Temperature dependent product distribution in photolysis of o-alkylphenacyl benzoates

Article abstract of DOI:10.1016/j.tetlet.2013.10.109

Temperature effect on photochemical reactions of ortho-alkylphenacyl benzoates, one of the recently developed photoremovable protecting groups (PPG), giving indanones (IN) and benzocyclobutenols (CB) was examined. As temperature was lowered, CB was formed preferentially over IN and the amount of IN increased as temperature was elevated. Arrhenius plot of ln(IN/CB) versus 1/T gave a straight line from which Ea_IN-Ea_CB and A _IN/A_CB were obtained. The least sterically hindered 2-methylphenacyl benzoate (1) gave the highest Ea_IN-Ea_CB and A_IN/A_CB among the ortho-alkylphenacyl benzoates tested in this research including 2,4,6-trimethylphenacyl benzoate (2) and 2,4,6-triisopropylphenacyl benzoate (3).

Full text of DOI:10.1016/j.tetlet.2013.10.109

Tetrahedron Letters 54 (2013) 7175–7179
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Temperature dependent product distribution in photolysis
of o-alkylphenacyl benzoates
⇑
Mi Jang, Bum Hee Lim, Hyuk Jun Ryu, Bong Ser Park
Department of Chemistry, Dongguk University (Seoul campus), Seoul 100-715, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Temperature effect on photochemical reactions of ortho-alkylphenacyl benzoates, one of the recently
developed photoremovable protecting groups (PPG), giving indanones (IN) and benzocyclobutenols
(CB) was examined. As temperature was lowered, CB was formed preferentially over IN and the amount
of IN increased as temperature was elevated. Arrhenius plot of ln(IN/CB) versus 1/T gave a straight line
from which EaIN–EaCB and AIN/ACB were obtained. The least sterically hindered 2-methylphenacyl benzo-
ate (1) gave the highest EaIN–EaCB and AIN/ACB among the ortho-alkylphenacyl benzoates tested in this
research including 2,4,6-trimethylphenacyl benzoate (2) and 2,4,6-triisopropylphenacyl benzoate (3).
Ó 2013 Elsevier Ltd. All rights reserved.
Received 12 August 2013
Revised 16 October 2013
Accepted 23 October 2013
Available online 1 November 2013
Keywords:
Temperature effect
Photochemistry
Photoremovable protecting group
Benzocyclobutenol
For the last two decades, photochemistry of ortho-alkylphenyl
ketones having a leaving group X such as chloride, carboxylates,
sulfonates, or phosphates at alpha position to carbonyl has
received much attention due to their application into photoremov-
able protecting groups (PPG) or photocages.1–3 Typically these
o-alkylphenacyl PPGs utilize an efficient release of HX together
with indanone formation upon photolysis. The reaction shares a
common feature with a well known photochemistry of ortho-alkyl-
phenyl ketones,4,5 which is a hydrogen abstraction reaction of
triplet excited state of the carbonyl, but the following step is
known to vary depending on the substituents at alpha position
to the carbonyl group and the reaction medium. When the alpha
substituent is a good leaving group such as Cl, the ground state
E-dienol formed from the excited state precursor gives the inda-
none in benzene, but the other isomer, Z-dienol, participates in
the formation of the same product in methanol.6 With a relatively
poor leaving group such as carboxylate, the E-dienol is known to be
the sole precursor of the indanone regardless of the solvent.7
Wessig had proposed the intermediacy of the 1,5-triplet biradical
formed by fast HX elimination from the initially formed 1,4-triplet
biradical in the case of the sulphonate leaving group.8 The mecha-
nistic picture known to date is shown in Scheme 1.
explained that solvation of the hydroxyl group in the E-dienol
intermediate by H-bond donor solvents and placement of the ste-
rically more demanding ortho-alkyl groups will force to twist the
enol C@C bond and make the CB formation easier and the IN
formation more difficult.
Significance of finding an optimum condition for the effective
release of protecting groups together with our continuous efforts
to understand the correlation of photochemical selectivity and
chemical structure led us to explore the temperature effect on pho-
tochemistry of ortho-alkylphenacyl benzoates.10–12 During the re-
search we found that Klan and co-workers had studied the
temperature effect of essentially the same system as our current
target molecule, but the information on the CB product was miss-
ing in their studies mainly because the exhaustive photolysis was
performed in their studies.13 Here we would like to report our re-
sults showing varying ratios of CB and IN photoproducts depending
on the reaction temperature and discuss a mechanistic reasoning
of our results.
