Hydroxylated HMPA enhances both reduction potential and proton donation in SmI2 reactions

Article abstract of DOI:10.1021/jo500161s

HMPA is known to increase the reduction potential of SmI₂. However, in many cases, the transferred electron returns from the radical anion of the substrate back to the Sm³⁺. This could be avoided by an efficient trapping of the radical anion: e.g., by protonation. However, bimolecular protonation by a proton donor from the bulk may be too slow to compete with the back electron transfer process. An efficient unimolecular protonation could be achieved by using a proton donor which complexes to SmI₂, in which case the proton is unimolecularly transferred within the ion pair. A derivative of HMPA in which one of the methyl groups was substituted by a CH₂CH₂OH unit was synthesized. Cyclic voltammetry studies have shown that it resembles HMPA in its ability to enhance the reduction potential of SmI₂, and reactivity studies show that it has also efficient proton shift capabilities. The various aspects of this additive were examined in the reactions of SmI₂ with three substrates: benzyl chloride, methyl cinnamate, and anthracene.

Full text of DOI:10.1021/jo500161s

Article
pubs.acs.org/joc
Hydroxylated HMPA Enhances both Reduction Potential and Proton
Donation in SmI2 Reactions
Sandipan Halder and Shmaryahu Hoz*
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
S
* Supporting Information
ABSTRACT: HMPA is known to increase the reduction potential
of SmI2. However, in many cases, the transferred electron returns
from the radical anion of the substrate back to the Sm3+. This could
be avoided by an efficient trapping of the radical anion: e.g., by
protonation. However, bimolecular protonation by a proton donor
from the bulk may be too slow to compete with the back electron
transfer process. An efficient unimolecular protonation could be
achieved by using a proton donor which complexes to SmI2, in
which case the proton is unimolecularly transferred within the ion
pair. A derivative of HMPA in which one of the methyl groups was substituted by a CH2CH2OH unit was synthesized. Cyclic
voltammetry studies have shown that it resembles HMPA in its ability to enhance the reduction potential of SmI2, and reactivity
studies show that it has also efficient proton shift capabilities. The various aspects of this additive were examined in the reactions
of SmI2 with three substrates: benzyl chloride, methyl cinnamate, and anthracene.
2). We have suggested that the reason for this dissimilarity is
that MeOH, in sharp contradistinction to t-BuOH, complexes
INTRODUCTION
■
Samarium iodide is one of the most useful reducing reagents
employed in synthetic chemistry.1,2 An important advantage of
this reagent is that its reactivity and product distribution can be
tuned and modulated by various additives.3 A classical example
is the use of MeOH in photocatalyzed reactions.4 When SmI2 is
excited in the visible region, it becomes a much better reducing
agent than it is in the ground state.5 However, once the
electron transfer takes place, the back electron transfer is highly
exothermic because it produces Sm2+ in its ground state.
Therefore, unless there is an efficient process competing with
the back electron transfer, no net reaction will take place. Such
a competing reaction is the mesolytic cleavage of alkyl halides
(eq 1).
to SmI2 and is, therefore, present in the vicinity of the radical
anion as it is formed. Hence, in the first case, cyclization occurs
at the radical level, whereas in the second case it is driven by the
negative charge (because of the sluggishness of the bimolecular
protonation), giving rise to a different cyclization product.
A second important additive is HMPA. The reduction
potential of SmI2 can be significantly boosted by complexing it
with HMPA.8 When four molecules of HMPA are complexed
to SmI2, its reduction potential is increased from −1.3 to −2.1
V, increasing significantly the range of substrates which can be
reduced by this reagent.9 Several derivatives of HMPA have
been described in the literature. These include a dimer of
HMPA (diHMPA)10 and TPPA11 as well as the anionic
derivative DPMPA.12
R−X + e− → R• + X−
(1)
We have shown that protonation of the radical anion could
also compete with the back electron transfer, provided it is
done unimolecularly.4 Protonation of the highly unstable
radical anion by a proton donor from the bulk is a bimolecular
reaction. However, the lifetime of the radical anion is too short
to enable such a protonation and, therefore, protonation cannot
prevent the fast back electron transfer. However, if a proton
donor such as MeOH is complexed to the SmI2,6 the
protonation takes place unimolecularly within the ion pair
efficiently, trapping the radical anion before it transfers its
electron back to the Sm3+. Using this strategy, we have
broadened the range of photocatalyzed reduction to include
substrates which previously were not amenable to photo-
catalytic reduction.4 Another example is the work of Procter et
al.,7 in which MeOH and t-BuOH lead to different products (eq
Received: January 23, 2014
Published: February 21, 2014
© 2014 American Chemical Society
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The last compound was recently successfully employed by
Reissig13 and was found to be better for γ-aryl ketone
cyclizations.
complexation constant may be due to an internal hydrogen
bond within HOMPA.
