Mechanism of 3′,5′-Dimethoxybenzoin Ester Photochemistry: Heterolytic Cleavage Intramolecularly Assisted by the Dimethoxybenzene Ring Is the Primary Photochemical Step

Full text of DOI:10.1021/jo971121t

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J . Org. Chem. 1997, 62, 8278-8279
resulting in the formation of a strained bicyclic interme-
diate. Ring opening with the loss of the acetate ion was
suggested to give the dimethoxycyclohexadienyl cation
3, followed by the benzofuran product 2 upon deproto-
nation. More recent versions of the mechanism have
included (a) initial homolysis of the C-X bond of 1
followed by single-electron transfer to generate R-keto-
cation 4, which then reacts to give 3,5a or (b) direct C-X
bond heterolysis to generate 4.7d With the growing
importance of the DMB system in applied photochemis-
try, it is appropriate to study the mechanism in more
detail, both for the intrinsic interest of the reaction and
in order that directions for potential improvements can9
be pursued. Herein we report the initial results of our
mechanistic investigations of several DMB esters 5-8
and show by nanosecond laser flash photolysis (LFP) that
3, which is formed within the laser pulse (∼10 ns), is in-
deed on the reaction pathway. We present evidence
supporting a new mechanism involving interaction of the
electron-rich dimethoxybenzene ring with the singlet n,π*
excited state of the acetophenone (probably via a singlet
exciplex), resulting in C-OCOR bond heterolysis to give
cyclohexadienyl cation 3 in the primary photochemical
step.
Mech a n ism of 3′,5′-Dim eth oxyben zoin Ester
P h otoch em istr y: Heter olytic Clea va ge
In tr a m olecu la r ly Assisted by th e
Dim eth oxyben zen e Rin g Is th e P r im a r y
P h otoch em ica l Step
Yijian Shi,1a J ohn E. T. Corrie,*,1b and Peter Wan*,1a
Department of Chemistry, Box 3065, University of Victoria,
Victoria, British Columbia, V8W 3V6 Canada, and National
Institute for Medical Research, The Ridgeway, Mill Hill,
London NW7 1AA, U.K.
Received J une 20, 1997
Photochemically removable protecting groups2 are
finding novel applications in the photorelease of biological
compounds,3 in the synthesis of biopolymer arrays,4 and
for photogenerating organic bases.5 The 3′,5′-dimethoxy-
benzoin (DMB) system (1), and to a lesser extent the 3′-
methoxybenzoin system, both orginally studied by Shee-
han et al.6a for carboxylate esters, can efficiently photo-
release a variety of functional groups7 with >300 nm
(typically ∼350 nm) irradiation. Although photolysis of
unsubstituted benzoin derivatives has been described by
several groups,6b,8 the reactions are generally less clean
than for the 3′,5′-DMB system. Furthermore, there are
significant mechanistic differences, since the photolysis
of DMB carboxylates and phosphates is unaffected by
triplet quenchers,6a,7d whereas unsubstituted benzoins
are quenched.6b,8a,b The present paper addresses the
photolysis of DMB derivatives (eq 1) at wavelengths >300
nm and, hence, exclusively involves n,π* excitation of the
acetophenone chromophore. The photoproduct arising
from the DMB moiety is the benzofuran 2, which is
photostable.
Product studies were carried out for 3′,5′-dimethoxy-
benzoin esters 5-8 differing in structure only at the R
group. In studies of benzyl and naphthylmethyl ester
photosolvolysis, Pincock and co-workers9 have shown a
remarkable dependence of the ratio of products derived
from ionic versus radical intermediates caused by the
rate of decarboxylation of the acyloxy radical. In those
studies, the pivalate ester gave the highest yield of
radical-derived products, consistent with a very fast rate
•
Sheehan et al.6a proposed a Paterno-Bu¨chi reaction of
the singlet n,π* photoexcited carbonyl group of the
acetophenone with the 3′,5′-dimethoxybenzene group,
of decarboxylation for the pivaloyloxy radical [(CH3)3CO2 ,
kd ) 1.1 × 1010 s-1].9a,b
Photolysis of 5-8 in CH3CN or 1:1 H2O-CH3CN gave
only the photocleavage products shown in eq 1 with
similar efficiencies for each ester. In contrast to the
results of Cameron et al.5a with the related 3,3′,5,5′-
tetramethoxybenzoin system, no trace of radical-derived
products for any of 5-8 was observed.10 The rates of
decarboxylation of acyloxy radicals RCO2. (for 5-8) span
(1) (a) University of Victoria. (b) National Institute for Medical
Research.
(2) (a) Pillai, V. N. R. In Organic Photochemistry; Padwa, A., Ed.;
M. Dekker: New York, 1987; Vol. 9, Chapter 3. (b) Binkley, R. W.,
Flechtner, T. W. In Synthetic Organic Photochemistry; Horspool, W.
M., Ed.; Plenum Press: New York, 1984; Chapter 7.