Ketones 1–3 were prepared by a routine synthetic procedure:
a-bromination of acetophenones using CuBr2 followed by carbox-
ylation of the resulting bromoacetophenones. The ketones in de-
gassed solution of toluene-d8 (0.02 M) were irradiated in an NMR
tube using Pyrex filtered light of a 450 W Hanovia medium pres-
sure mercury arc lamp, and the progress of the reaction was mon-
itored by 1H NMR spectroscopy at regular time intervals. Photolysis
was done at various temperatures (from À30 °C to 100 °C). The de-
sired temperatures were attained by a Neslab CC-100II immersion
cooler for low temperature and by heated silicon oil bath for high
temperature. The product ratios, IN/CB, were taken using 1H NMR
integration of the corresponding peaks of each product. Table 1
Recently, we have reported that photolysis of o-alkylphenacyl
carboxylates gives not only the indanone (IN) but also the benzo-
cyclobutenol (CB).9 Product selectivity of CB over IN increases as
hydrogen bond donor ability of the solvent increases and as the
size of ortho-alkyl group becomes larger. The results were
⇑
Corresponding author.
E-mail address: parkbs@dongguk.edu (B.S. Park).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.109

7176
M. Jang et al. / Tetrahedron Letters 54 (2013) 7175–7179
O
OH
O
X
- HX
S1
T1
X = OMs
ν
h
X
OH
O
X = Cl, OCOR
Benzene
X
X
OH
+
Z
E X = OCOR
MeOH
X = Cl
MeOH
MeO
O
O
+
Scheme 1. Various reaction pathways of 2,5-dimethylphenacyl photoremovable protecting group.
Table 1
Product ratios in photolysis of ketones 1–3 in toluene-d8 at various temperatures
Compounds
Irrad. Temp (°C)
Irrad. Temp (1000/K)
IN/CB
ln(IN/CB)
1
À30
À25
À15
0
10
20
4.1
4.0
3.9
3.7
3.5
3.4
3.4
4.0
3.7
3.4
3.1
2.9
2.7
3.7
3.4
3.1
3.0
2.9
2.7
0.29 0.04
0.44 0.05
0.64 0.06
1.5 0.1
2.0 0.2
3.2 0.3
À1.2
À0.82
À0.44
0.41
0.69
1.2
25
3.6 0.3
1.3
2
3
À25
0.42 0.03
0.88 0.08
1.7 0.2
2.1 0.2
3.5 0.3
À0.87
À0.13
0.53
0.74
1.3
0
25
50
75
100
0
25
50
65
75
4.6 0.4
1.5
0.36 0.03
0.61 0.05
1.2 0.1
1.6 0.2
1.7 0.2
À1.0
À0.50
0.18
0.47
0.53
0.92
100
2.5 0.2
summarizes the IN/CB ratios of photolysis of ketones 1–3 in tolu-
ene-d8 at various temperatures and Figure 1 shows the Arrhenius
plots of the experimental data. Here we chose the IN/CB ratios at
low conversion (<5%) to minimize other contributing factors such
as buildup of acids and thermal conversion between the photo-
vious study, we have proposed that both IN and CB come from the
same intermediate, the E-dienol (Scheme 2).9 The Z-dienol would
return to the starting ketone via 1,5-hydrogen transfer so rapidly
that other reactions such as CB or IN formation could not compete
with, just like most other ortho-alkyl phenyl ketones would do.14
The CB formation occurs via conrotatory cyclization of the E-die-
products, vide infra. From the slope and intercept of the plot, EaIN
–
EaCB and AIN/ACB were obtained, respectively (Table 2)
nol,15 while the IN formation requires the cleavage of a
r bond con-
R
R
O
R
O
OH
R'
OCOPh
OCOPh
ν
h
+
R'
R
R'
R
CHR'2
R
R'
+
1 : R = R' = H
PhCOOH
2 : R = Me, R' = H
CB
3 : R = i-Pr, R' = Me
IN
.
necting the carboxylate leaving group. Thus, it is understandable to
see the results of EaIN–EaCB >0 for the reactions of all the ketones
studied here.
