknowledgements
neously or subsequently to the electron transfer there
is a rate determining proton transfer from the coordi-
nated acidic alcohols to the developing dianion.
The Carl Trygger Foundation and the Swedish
Research Council (K 5104-1292/2001) supported this
work.
The rate enhancements are strongly dependent on the
number of ethereal oxygens in the polydentate alco-
hols. The results of the kinetic studies indicate that
chiral glycols are promising for asymmetric reduc-
tions. Currently, we are preparing chiral ethers to
explore their potential in SmI2-mediated asymmetric
synthesis.
References
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Experimental part
The SmI2 (0.1 M) was purchased from Aldrich and
kept inside a glove box (Mecaplex GB80 equipped
with a gas purification system that removes oxygen
and moisture). Inside the glove box there was a nitro-
gen atmosphere and the typical moisture content was
less than 2 ppm. All glassware was dried in an oven
at 140°C for no less than 24 h before use. In a stan-
dard procedure, SmI2 (5.0 ml, 0.1 M, Aldrich) was
added to a dry flask, fitted with a septum and con-
taining a magnetic stirrer bar inside the glove box.
The flask was kept under a nitrogen atmosphere dur-
ing the reaction. The proton donor e.g. MeOH (1
equiv.) was added to the reaction vessel containing
the THF solution of SmI2 with stirring. To this mix-
ture was then added the ketone, 3-heptanone (10 ml,
0.14 equiv.), at 20°C. A small portion of the mixture
(100 ml) was removed via a syringe and quenched
with I2 in n-hexane (0.1 M, 0.1 ml) including 1-hex-
anol (0.016 M) as internal standard. To the quenched
solution was added diethyl ether (1 ml) and HCl
(0.12 M, 0.1 ml) to dissolve the inorganic salts. The
organic layer was transferred to a vial and 1.0 ml was
injected on the GC. The components were separated
using a fused silica capillary column DBWX-30W
(¥=0.25 mm, length=30 m), using hydrogen as car-
rier gas at a flow rate of 2 ml/min. The injector
temperature was 225°C, the column temperature was
initially 70°C for 4 min, then heated to 220°C (10°C/
min), and the detector temperature was 250°C. Reten-
tion times: 3-heptanone, 4.0 min, 3-heptanol, 6.6 min
and 1-hexanol 7.6 min.
The reported initial rates for the reductions are the
result of a minimum of three independent measure-
ments, corrected for their individual GC detector
responses.
10. Duncalf, D. J.; Hitchcock, P. B.; Lawless, G. A. Chem.
Commun. 1996, 269.
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