Thus, the additives HMPA and its derivatives and MeOH (or
other ligands that complex to SmI2 such as water and glycols)
are both found to be very useful in SmI2 reductions.
Unfortunately, however, these additives compete with each
other for the binding sites of SmI2 and, as a result, they
mutually reduce each other’s efficiency. In this paper we report
the effect obtained by the combination of these two functions
into a single molecule. This molecule is a derivative of HMPA
(HOMPA) in which, one of the NMe2 units is replaced by N-
methylethanolamine.
An additional experiment was performed in order to assess
the origin of the increased reduction potential of the
HOMPA−SmI2 complex. We have found that this increase is
most probably due to the fact that HOMPA complexes more
strongly to the product Sm3+ than to Sm2+ in a way similar to
that for HMPA.18 Figure 1 shows the spectra of (a) SmI2, (b)
SmI2 to which 2.5 mM of HOMPA was added, (c) SmI2 to
which 5 mM of HOMPA was added, and (d) the solution
where to the composition presented in (c) 2.5 mM of SmI3 was
added. When HOMPA complexes to SmI2, its spectrum is
changed in a manner similar to that of the HMPA complex.
Figure 1d shows clearly that, upon the addition of Sm3+, the
SmI2 retains its original spectrum, indicating a stronger ligation
of HOMPA to Sm3+ than to Sm2+. This enhanced affinity for
Sm3+ is probably the primary cause for the increased reduction
potential.
RESULTS AND DISCUSSION
■
HOMPA was synthesized (eq 3) following a synthesis similar
to that in the literature.14
Next, the kinetics of the reaction of SmI2 with benzyl
chloride in the presence of HOMPA were measured with
HMPA as a reference point. As mentioned above, this reaction
was chosen because its rate is independent of proton donor
concentration and, therefore, reflects only the ability of
complexed SmI2 to donate an electron. In addition, it should
be pointed out that Flowers has found that in the reduction of
alkyl halides by SmI2 a unique mechanism is operative.19 That
is, HMPA forms a complex with primary alkyl halides activating
the C−X bond, thereby enhancing reaction rate. However, the
early leveling off of the rate with respect to HMPA
concentration described by Daasbjerg et al. for the reactions
of benzyl chloride suggests that there is no such effect with
benzyl chloride.17
In the reaction with benzyl chloride, its concentration was 25
mM, that of SmI2 was 2.5 mM, and that of the additives ranged
from 5 to 20 mM. At the low concentrations (5 and 10 mM) of
HOMPA and HMPA, the reactions obeyed pseudo-first-order
kinetics only for the first part of the reaction because the affinity
of the two phosphoramides toward the Sm3+ generated in the
first part is, as we have shown above, much higher than that to
Sm2+. Therefore, the ability of the SmI2 to reduce the substrate
was reduced as the reaction progressed, due to the diminishing
concentrations of the chelating phosphoramides. First-order
analysis was successfully conducted only on the first 40−70% of
reaction for the two concentrations, respectively. Pseudo-first-
order rate constants are given in Table 2. Kinetic traces are
shown in the Figure S1 (Supporting Information).
We have quantified its effect on the reduction potential of
SmI2 in two ways: (a) measuring its reduction potential by
cyclic voltammetry and (b) measuring its effect on the reactivity
of SmI2 toward benzyl chloride. The latter was chosen because
the cleavage of the C−Cl bond does not necessitate
protonation; therefore, only the “HMPA like” properties are
examined.15
Cyclic voltammetry was performed under the following
conditions: working electrode, glassy carbon; reference
electrode, Ag/AgNO3 in THF; counter electrode, Pt wire;
electrolyte, 0.1 M tetrabutylammonium hexafluorophosphate; 2
mL electrochemical cell at a scan rate of 100 mV/s. The results
are given in Table 1.