For all the compounds studied, the lower temperature preferred
CB over IN, which implied that EaIN is larger than EaCB. In the pre-

M. Jang et al. / Tetrahedron Letters 54 (2013) 7175–7179
7177
Scheme 3) is much more developed in the transition state going
to the IN from 1 than from 2 or 3. The difference could also origi-
nate from different entropy at the transition states going to the CB,
but it is most likely that the IN forming process contributes more
to the entropy differences because it involves bond cleavages to
form two molecules. Considering that the IN formation requires al-
most planar geometry of the acetyl moiety and the phenyl ring, the
E-dienol from 1 can adopt such geometry relatively more easily
than those from 2 and 3 can do, which may envision the more bond
cleaved transition state for 1. (Scheme 3) In other words, the steri-
cally less demanding ketone 1 takes late transition state along the
reaction coordinate to the IN formation in terms of the degree of C–
X bond cleavage, while the sterically more demanding ketones 2
and 3 take relatively early transition state.
Our quantum chemical calculation using GAUSSIAN 09 suite of
programs (Geometry optimization at B3LYP)16 supported the
above explanation for the different behaviors of the mono alkyl
and tri alkyl substituted ketones. The difference of the bond a in
Scheme 3 between the starting ketone and the transition state
was 0.957 Å and 0.779 Å for 1 and 3, respectively. Along the reac-
tion coordinate toward the IN formation, the bond connecting the
departing group is more stretched in 1 than 3 at the transition
state. (Scheme 4)
1.5
1.0
1
2
3
0.5
0.0
-0.5
-1.0
-1.5
2.6
2.8
3.0
3.2
3.4
3.6
3.8
4.0
4.2
1000/K
Figure 1. Arrhenius plot of photolysis of 1–3.
Table 2
EaIN–EaCB, AIN/ACB and
D
Sà SàCB obtained from arrhenius plot of photolysis of 1–3
–D
IN
Compounds
EaIN–EaCB (kcal/mol)
AIN/ACB
D –D
Sà Sà (cal/mol K)
IN CB
Our experimental data of the temperature effect on photolysis
of 1–3 can be considered as another example of entropy driven
selectivity.17–19 At high temperature, contribution of entropy in-
creases, and the product selectivity can mainly be determined by
the entropy. As Figure 1 shows, the IN/CB ratio increases as the
photolysis temperature is raised. Furthermore, the ratio is higher
for the less sterically demanding ketone at a given temperature
at least above À25 °C. The results are consistent with the idea that
the C–X bond is more separated in the T.S. of 1 than 2 or 3, which
1
2
3
6.7
3.5
4.0
3.3 Â 105
5.9 Â 102
5.6 Â 102
6.4
3.2
3.2
One thing noticeable from Figure 1 and Table 2 is that the
mono-alkyl substituted ketone, 1, behaves differently from the
tri-alkyl substituted ones, 2 and 3. The slope of the Arrhenius plot
is the steepest for 1, which results in the largest value of both EaIN
–
would give the highest value of
D
Sà for the IN formation from 1. At
EaCB and AIN/ACB. The first thing that came to our mind to explain
the difference of two groups was the steric hindrance caused by
the extra alkyl group. However, it was not straightforward to relate
the steric hindrance to the observed trends of EaIN–EaCB and AIN
ACB. We will try to analyze it in more detail below.
Let us call our attention to AIN/ACB first. The A factor is related to
the reaction entropy. It is not difficult to understand why AIN is lar-
ger than ACB. The IN forming process involving separation into two
molecules will most likely increase the entropy, while the CB for-
mation will accompany much less changes in entropy. Much larger
AIN/ACB of 1 than those of 2 and 3 implies that cleavage of the bond
low temperature (below À25 °C) the IN/CB ratio of 1 can go lower
than that of 2 or 3, where now the enthalpic contribution starts to
prevail.
D
Hàof the IN formation from 1 would be larger than that of
/
2 or 3 due to the more cleaved C–X bond in the T.S., which can
increase the reaction barrier.
There is another important factor which has to be discussed in
determining the IN/CB ratios. In our experiment we observed that
the product ratios, IN/CB, increased as the irradiation time got
longer. The results can be understood if we consider the IN forming
reaction is autocatalytic: As the reaction proceeds, benzoic acid
starts to accumulate in the solution, which then contributes to
connecting a-carbon to the carbonyl and the benzoate (bond a in
Scheme 2. Reaction mechanism of photochemical reactions of o-alkylphenacyl benzoates.

