Isotope effects in photochemistry. 1. o-nitrobenzyl alcohol derivatives

Article abstract of DOI:10.1021/ja049686b

The photolysis of o-nitrobenzyl alcohol derivatives shows a strong kinetic isotope effect (KIE up to 8.3) at the benzylic center. For some derivatives, the KIE is wavelength dependent, suggesting the involvement of higher excited states. In addition to th

Full text of DOI:10.1021/ja049686b

Published on Web 05/22/2004
Isotope Effects in Photochemistry. 1. o-Nitrobenzyl Alcohol Derivatives
Aure´lien Blanc and Christian G. Bochet*
Department of Chemistry, UniVersity of Fribourg, Chemin du Muse´e 9, CH-1700 Fribourg, Switzerland
Received January 17, 2004; E-mail: christian.bochet@unifr.ch
Scheme 1
The kinetic isotope effect (KIE) has been of fundamental interest
in organic chemistry for the elucidation of reaction mechanisms
for several decades.1 On the other hand, it is only recently that its
potential as a synthetic tool has been exploited.2 The C-D bond is
slightly stronger than the C-H bond, mainly due to the difference
in the zero-point energies; hence, a reaction in which a C-H(D)
bond is broken in the rate-determining step will be affected by iso-
topic substitution. For example, it has been shown that the low-
temperature deprotonation of N-Boc allylic amines by n-BuLi/
sparteine is 86 times slower for the R-dideuterated derivative; sim-
ilar results were found for various lithiation reactions.3-5 This obser-
vation led to the use of deuterium substitution to protect protons.6
We are interested in developing photolabile protecting groups
sensitive to specific wavelengths; o-nitrobenzyl alcohol derivatives
seemed to be promising candidates.7,8 They are well-known to react
upon irradiation through benzylic hydrogen abstraction by the
Scheme 2. Measurement of the Isotope Effect.
excited nitro group, followed by a subsequent cascade of reactions
that result eventually in fragmentation (Scheme 1).9
Alkyl substitution at the benzylic position was shown to
significantly shorten the reaction times and increase the quantum
yields.10 This suggests that the abstraction of the benzylic hydrogen
is the rate-determining step or one of multiple rate-determining
steps, regardless of whether the process occurs in a sigmatropic or
radical fashion.11 If this is the case, one should expect a significant
isotope effect when substituting the two benzylic hydrogens by
deuterium atoms. This opens very interesting perspectives, because
it would allow the overall observed reaction rate to be tuned without
changing the absorbance, as would the introduction or modification
of substituents on the aromatic ring.7 For reactions with a low
quantum yield, slowing down process A corresponds to a reduction
in quantum yield.
The kinetic isotope effect was measured by the photolysis of an
equimolar mixture of esters 1 and 2 for various irradiation times,
followed by GC determination (using tetradecane as an internal
standard) of the C11H23CO2Me/C9H19CO2Me ratio after derivati-
zation with TMSCHN2. A modified version of a known equation
was used to extrapolate the isotope effect as the ratio at zero-
conversion.12 Since the reactivity of the monodeuterated ester
contaminant is unknown, we must consider our measurements as
lower limits of the true isotope effects. We also ruled out deceptive
analytical effects by performing the reverse experiment, with
deuterated 1b and protiated 2b. Irradiation at 420 nm of acetonitrile
solutions at room temperature gave KIEs of 8.3 (1a/2a), 3.3 (1b/
2b), 4.3 (1c/2c), and 4.1 (1d/2d) (Scheme 2). The KIE for the 1a/
2a pair is very high (in fact higher than the maximal value of 7.5
calculated at 25 °C for cases without tunneling).13 This confirms
the hypothesis that the benzylic hydrogen abstraction is the rate-
determining step.14 However, the significant variation in the
magnitude of the KIE with different aromatic substituents suggests
a displacement of the position of the transition state along the
reaction coordinate and/or a change in the relative rates of the
individual steps.15
To measure the isotope effects on variously substituted deriva-
tives, we synthesized the hydrogenated and dideuterated esters 1a-d
and 2a-d.
The series 1 was prepared by simple acylation of the readily
available corresponding benzylic alcohols derivatives with dode-
canoyl chloride. Series 2 was prepared by the reduction of acid
chlorides (prepared in situ by the reaction of the carboxylic acid
with thionyl chloride) with NaBD4 in THF (65-94%, isotopic puri-
ties: 96% (2a), 91% (2b), 92% (2c), 92% (2d)), followed by acyla-
tion with decanoyl chloride (CHCl3, Et3N, DMAP, 84-96%). Minor
side-products are the monodeuterated esters, which could not be
separated. 2d was prepared by a Suzuki coupling between phenyl-
boronic acid and d2-4-Cl-2-nitrobenzyl alcohol under palladium
catalysis (71%), followed by acylation with decanoyl chloride.
