Reduction of 4-styrylpyridine by SmI2: An inner sphere electron tranfer case where the binding site differs from the reaction center

Article abstract of DOI:10.1021/ol402484j

In the reduction of 4-styrylpyridine by SmI₂, the binding site for SmI₂ differs from the reaction center. MeOH and TFE exhibit an unprecedented behavior showing a sigmoidic effect on the reaction rate, which levels off around 0.5-1 M. The reactions display autocatalytic behavior and a U shape dependence of the reaction rate on the HMPA concentration. With high likelihood, the reactions involve a proton coupled electron transfer step.

Full text of DOI:10.1021/ol402484j

ORGANIC
LETTERS
2013
Vol. 15, No. 20
5262–5265
Reduction of 4‑Styrylpyridine by SmI2: An
Inner Sphere Electron Tranfer Case Where the
Binding Site Differs from the Reaction Center
Ramesh Yella and Shmaryahu Hoz*
Department of Chemistry, Bar-Illan University, Ramat-Gan 52900, Israel
shoz@mail.biu.ac.il
Received August 29, 2013
ABSTRACT
In the reduction of 4-styrylpyridine by SmI2, the binding site for SmI2 differs from the reaction center. MeOH and TFE exhibit an unprecedented behavior
showing a sigmoidic effect on the reaction rate, which levels off around 0.5ꢀ1 M. The reactions display autocatalytic behavior and a U shape dependence
of the reaction rate on the HMPA concentration. With high likelihood, the reactions involve a proton coupled electron transfer step.
In a previous work we described the reduction of three
systems BAI, BMI, and BPI by SmI2.1,2 All these nitrogen
containing substrates exhibit autocatalytic kinetics (reaction
rates do not decrease but rather increase as the reaction
progresses), and the catalyst is the Sm3þ generated in the
course of the reaction.
In addition, as will be shown below, the reaction displays a
novel role for the proton donor with a high probability of a
proton coupled electron transfer (PCET) mechanism.
The reaction of 4SP with SmI2 yields the dimer cleanly
(eq 1). However, as will be shown below, the kinetics of this
simple reaction are rather complex. Therefore, kinetic
traces instead of rate constants will be presented through-
out this paper.
The reactivity order was BPI > BMI > BAI. This reac-
tivity order is not in accord with the electron affinity of these
substrates but rather with the accessibility of the lone pair on
the nitrogen. The purpose of the present work is to examine the
effect of removal of the nitrogen from the reaction center to a
side location. Thus, using BAI as the starting point we moved
the nitrogen atom from the reaction center;the central double
bond;to one of the rings to give 4-styrylpyridine (4SP).
In this work, the effect of the following additives on the
reaction was examined using a stopped flow spectrometer
to follow the disappearance of SmI2 at 619 nm: MeOH,
trifluoroethanol (TFE), HMPA, and SmI3. Figures 1 and 2
show the effect of the concentration of MeOH and of TFE.
As can be seen in the highest trace in each figure, in the
absence of a proton donor the reaction manifests auto-
catalytic behavior as do the imines BAI, BMI, and BPI.1
The catalyst generated in the course of the reaction is most
Preliminary experiments have indeed shown that 4SP reacts
with SmI2 at least an order of magnitude faster than BAI.
(1) Rao, C. N.; Hoz, S. J. Am. Chem. Soc. 2011, 133, 14795.
r
10.1021/ol402484j
Published on Web 10/07/2013
2013 American Chemical Society