Table 1. Oxidation Potential of SmI2 in THF in the Presence
a
of Various Concentrations of HOMPA and HMPA
b
[additive] (mM)
HOMPA (V)
HMPA (V)
HMPA (V)
5
10
15
20
−1.15
−1.18
−1.42
−1.99
−1.3
−1.46
−2.05
−2.05
−2.05
−1.99
−2.08
[SmI2] = 2.5 mM. Data from Flowers et al.9
a
b
We have also measured the reduction potential of HMPA
itself in order to calibrate our results against the original data of
Flowers. Table 1 shows that our measured potentials are in
reasonable agreement with those reported by Flowers. The data
show that HOMPA lags behind HMPA in enhancing the
reduction potential of SmI2 at low concentrations. However, at
higher concentrations (20 mM; 8 equiv)16 it exhibits a
reduction potential close to that of HMPA. This suggests
that HOMPA’s complexation constant to SmI2 is smaller than
that of HMPA. However, once it occupies all the sites17 it
induces an effect similar to that of HMPA. The smaller
Interestingly, in spite of the lack of linearity in the reduction
potentials of SmI2 between the two additives, the rate constants
are linearly related (Figure 2).
The next substrate in our investigation was methyl
cinnamate. It reacts very quickly, and the reduction is
completed in less than 1 min. Methyl cinnamate was chosen
in order to demonstrate the different effect the two additives
have on the product distribution. In the preparative reactions
we have used the following concentrations: methyl cinnamate,
0.04 M; SmI2, 0.084 M, phosphoramide additives, 0.34 M each.
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Table 2. Pseudo-First-Order Rate Constants for the
Reactions of SmI2 (2.5 mM) with Benzyl Chloride (25 mM)
in the Presence of Various Concentrations of
a
Phosphoramide Additives
[phosphoramide] (mM)
kHOMPA (s−1
)
kHMPA (s−1
)
5
10
15
20
0.04
0.13
0.19
0.26
0.26
0.70
1.02
1.32
a
The pseudo-first-order rate constant in the absence of phosphor-
amide is 0.0017 s−1.
Figure 2. Plot of the pseudo-first-order rate constants for the
reduction of benzyl chloride in the presence of HMPA as a function of
the rate constants in the presence of HOMPA.
Scheme 1 shows the product distribution under each set of
conditions used. As can be seen, the reactions of HOMPA and
Scheme 1
HMPA are entirely different. The cyclization reaction observed
in the presence of HMPA is documented in the literature,20 and
its absence in the reaction with HOMPA is most probably due
to the efficient protonation of the carbanion α to the ester
group by the OH of HOMPA, thus preventing the cyclization
step (eq 4).
Figure 1. Visible spectra of (a) 5 mM SmI2, (b) 2.5 mM SmI2 + 2.5
mM HOMPA, (c) 2.5 mM SmI2 + 5 mM HOMPA, and (d) 2.5 mM
SmI2 + 5 mM HOMPA + 2.5 mM SmI3.
When MeOH was added to the reactions in the presence of
HMPA, its concentration was 0.5 M. When only MeOH was
used as a reference additive, its concentration was 2 M.
The equivalence of HOMPA to the combination of HMPA
and MeOH is evident from the similarity in their product
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distributions, showing that HOMPA can fulfill both functions
simultaneously. In the presence of only MeOH the reduced
monomer was the sole product.
It should be pointed out that HOMPA has a technical
advantage over HMPA. Usually, because HMPA is highly
soluble in many solvents, it is very difficult to get rid of in the
course of the reaction workup. However, using water with
sodium bicarbonate and ether in the workup leaves the organic
ethereal solution free of HOMPA, which is quantitatively
transferred to the aqueous phase. We found out that it is
possible to recover it (60%) from the reaction mixture and
reuse it without seriously affecting its efficacy. On the other
hand, HOMPA has the disadvantage that, like other proton
donors, it enhances the decay of SmI2.21
In conclusion, HOMPA increases the reduction potential of
SmI2 and at the same time serves also as a proton donor. It
competes effectively with the combination of HMPA and
MeOH. To the best of our knowledge, there is no information
regarding its carcinogenic22 nature relative to that of HMPA.
Because of its complexity, the reaction was not amenable to
simple kinetic analysis. However, determination of the reaction
half-life using stopped flow spectroscopy showed that under the
conditions [methyl cinnamate] = 25 mM, [SmI2] = 2.5 mM
and [phosphoramide additives] = 10 mM each, the half-life for
the HMPA in the presence of 0.5 M MeOH was 0.005 s, that
for HMPA itself was 0.014 s, that for 0.5 M MeOH was 7.8 s,
and for HOMPA the reaction was over in the dead time of the
instrument (Figure S2, Supporting Information). Thus,
although these reactions are relatively fast, that of HOMPA is
faster than that of the combination of HMPA and MeOH.
The last substrate to be examined was anthracene. Unlike the
case for methyl cinnamate, this substrate gives a single product,
9,10-dihydroanthracene (eq 5).