We have previously demonstrated a strong dependence of the
overall reaction rate on the wavelength.7 Hence, we measured the
KIE at the wavelengths of 254, 350, and 420 nm (Table 1).
To our surprise, a very strong dependence was observed for the
1a/2a pair. The same trend was also found for 1c/2c, albeit to a
smaller extent. On the other hand, it was almost absent for 1b/2b
9
7174
J. AM. CHEM. SOC. 2004, 126, 7174-7175
10.1021/ja049686b CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Site Differentiation Using the Isotope Effect.
modulated lability has already been successfully applied in solid-
phase peptide synthesis.19,20
These experiments show unambiguously that the successful use
of the KIE in classical organic synthesis can also be extended to
photochemical reactions and that careful selection of the irradiation
wavelength is an additional handle to control the outcome of a
reaction. We also established experimental evidence for the
importance of higher excited states in an apparently well-understood
reaction. This is of highest importance for the development of
wavelength-selective photochemical reactions, where the kinetic and
spectroscopic parameters need to be optimized separately. Further
studies in the exact mechanism by flash photolysis and in the
synthetic applications are currently underway.
Table 1. Wavelength-Dependence of the Isotope Effect
λ
kH/kD 1a/2a
kH/kD 1b/2b
kH/kD 1c/2c
kH/kD 1d/2d
254
350
420
3.8
5.8
8.3
3.0
3.0
3.3
3.1
4.2
4.3
3.6
4.2
4.1
Acknowledgment. The financial support of the Swiss National
Science Foundation (Grant 620-066063) is gratefully acknowledged.
Supporting Information Available: Selected experimental pro-
cedures and isotope effect measurements, equations used to calculate
the KIE, and UV spectra of 1a/2a (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
and 1d/2d. A comparison of superimposable UV-vis spectra for
the protic and deuterated series rules out differential absorption.16
These results could suggest that the position of the transition
state or the conical intersection along the reaction coordinates and/
or the activation energy is wavelength-dependent. This explanation
is not reasonable, since the wavelength of the incident light is an
external factor, which should alter neither the molecular shape nor
the properties. On the other hand, one could consider that seVeral
energy surfaces are involved. However, photochemical and pho-
tophysical (e.g., fluorescence) processes usually occur from the first
excited state (either singlet S1 or triplet T1), regardless of the initial
excitation. This is known as the Kasha rule and is the consequence
of very fast internal conversion. The implication of a higher excited
state would represent a violation of this rule.17
References
(1) Wiberg, K. B. Chem. ReV. 1955, 55, 713-743. Westheimer, F. H. Chem.
ReV. 1961, 61, 265-273. Kwart, H. Acc. Chem. Res. 1982, 15, 401-
408.
(2) Clive, D. L. J.; Tao, Y.; Khodabocus, A.; Wu, Y. J.; Angoh, A. G.; Bennett,
S. M.; Boddy, C. N.; Bordeleau, L.; Kellner, D.; Kleiner, G.; Middleton,
D. S.; Nichols, C. J.; Richardson, S. R.; Vernon, P. G. J. Am. Chem. Soc.
1994, 116, 11275-11286.
(3) Clayden, J.; Pink, J. H.; Westlund, N. F.; Wilson, X. Tetrahedron Lett.
1998, 39, 8377-8380.
(4) Pippel, P. J.; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J. Am. Chem.
Soc. 2001, 123, 4919-4927.
(5) Hoppe, D.; Paetow, M.; Hintze, F. Angew. Chem., Int. Ed. Engl. 1993,
32, 394-396.
Irradiation at 420 nm furnishes just enough energy to reach the
S1 state, from which the reaction occurs with an intrinsically large
kinetic isotope effect. Excitation at 254 nm populates a higher
energy surface (S2), where the shape of the energy surface state is
different and shows a smaller KIE. This would be possible only if
the chemical reaction is faster than the relaxation. This hypothesis
is in agreement with the quasi-absence of wavelength-dependence
for the series b, where excited states are significantly lower (as
(6) Vedejs, E.; Little, J. J. Am. Chem. Soc. 2002, 124, 748-749.
(7) Bochet, C. G. Tetrahedron Lett. 2000, 41, 6341-6346.
(8) (a) Blanc, A.; Bochet, C. G. J. Org. Chem. 2002, 67, 5567-5577. (b)
Bochet, C. G. Angew. Chem., Int. Ed. 2001, 40, 2071-2073.
(9) Patchornik, A.; Amit, B.; Woodward, R. B. J. Am. Chem. Soc. 1970, 92,
6333-6335. See also ref 15.
(10) Reichmanis, E.; Smith, B. C.; Gooden, R. J. Polym. Sci. Polym. Chem.