If it is done from within the complex of the proton donor
and SmI2, the logꢀlog plot will exhibit a sigmoidic shape
with leveling off around a 4 M solution.3 This is achieved
when all the coordination sites on samarium are occupied
as in the case of MeOH. In the present case we see a
different behavior. In spite of the absence of exact rate
constants, it is clear that the reactions are enhanced by the
proton donors. However, rate leveling takes place much
before the proton donor concentration reaches 4 M. This
behavior does not correspond to protonation from the
bulk nor to protonation from within the SmI2 coordina-
tion sphere. The latter is evidenced by the fact that the
leveling off takes place at a proton donor concentration
much smaller than 4 M and by the behavior with TFE
which does not complex to SmI2. The leveling off concen-
tration is in line with the formation of a hydrogen bond
between the pyridine nitrogen of 4SP and the alcohol.
Once saturation is achieved, an additional amount of
alcohol will not affect the rate. In accordance with this is
the fact that the more acidic alcohol, TFE, reaches satura-
tion at 0.1 M, whereas MeOH levels off only around 0.5 M.
The rate enhancement due to this hydrogen bonding may
be due to either an increase in the electron affinity of the
substrate or a PCET (proton coupled electron transfer).4
This point will be discussed below.
Figure 1. Kinetic traces showing the effect of MeOH concentra-
tion on the reaction of SmI2 (0.5 mM) with 4SP (5 mM).
Figure 2. Kinetic traces showing the effect of TFE concentration
on the reaction of SmI2 (0.5 mM) with 4SP (5 mM).
probably the Sm3þ. As more and more proton donor is
added to the reaction mixture, the autocatalytic nature
gradually disappears and the kinetics become more char-
acteristic of a pseudo-first-order reaction. Consequently,
to determine the kinetic order in the substrate, which
turned out to be 1, we have used 4 M MeOH (Table S1
and Figure S1).
Figure 3. Kinetic traces showing the effect of Sm3þ concentra-
tion on the reaction of SmI2 (0.5 mM) with 4SP (5 mM). No
proton donor was added.
In general, if the protonation is by proton donors from
the bulk, the kinetic order in the proton donor should be 1.
As we have seen, the reaction is autocatalytic, and as was
the case with BAI, it is highly likely that the catalyst is the
Sm3þ generated in the course of the reaction. It is postu-
lated that it causes a rate enhancement by complexing to
the pyridine nitrogen of the substrate, increasing thereby
its electrophilicity. To test this postulate, SmI3 was prepared
externally and added to the reaction mixture. Figure 3 shows
the effect of Sm3þ on the reaction.
It is clear that even at a concentration which is a fraction
of the millimolar concentration (concentrations similar to
those generated in the course of the reaction), Sm3þ
significantly catalyzes the reaction. To assess its complexation
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Org. Lett., Vol. 15, No. 20, 2013
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to the nitrogen lone pair, we have performed ab initio
calculations at the B3LYP/SDD level,5 on the interaction
energy between pyridine and SmCl3. We have examined
multiplicities 2, 4, 6, and 8 for Sm3þ (Tables S2, S3). The
complexation energies of the most stable electronic config-
uration (multiplicity 6) and that of the lowest multiplicities
were ꢀ38.1 and ꢀ39.3 kcal/mol, indicating a strong affinity
of the pyridine to the positively charged samarium.
Thus, the two additives discussed above, ROH and
Sm3þ, act by coordinating to the pyridine nitrogen lone
pair. Thequestion is, does SmI2 itself alsocoordinate tothe
pyridine nitrogen? This was examined by spectral analysis
as well as by ab initio calculations. Generally, complexa-
tion is evident from a change in the absorption spectrum of
SmI2. However, the high reactivity of 4SP does not enable
such a spectral measurement. Pyridine, the complexing
part of the substrate, also reacts with SmI2. Therefore, the
spectrum of SmI2 with a pyridine derivative, 4-methox-
ypyridine, which shows a relatively low reactivity toward
SmI2, was examined. It was found that, even at a 50 mM
concentration of 4-methoxypyridine, the double humped
spectrum of SmI2 is significantly distorted, indicating com-
plexation to SmI2. The spectrum is further distorted at higher
concentrations (Figure S2). Interestingly, HMPA induces
upon complexation the coalescence of the two humps and a
blue shift.6 MeOH causes a coalescence with no shift,7 and the
4- methoxypyridine causes coalescence with a red shift.8 Ab
initio calculations were carried out examining multiplicities 1,
3, 5, 7, 9, and 11 of SmCl2 (Table S4). The interaction of
pyridine with Sm2þ at the most stable multiplicity (7) and at
its lowest multiplicity (1) was found to have complexation
energies of ꢀ29.4 and ꢀ29.5 kcal/mol, respectively (Table S3).
Thus, the spectral and computational evidence support
the complexation of SmI2 to the substrate. To demonstrate
that this complexation has indeed a significant effect on
the reaction rate, we examined the effect of HMPA on the
reaction. In general, HMPA accelerates such reactions due
to the increase in the reduction potential of the SmI2
coordinated to HMPA.9 If the electron transfer is of an
Figure 4. Effect of HMPA on the reaction of SmI2 (0.5 mM) with
4SP (5 mM) in the presence of 25 mM MeOH.
inner sphere nature,10 the addition of HMPA may reduce
the reaction rate. In the present case, in the absence of
HMPA the reaction reaches 90% completion in less than
0.1 s. The addition of HMPA slows the reaction until, at
0.6 mM HMPA, the reaction reaches 90% completion
after more than 1 s (Figure 4). A further increase in HMPA
concentration induces rate enhancement, probably due to
the formation of fully HMPA-coordinated SmI2. At inter-
mediate concentrations, complex behavior is exhibited
because of a competition between Sm2þ and the generated
Sm3þ for HMPA. Thus, at concentrations of 0.3 and 0.6
mM HMPA, the HMPA is inhibitive.
It should be noted that the autocatalytic behavior
observed in these cases does not follow the traditional
scenario, namely generation of a catalyst in the course of
the reaction, but rather is due to the removal of the
inhibitor (HMPA) by Sm3þ
.
The fact that ROH, Sm3þ, and SmI2 compete for
coordination to the lone pair on the nitrogen clearly
explains why the kinetics of these reactions are not amen-
able to simple kinetic analysis. Furthermore, the variation
in the concentrations of these complexants, as the reaction
progresses, adds to the difficulty of the analysis. In the
above we have touched only upon first-order effects. A
detailed kinetic analysis should also consider the interac-
tion of Sm3þ and SmI2 with ROH and its effect on their
ability to coordinate to the nitrogen.
(5) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery Jr.,
J. A.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople,
J. A. GAUSSIAN 03, revision A.04; Gaussian Inc., Pittsburgh, 2003.
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Because of the steric accessibility of the lone pair on the
pyridine nitrogen, the additives in the reaction of 4SP
display unique behavior. Alcohols enhance the reaction,
but their effect is leveled off after hydrogen bond satura-
tion is achieved at less than 1 M ROH concentration. Sm3þ
is very effective in enhancing the reaction, and HMPA at a
(7) Yacovan, A.; Bilkis, I.; Hoz, S. J. Am. Chem. Soc. 1996, 118, 261.
(8) It is possible that the direction of the shift is controlled by
interactions taking place outside of the σ framework such as back-
donation etc.
(9) (a) Rao, C. N.; Hoz, S. J. Org. Chem. 2012, 77, 9199. (b) Choquette,
K. A.; Sadasivam, D. V.; Flowers, R. A., II. J. Am. Chem. Soc. 2010, 132,
17396. (c) Flowers, R. A., II Synlett 2008, 1427. (d) Sadasivam, D. V.;
Antharjanam, P. K. S.; Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc.
2008, 130, 7228. (e) Shabangi, M.; Flowers, R. A., II. Tetrahedron Lett.
1997, 38, 1137. (f) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett.
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Eur. J. 2000, 6, 3747. (f) Miller, R. S.; Sealy, J. M.; Shabangi, M.;
Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A., II. J. Am. Chem. Soc.
2000, 122, 7718. (g) Enemærke, R. J.; Daasbjerg, K.; Skrydstrup, T.
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5264
Org. Lett., Vol. 15, No. 20, 2013