(3) (a) Corrie, J . E. T.; Trentham, D. R. In Bioorganic Photochem-
istry; Morrison, H., Ed.; Wiley: New York, 1993; Vol. 2, pp 243-305.
(b) Adams, S. R.; Tsien, R. Y. Annu. Rev. Physiol. 1993, 55, 755. (c)
Kaplan, J . H. Annu. Rev. Physiol. 1990, 52, 897.
(4) Pease, A. C.; Solas, D.; Sullivan, E. J .; Cronin, M. T.; Holmes,
C. P.; Fodor, S. P. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 5022.
(5) (a) Cameron, J . F.; Willson, C. G.; Fre´chet, J . M. J . J . Am. Chem.
Soc. 1996, 118, 12925. (b) Pirrung, M. C.; Huang, C.-Y. Tetrahedron
Lett. 1995, 36, 5883.
(8) (a) Gee, K. R.; Keuper, L. W., III; Barnes, J .; Dudley, G.; Givens,
R. S. J . Org. Chem. 1996, 61, 1228. (b) Givens, R. S.; Athey, P. S.;
Matuszewski, B.; Kueper, L. W., III; Xue, J .-Y.; Fister, T. J . Am. Chem.
Soc. 1993, 115, 6001. (c) Peach, J . M.; Pratt, A. J .; Snaith, J . S.
Tetrahedron 1995, 51, 10013.
(9) (a) Pincock, J . A. In CRC Handbook of Organic Photochemistry
and Photobiology; Horspool, W. M., Song, P.-S., Eds.; CRC Press: Boca
Raton, FL, 1995; Chapter 32. (b) Hilborn, J . W.; Pincock, J . A. J . Am.
Chem. Soc. 1991, 113, 2683. (c) Hilborn, J . W.; MacKnight, E.; Pincock,
J . A.; Wedge, P. J . J . Am. Chem. Soc. 1994, 116, 3337.
(6) (a) Sheehan, J . C.; Wilson, R. M.; Oxford, A. W. J . Am. Chem.
Soc. 1971, 93, 7222. (b) Sheehan, J . C.; Wilson, R. M. J . Am. Chem.
Soc. 1964, 86, 5277.
(7) (a) Baldwin, J . E.; McConnaughie, A. W.; Moloney, M. G.; Pratt.
A. J .; Shim. S. B. Tetrahedron 1990, 46, 6879. (b) Corrie, J . E. T.;
Trentham, D. R. J . Chem. Soc., Perkin Trans. 1 1992, 2409. (c)
Thirlwell, H.; Corrie, J . E. T.; Reid, G. P.; Trentham, D. R.; Ferenczi,
M. A. Biophys. J . 1994, 67, 2436. (d) Pirrung, M. C.; Shuey, S. W. J .
Org. Chem. 1994, 59, 3890. (e) Pirrung, M. C.; Bradley, J .-C. J . Org.
Chem. 1995, 60, 6270. (f) Rock, R. S.; Chan, S. I. J . Org. Chem. 1996,
61, 1526.
(10) Conversions were taken to about 40-60% with excellent
material balance by 1H (300 MHz) NMR. The molar ratio of products
2 and the carboxylic acid RCO2H is essentially unity as determined
by 1H NMR in samples photolyzed in sealed NMR tubes. The quantum
yield (λex ) 366 nm) for reaction of 5 in 100% CH3CN as reported by
Sheehan et al.6a is 0.64 ( 0.03. Using this value as secondary reference,
we have found that all of 5-8 react with the same quantum efficiency
(100% CH3CN; λex ) 350 nm).
S0022-3263(97)01121-3 CCC: $14.00 © 1997 American Chemical Society

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J . Org. Chem., Vol. 62, No. 24, 1997 8279
is further supported by the observation that chemical
yields for formation of 2 from 5-8 were also not affected
by the presence of oxygen.
The results described to this point do not give any
direct information as to the pathway for photogenerating
3, the only intermediate observable by ns LFP. We have
no direct evidence to rule out initial formation of the
R-keto cation 4, although if it is formed, it would have to
rearrange to 3 within 10 ns, which is not unreasonable.
R-Keto cations are highly reactive carbocations, and those
with an R-phenyl group (e.g., 4) are known to rearrange
to the corresponding benzofuran or undergo nucleophilic
attack by solvent.15 However, we have not observed any
trace of the corresponding nucleophilic trapping product
1 (X ) OH) in photolyses of 5-8 carried out in 1:1 H2O-
CH3CN, which suggests that 4 is either not formed or
rearranges very quickly to 3.16
We propose a new mechanism for 3′,5′-dimethoxyben-
zoin photosolvolysis. The primary step is a charge-
transfer interaction of the electron-rich dimethoxyben-
zene ring with the electron-deficient oxygen of the n,π*
singlet excited acetophenone, to form an intramolecular
exciplex 10 (eq 3), which can return to 5 or react to give
3. The m-dimethoxy substituents strongly activate the
F igu r e 1. Transient absorption observed on LFP of flowing,
oxygen-purged 100% CH3CN solutions of 5. Decay traces taken
at 300 ns intervals [Inset: single-exponential decay of tran-
sient with kd ) (1.0 ( 0.1) × 106 s-1].