7178
M. Jang et al. / Tetrahedron Letters 54 (2013) 7175–7179
δ+
H
OH
O
-
X δ
O
X
+
HX
bond a
-
CH2
OH
δ
+
H
R
R
δ O
R
O
-
X δ
X
+
HX
R'
R
CR'2
-
δ
R
R
R'
R'
R'
Scheme 3. Proposed transition states for indanone formation.
H
1
O
C
1
4
O
Ph
2
C
C
C
O
3
5
6
3
C
2
C
1
(a)
(b)
(d)
1
H
1
O
1
C
4
O
Ph
2
C
C
C
6
3
2
5
C
O
3
C
1
3
(c)
Distance ( )
Distance ( )
Distance ( )
Distance ( )
Ⴄ(b)-(a)
Ⴄ(d)-(c)
in structure (a)
1.359
in structure (b)
1.375
in structure (c)
1.366
in structure (d)
1.398
C1-C2
C2-C3
C3-C4
C4-C5
C4-O1
O1-H1
C5-O2
O2-C6
C6-O3
0.016
-0.028
0.066
-0.103
-0.052
0.153
0.957
-0.083
0.056
0.032
-0.038
0.072
-0.107
-0.028
0.049
0.779
-0.065
0.037
1.484
1.456
1.494
1.456
1.374
1.440
1.367
1.439
1.499
1.396
1.502
1.395
1.361
1.309
1.364
1.336
0.982
1.135
0.983
1.032
1.467
2.424
1.470
2.249
1.343
1.260
1.340
1.275
1.227
1.283
1.227
1.264
Scheme 4. Comparison of geometries obtained by a quantum chemical calculation; (a) E-dienol intermediate from 1; (b) transition state structure going toward IN from 1; (c)
E-dienol intermediate from 3; (d) transition state structure going toward IN from 3.
enhancing the departing rate of the benzoate leaving group to form
more indanones.20 As an example, Figure 2 shows the increasing
trend of the IN to CB ratios with time for 1 and 2.
C–X bond cleavage would occur in the transition state, which then
increase the IN/CB ratio. In the case of o-alkylphenacyl mesylates,
however, it still cannot be ruled out that the radical pathway of
the IN formation is occurring via ‘spin center shift’ of the 1,4-birad-
ical intermediate shown in Scheme 2 as proposed by Wessig.21
The IN/CB ratios can also be affected by the thermal conversion
if the CB can convert to the IN within a similar time scale of pho-
tolysis. Thus, we performed thermolysis experiments by heating
the CB in an NMR tube at 115 1 °C using an oil bath and found
that the thermal conversion of the CB to the IN was too slow to af-
fect our analysis of temperature effect on photolysis discussed
above.22 In the thermolysis of the CB, only a few percents’ conver-
sion was made in two hours while the irradiation time did not
We also measured the IN/CB ratios in photolysis of 1 and 2 in
benzene with benzoic acid added, and found that the IN became
the major product with a trace amount of the CB when adding
one equiv of the acid. The effect of acids on IN/CB ratio is also con-
sistent with our previous findings that addition of N-methylimid-
azole increased the amount of the CB over the IN and that the CB
analogs were never detected in photolysis of o-alkylphenacyl chlo-
ride and mesylates having stronger acid leaving groups.9 These re-
sults can also be understood in view of the transition state
discussed above. The better the leaving groups are, the more the

M. Jang et al. / Tetrahedron Letters 54 (2013) 7175–7179
7179
3. Bergmark, W. R.; Barnes, C.; Clark, J.; Paprian, S.; Marynowski, S. J. Org. Chem.
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4.0
4. Klan, P.; Wirz, J. Photochemistry of Organic Compounds: From Concepts to
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5. Wagner, P. J.; Park, B. S. Org. Photochem. 1991, 11, 227–368.
6. Pelliccioli, A. P.; Klan, P.; Zabadal, M.; Wirz, J. J. Am. Chem. Soc. 2001, 123, 7931–
7932.
7. Zabadal, M.; Pelliccioli, A. P.; Klan, P.; Wirz, J. J. Phys. Chem. A 2001, 105, 10329–
10333.