EXPERIMENTAL SECTION
■
General Procedures. All reagents were purified prior to use
following literature procedures.23 All of the reactions were carried out
in oven-dried glassware under a nitrogen or argon atmosphere using
anhydrous solvents. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded at 400 and 700 MHz. Carbon nuclear magnetic
resonance (13C NMR) and phosphorus nuclear magnetic resonance
(31P) spectra were recorded at 100 MHz and at 175 and 162 MHz,
respectively. Mass spectra (MS) were obtained using EI/CI mass
spectrometers. SmI2 solutions (0.1 M in THF) were prepared
according to a reported procedure24,25 and diluted as needed. The
concentration of the SmI2 solutions was determined by spectroscopic
techniques (λ 619 nm; ε = 635). The reactions of SmI2 with the
various substrates were performed in volumetric flasks (10/20 mL)
under a nitrogen atmosphere in the glovebox.
This substrate was used because, unlike the case for methyl
cinnamate, trapping the radical anion and preventing the back
electron transfer can be achieved only by protonation, whereas
in the case of methyl cinnamate, dimerization may also prevent
the back electron transfer. We therefore expect this case to be a
good demonstration of the importance of the capabilities of
HOMPA as a proton donor in a comparison with HMPA itself.
Scheme 2 shows the product distribution as a function of the
added additive(s).
The cyclic voltammetry experiments were performed using a
standard glassy-carbon electrode as a working electrode with Pt wire as
an auxiliary electrode and silver/silver nitrate electrode as a reference
electrode at a 100 mV/s scan rate. A 0.1 M solution of
tetrabutylammonium hexafluorophosphate (NBu4PF6) in THF was
used as electrolyte. The concentration of SmI2 was 2.5 mM for all
experiments.
Scheme 2
The kinetics experiments were performed using a stopped-flow
spectrophotometer inside the glovebox under a nitrogen atmosphere
at room temperature. The reactions were monitored at the λmax value
of SmI2 (619 nm). The additive and substrate were contained in one
syringe, and the SmI2 solution was contained in the other. Each set of
experiments was repeated two to three times. Within a set, each
measurement was routinely repeated three times. At the end of each
series, the first measurement was repeated to ensure reproducibility
within a set. The deviation usually observed was less than 5%. First-
order kinetics were analyzed using Kinet Asyst (v. 2.2, Hi-Tech Ltd.).
Synthesis of HOMPA. To a solution of N-methylethanolamine
(2.82 mL, 35.17 mmol) and triethylamine (6.6 mL, 46.9 mmol) in 20
mL of dry dichloromethane was slowly added N,N,N′,N′-tetramethyl-
phosphorodiamidic chloride (3.47 mL, 23.45 mmol) at room
temperature and the mixture was stirred for 12−14 h. After
completion of the reaction as monitored by TLC (silica gel 60 F254
precoated plates), the reaction mixture was filtered to remove the
triethylamine hydrochloride salt. The organic layer was washed with
water and brine solution and dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the crude reaction
mixture was purified by column chromatography on silica gel (60−120
mesh) using 4% methanol in chloroform to afford 2.95 g of pure
HOMPA (60% yield) as a colorless liquid: 1H NMR (400 MHz,
CDCl3) δ 2.58−2.60 (m, 15H), 3.04−3.05 (m, 2H), 2.02 (br s, 2H),
4.62 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 33.89, 33.93, 36.21,
36.25, 52.2, 51.3, 59.0; 31P NMR (162 MHz, CDCl3) δ 28.4; HRMS
(Q-TOF ESI positive mode) calcd 210.1371 for C7H21N3O2P, found
210.1369. For spectral data, see the Supporting Information.
Concentrations were the same as those used to generate the
data of Scheme 1. Yields reported are NMR yields. All of the
reactions were quenched with I2 solution after 1 min. As can be
seen, HOMPA yielded after 1 min ca. 70% of 9.10-
dihydroanthracene, while HMPA yielded only 7% (probably
due to a trace of water in the solution or to proton transfer
from THF). The combination of HMPA and MeOH gave
results similar to those of HOMPA, while MeOH did not
enable any reaction. Thus, a comparison of the HOMPA
reaction with that of MeOH shows HOMPA’s ability to
increase the reduction potential of SmI2, and a comparison with
the HMPA reaction demonstrates that it utilizes its ability to
function as a proton donor.