4 orders of magnitude9a,11 and the fact that all of 5-8
cleanly gave the same reaction (eq 1) argues against a
mechanism involving initial homolysis of the C-OCOR
bond, followed by electron transfer.
Nanosecond laser flash photolysis (YAG, 355 nm, <30
mJ ) of flowing solutions of each of 5-8 in 100% CH3CN
(purged with O2) gave the same absorption transient at
485 nm, which was formed within the laser pulse (∼10
ns) and decayed with first-order kinetics, kd ) 1.0 × 106
s-1 (Figure 1). Addition of small amounts of water (1-
5%) resulted in faster decays of this transient: at 5% H2O
the decay was too rapid to allow its observation after the
laser pulse. When 2 was dissolved in concentrated H2SO4
(or D2SO4), a visible band at 440 nm was observed that
had a band shape similar to the 480 nm band observed
on LFP. Workup of a solution of 2 dissolved in 2:1 20%
D2SO4-CH3CN resulted in >90% exchange at the 4-posi-
tion (asssigned by NOE studies), the site expected in
thermal protonation of 2 (eq 2). We therefore assign the
2′-position of the benzene ring toward bonding to the
carbonyl oxygen, giving rise to cation 3 in the primary
photochemical step. This explains why such a substitu-
tion pattern of methoxy groups gives rise to the highest
yields in benzoin ester photosolvolysis and photodepro-
tection. This mechanism also explains why no solvent-
substitution or radical-derived products are observed in
3′,5′-dimethoxybenzoin photochemistry. More rational
approaches to improving the photochemical efficiency of
benzoin photodeprotection can now be pursued.
Ack n ow led gm en t. This work was supported by the
National Sciences and Engineering Research Council
(NSERC) of Canada and the Medical Research Council,
U.K., for which we are grateful. We thank Z. Chen for
help in some ancillary experiments.
Su p p or tin g In for m a tion Ava ila ble: Preparation of es-
ters 6-8, representative photolyses, thermal deuterium ex-
change of 2, representative absorption spectra of substrates,
and a description of the laser flash photolysis experiments (7
pages).
440 nm band to cyclohexadienyl cation 9. The band at
485 nm observed in LFP is assigned to 3, the cyclohexa-
dienyl cation precursor to 2 in the photoreaction. The
longer λmax of 3 may be qualitatively explained by its more
extended simple polyene-type π-conjugation, whereas 9
may be regarded as an allyl cation conjugated to a furan
ring.
LFP studies of 5 in N2-purged CH3CN solutions gave
an additional transient with λmax ) 330 and 420 nm and
kd ≈ 106 s-1. Introduction of air resulted in faster decay
of this transient without affecting the 485 nm transient
assigned to 3. We therefore assign the 330, 420 nm
transient to the triplet state of 5.12 Because the 485 nm
transient assigned to 3 is formed in the presence or
absence of oxygen with similar yields, the reaction of 5-8
most likely proceeds via their singlet excited states. This
J O971121T
(12) The acetophenone moiety is the essential chromophore of these
benzoins at 350 nm excitation. The triplet state of a variety of
acetophenones has been reported to have absorptions in the 330-455
nm region13 and for acetophenone itself has a triplet lifetime of ∼0.1-
0.2 µs,14 which is readily quenchable by dissolved oxygen.
(13) Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of Photo-
chemistry, 2nd ed.; M. Dekker: New York, 1993.
(14) Lutz, H.; Lindqvist, J . J . Chem. Soc. D 1971, 493.
(15) Creary, X. Chem. Rev. (Washington, D.C.) 1991, 91, 1625.
(16) Pirrung and Shuey7d and Cameron et al.5a have suggested that
4 is formed in the primary photochemical step since the 3,5-dimethoxy-
substitution pattern on the nonbenzoyl ring (both meta to the benzylic
position) is known to enhance heterolytic cleavage at the benzylic pos-
ition, (Zimmerman’s meta-effect17 (more correctly meta-ortho effect)17a).
However, since only the acetophenone moiety is electronically excited
at λexcit >300 nm and energy transfer from acetophenone to dimethoxy-
benzene is prohibitive (Es ) 79 and 95 kcal mol-1, respectively),13 it is
not clear how Zimmerman’s meta-effect can operate here.
(11) Chateauneuf, J .; Lusztyk, J .; Ingold, K. U. J . Am. Chem. Soc.
1988, 110, 2886.
(17) (a) Zimmerman, H. E. J . Am. Chem. Soc. 1995, 117, 8988. (b)
Zimmerman, H. E.; Sandel, V. R. J . Am. Chem. Soc. 1963, 85, 915.