8. Wessig, P.; Glombitza, C.; Muller, G.; Teubner, J. J. Org. Chem. 2004, 69, 7582–
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9. Park, B. S.; Ryu, H. Tetrahedron Lett. 2010, 51, 1512–1516.
10. Sebej, P.; Lim, B. H.; Park, B. S.; Givens, R. S.; Klan, P. Org. Lett. 2011, 13, 644–
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11. Park, B. S.; Jeong, S. Bull. Korean Chem. Soc. 2009, 30, 3053–3056.
12. Chang, D. J.; Nahm, K.; Park, B. S. Tetrahedron Lett. 2002, 43, 4249–4252.
13. Literak, J.; Relich, S.; Kulhanek, P.; Klan, P. Mol. Diver. 2003, 7, 265–271.
14. It is known that E-dienols can also return to starting ketones as shown in
Scheme 2. (See Iida, K.; Komada, K.; Saito, M.; Yoshioka, M. J. Org. Chem. 1999,
64, 7407–7411) This route can affect the efficiency of product formation
especially at high temperature over 150 °C. However, the contributing factor is
negligible at current temperature range, which is below 100 °C and at low
conversion.
1
2
10
15
20
25
30
35
40
45
Time (min)
15. Wagner, P. J.; Subramanyam, D.; Park, B. S. J. Am. Chem. Soc. 1991, 113, 709–
710.
Figure 2. A plot of IN/CB versus irradiation time in photolysis of 2-methylphenacyl
benzoate and 2,4,6-trimethylphenacyl benzoate at 25 °C.
16. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, M. C.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. GAUSSIAN 09, revision A.02;
Gaussian Inc.: Wallingford, CT, 2009. All stationary points such as reactant,
intermediates and transition states were optimized to the B3LYP/6-31G(d)
level. And frequency calculations were also carried out at B3LYP/6-31G(d) to
verify that the optimized structures are transition states or minima by having
one or no imaginary frequencies. The intrinsic reaction coordinate (IRC)
calculations were subsequently carried out to ensure that transition states
connect the appropriate intermediates and products on the potential, energy
surface.
exceed 40 min for complete conversion. Since the data shown in
Table 1 were taken at low conversion (<5%) of the photolysis, it
is safe to say that both contributing factors of acids and the
thermal conversion to our data are minor.
In summary, we have examined temperature effect on product
selectivity in photolysis of ortho-alkylphenacyl benzoates giving
indanones (IN) and benzocyclobutenols (CB). As temperature was
lowered, the CB was preferred over the IN and the amount of the
IN increased as temperature was elevated. Arrhenius plot of
ln(IN/CB) versus 1/T gave a straight line from which EaIN–EaCB and
AIN/ACB were obtained. The least sterically hindered 2-methylphe-
nacyl benzoate (1) gave the highest EaIN–EaCB and AIN/ACB among
the ortho-alkylphenacyl benzoates tested in this research including
2,4,6-trimethylphenacyl benzoate (2) and 2,4,6-triisopropylphena-
cyl benzoate (3). It was proved that high temperature was benefi-
cial in effective release of protecting groups and entropy factors
play an important role on temperature effect of product selectivity
especially in mono-alkyl substituted phenacyl PPG.
17. Wagner, P. J.; Zand, A.; Park, B. S. J. Am. Chem. Soc. 1996, 118, 12856–12857.
18. Fukuhara, G.; Mori, T.; Wada, T.; Inoue, Y. Chem. Commun. 2005, 4199–4201.
19. Lewis, F. D.; Johnson, R. W.; Kory, D. R. J. Am. Chem. Soc. 1974, 96, 6100–6109.
20. For a recent example of autocatalytic reaction induced by acid coproducts;
Ferrer, F. E.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133,
10161–10170.
21. Wessig, P.; Clemens, G.; Gunnar, M.; Jannek, T. J. Org. Chem. 2004, 69, 7582–
7591.
22. The CB from 1 gave only a trace amount of the IN upon thermolysis, while the
CB of 2 and 3 gave the IN as major product. The details of our thermolysis
experiments will be described elsewhere.
References and notes
1. Klan, P.; Zabadal, M.; Hegar, D. Org. Lett. 2000, 2, 1569–1571.
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