implies a sequential proton transfer (PT)/ET followed
by ET/PT steps. Motion along the diagonal implies that
the proton transfer is coupled to the electron transfer
(PCET).4
In this mechanism the changes in the geometries of the
reactants and the solvent reorganization, which bring the
HOMO of the donor to the same energy level as the
LUMO of the acceptor, are accompanied by the motion
of the proton toward the nitrogen along the hydrogen
bond. Counterclockwise motion along the scheme periph-
ery is highly unlikely because of the high endothermicity of
the first step in this relatively nonpolar solvent (THF). It is
more difficult to decide between the PCET path and
clockwise motion because of the electrostatic interactions
involved. We have found that the electrostatic interactions
contribute ca. 25 kcal/mol to the energy of the electron
transferprocess.12 ThisisinlinewithSaveant’sfinding that
the electron transfer could be coupled not only to proton
transfer but also to the formation of an ion pair.13 Since the
proton transfer is endothermic, according to the Hammond
postulate14 the transition state generating the methoxide
anion is late. This gives some advantage to the PCET
mechanism over the peripheral clockwise path, as it leads
to a hardꢀhard (MeOꢀꢀSm3þ) interaction rather than to a
softꢀhard (radical anionꢀSm3þ) one.15
Figure 5. Schematic presentation of possible reaction mechanisms.
low concentration slows down the rate, but enhances it at a
higher concentration. Because HMPA usually enhances
the reactions of SmI2, its present effect (at 0.6 mM) of
lowering the reaction rate can be used to induce selectivity
between substrates (or functional groups within a molecule)
containing a pyridine ring and other substrates.11 This nicely
demonstrates the importance of understanding the mechan-
ism and the role of additives in synthetic chemistry. Similarly,
the unique dependence on the proton donor concentration
could also be employed to discriminate between pyridine
containing substrates and substrates that show higher order
kinetics in the alcohol.
Supporting Information Available. Tables S1ꢀS4, Fig-
ures S1 and S2, general information, experimental pro-
1
cedures, copies of H and 13C NMR spectra of starting
Figure 5 shows a schematic presentation of possible reac-
tion mechanisms. Motion along the periphery of the scheme
material, and full characterization spectra of products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Using half-lives as a criterion for the reaction rate, in the absence
of HMPA, 4SP is 140 times faster than acetophenone and in the presence
of 0.6 mM HMPA acetophenone is 13 times faster than 4SP ([substrate]
5 mM, [SmI2] 0.5 mM, [MeOH] 25 mM).
(15) (a) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533. (b)
Chemical Hardness, Structure and Bonding; Sen, K. D., Ed.; Springer-
Verlag: Berlin, Heidelberg, 1993.
(12) Farran, H.; Hoz, S. Org. Lett. 2008, 10, 4875.
ꢀ
(13) Saveant, J.-M. J. Am. Chem. Soc. 2008, 130, 4732.
(14) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334.
The authors declare no competing financial interest.
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