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Reaction of Methyl Cinnamate and SmI2 in the Presence of
HOMPA. A solution of methyl cinnamate (32.4 mg, 0.04 M) in THF
and HOMPA (355.7 mg, 0.34 M) was mixed in a volumetric flask
inside the glovebox. Then 0.1 M SmI2 in THF solution (4.2 mL, 0.084
M) was added to the reaction mixture. The total volume of the
reaction mixture was 5 mL. There was immediate decolorization of the
SmI2 solution. Then the reaction mixture was diluted to 20 mL with
diethyl ether and quenched with 5% aqueous NaHCO3. The organic
and aqueous layers were separated, and the aqueous layer was
extracted with diethyl ether (3 × 5.0 mL). The combined organic layer
was washed with 5% aqueous phosphate buffer solution (2 × 5.0 mL)
and brine solution (10 mL) and dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the crude reaction
AUTHOR INFORMATION
Corresponding Author
*E-mail for S.H.: shoz@mail.biu.ac.il.
Notes
■
The authors declare no competing financial interest.
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1
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Reaction of Methyl Cinnamate and SmI2 in the Presence of
HMPA. A solution of methyl cinnamate (129.7 mg, 0.04 M) in THF
and HMPA (1.2 mL, 0.34 M) were mixed. Then 0.1 M SmI2 in THF
solution (16.8 mL, 0.084 M) was added to the reaction mixture. The
total volume of the reaction mixture was 20 mL. The reaction was
stopped after a given time, and the excess SmI2 was quenched with
iodine solution. The reaction mixture was then diluted to 40 mL with
diethyl ether and quenched with 5% aqueous NaHCO3 and 5%
aqueous Na2S2O3 solution. The organic and aqueous layers were
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and dried over anhydrous Na2SO4. After removal of the solvent under
reduced pressure, the crude reaction mixture was purified by column
chromatography on silica gel (60−120 mesh) using 10% ethyl acetate
in petroleum to afford pure product (73.0 mg) in 62% yield as a white
solid: mp 122−124 °C (lit.26 mp 126 °C), analyzed by 1H (700 MHz)
and 13C (175 MHz) NMR and mass spectra.
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HMPA and MeOH. This reaction was performed with methyl
cinnamate (129.7 mg, 0.04 M) in the presence of 0.1 M SmI2 in THF
solution (4.2 mL, 0.084 M), HMPA (0.3 mL, 0.34 M), and MeOH
(0.1 mL, 0.5 M) as additive. The workup procedure was same as that
(15) A similar approach was used by Flowers et al.: Teprovich, J. A.,
Jr.; Balili, M. N.; Pintauer, T.; Flowers, R. A., II Angew. Chem. 2007, 46,
8160−8163.
(16) It is important to note that the number of equivalents by itself is
not a sufficient parameter and must be accompanied by the
concentration of one of the components. The same number of
equivalents may cause a near-saturation in complex formation at high
concentrations but very little complexation for a very dilute reaction.
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1
mentioned above. The crude reaction mixture was analyzed by H
(400 MHz) and 13C (100 MHz) NMR; it contained a mixture of
dimer and monomer product in a ratio of 80:20.
Reaction of Methyl Cinnamate and SmI2 in the Presence of
MeOH. This reaction was performed with methyl cinnamate (129.7
mg, 0.04 M) in the presence of 0.1 M SmI2 in THF solution (4.2 mL,
0.084 M) and MeOH (0.4 mL, 2.0 M) as additive. The workup
procedure was same as that mentioned above. The crude reaction
mixture was analyzed by 1H (400 MHz) and 13C (100 MHz) NMR. It
contained only the monomer.
(20) Shinohara, I.; Okue, M.; Yamada, Y.; Nagaoka, H. Tetrahedron
Lett. 2003, 44, 4649−4652.
Reaction of Anthracene and SmI2. The procedure was similar to
that of the reactions of methyl cinnamate. The crude reaction mixture
1
was analyzed by H (400 MHz) and 13C (100 MHz) NMR, and the
(21) It is well-known that SmI2 has a natural decay. Therefore, in the
commercial product the SmI2 is stabilized with Sm metal flakes. This
decay is enhanced in the presence of proton donors: Rao, C. N.; Hoz,
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that Matsukawa and Flowers managed to run the reaction of Sm2+ in
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1221−1223. Prasad, E.; Flowers, R. A., II J. Am. Chem. Soc. 2005, 127,
18093−18099.
analytical data of the product 9,10-dihydroanthracene matched the
values reported in the literature.27
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving kinetic traces for the reactions of benzyl chloride
and methyl cinnamate and spectral data for HOMPA. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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