Ed. 1985, 23, 1-8.
(11) (a) Schwo¨rer, M.; Wirz, J. HelV. Chim. Acta 2001, 84, 1441-1458. (b)
Il’Ichev, Y. V.; Wirz, J. J. Phys. Chem. A 2000, 104, 7856-7870. (c)
Gravel, D.; Giasson, R.; Blanchet, D.; Yip, R. W.; Sharma, D. K. Can. J.
Chem. 1991, 69, 1193-1200. (d) Yip, R. W.; Sharma, D. K.; Giasson,
R.; Gravel, D. J. Phys. Chem. 1984, 88, 5770-5772. (e) Yip, R. W.;
Sharma, D. K.; Giasson, R.; Gravel, D. J. Phys. Chem. 1985, 89, 5328-
5330. (f) Yip, R. W.; Wen, Y. X.; Gravel, D.; Giasson, R.; Sharma, D.
K. J. Phys. Chem. 1991, 95, 6078-6081.
(12) Balavoine, G.; Moradpour, A.; Kagan, H. B. J. Am. Chem. Soc. 1974,
96, 5152-5158. The KIE was calculated from a measurement at low
conversion (<15%) using an equation based on first-order kinetics. See
Supporting Information.
shown by the UV-vis spectra, 1a λmax ) 258 nm and 1b λmax
)
346 nm) and that the S2 state (with low KIE) can be reached even
at 420 nm. The implication of the S2 state is also compatible with
a triplet-based scheme, where the S2-T1 intersystem crossing is
much faster than the S1-T1 transition, according to the El-Sayed
selection rules.18 If this mechanism operates, our experimental evi-
dence suggests that the singlet-based transition state presents a large
KIE, whereas the triplet-based transition state shows a smaller one.
This particularly strong isotope effect opens new perspectives
in wavelength-based protecting group differentiation. To verify this,
we prepared diesters 3a and 3b, where both termini are protected
by ortho-nitrobenzyl alcohol derivatives. Chromatic orthogonality
was shown earlier to be rather poor (3.8:1 at 254 nm and 1:1.5 at
420 nm) for the hydrogen-substituted variant.7 Upon isotopic
substitution at the benzylic center, we expected the differentiation
to be significantly higher on the basis of the above results.
Hence, as a negative control, the photolysis of 3a at 420 nm
gave only a 2.4:1 ratio of monoesters 4a and 5a (37 and 15% yields,
respectively), together with 33% yield of totally deprotected
pentanedioic acid 6 and 15% yield of starting material (Scheme
3). On the other hand, in the isotopically substituted substrate, the
selectivity was raised to 14:1 (70% yield of 4b and 5% yield of
5b), with only 8% yield of totally deprotected 6 and 17% yield of
starting material. Subsequent photolysis of 4b at a shorter wave-
length would continue the deprotection to 6. A wavelength-based,
(13) Jones, R. A. Y. Physical and Mechanistic Organic Chemistry, 2nd ed.;
Cambridge University Press: New York, 1984; pp 29-37.
(14) Kwart, H. M.; Brechbiel, W. R.; Acheson, M.; Ward, D. C. J. Am. Chem.
Soc. 1982, 104, 4671-4672.
(15) Corrie, J. E. T.; Barth, A.; Munasinghe, V. R. N.; Trentham, D. R.; Hutter,
M. C. J. Am. Chem. Soc. 2003, 125, 8546-8554. See also: Il’ichev, Y.
V.; Schworer, M. A.; Wirz, J. J. Am. Chem. Soc. 2004, 126, 4581-4595.
(16) Temperature of the reaction mixture increases slightly over the time, but
measurements between 5 and 30 min showed no variation in the KIE.
(17) Only in rare cases, when the higher excited states (S2, S3, ...) are sufficiently
distant from S1, is internal conversion inefficient and do reactions from
these states occur (among the famous examples are the naphthalene
fluorescence and the Norrish type I reaction of thioketones). For a
discussion, see: Turro, N. J.; Ramamurthy, V.; Cherry, W.; Farneth W.
Chem. ReV. 1978, 78, 125-145.
(18) Klessinger, M.; Michl, J. Excited States and Photochemistry of Organic
Molecules; VCH: New York, 1995; p 255. See also: Lower, S. K.; El-
Sayed, M. A. Chem. ReV. 1966, 66, 199-241.
(19) Ladlow, M.; Legge, C. H.; Neudeck, T.; Pipe, A. J.; Sheppard, T.; Yang,
L. L. Chem. Commun. 2003, 2048-2049
(20) Kessler, M.; Glatthar, R.; Giese, B.; Bochet, C. G. Org. Lett. 2003, 5,
1179-1182.
JA049686B
9
J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004 7175