Diastereoselectivity control in photosensitized addition of methanol to (r)-(+)-limonene

Article abstract of DOI:10.1021/jo025782o

Highly diastereodifferentiating bimolecular asymmetric photoreaction was achieved in the photosensitized polar addition of methanol to (R)-(+)-limonene. The diastereomeric excess (de) of the photoadduct could be controlled and fine-tuned by changing the i

Full text of DOI:10.1021/jo025782o

Dia ster eoselectivity Con tr ol in P h otosen sitized Ad d ition of
Meth a n ol to (R)-(+)-Lim on en e†
Sang Chul Shim,*,‡ Dong Suk Kim,‡ Dong J in Yoo,§ Takehiko Wada,| and Yoshihisa Inoue*,|
Center for Molecular Design and Synthesis, Department of Chemistry and School of Molecular Science
(BK-21), Korea Advanced Institute of Science and Technology (KAIST), 373-1 Guseong-Dong, Yuseong-Gu,
Daejeon 305-701, Korea, Department of Chemistry, Seonam University, Namwon 590-711, Korea, ICORP
Entropy Control Project, J ST, 4-6-3 Kamishinden, Toyonaka 560-0085, J apan, and Department of
Molecular Chemistry, Osaka University, 2-1 Yamada-oka, Suita 565-0871, J apan
inoue@chem.eng.osaka-u.ac.jp
Received April 1, 2002
Highly diastereodifferentiating bimolecular asymmetric photoreaction was achieved in the photo-
sensitized polar addition of methanol to (R)-(+)-limonene. The diastereomeric excess (de) of the
photoadduct could be controlled and fine-tuned by changing the internal/external factors such as
solvent polarity, reaction temperature, and structure of the sensitizers. The de increased from 23%
obtained upon xylene photosensitization in pure methanol at room temperature to >96% upon
singlet sensitization with methyl benzoate at -75 °C in 0.5 M methanol/diethyl ether solution.
In tr od u ction
state, are inherently free from the temperature restric-
tions and therefore advantageous for investigating the
effect of the entropy factor upon stereoselectivity over a
wide temperature range. In the diastereodifferentiating
Paterno`-Bu¨chi photocycloaddition of optically active
phenylglyoxylic esters with several alkenes, Scharf et al.6
showed that the diastereoselectivity of the oxetane
produced not only depends on the irradiation tempera-
ture but also gives a bent Eyring plot as a consequence
of the alteration of the rate-determining step responsible
for the diastereoselectivity, which unfortunately limits
the maximum diastereomeric excess (de) below 70-75%.
We have studied the enantiodifferentiating Z-E photoi-
somerization of cyclooctene sensitized by optically active
sensitizers and observed the enhancement of the enan-
tiomeric excess (ee) by changing the irradiation temper-
ature and structure of the sensitizers. More recently, we
have revealed that the product chirality can be controlled
by changing the solvent polarity and pressure in this
photoisomerization to give ee’s of up to 74%.7
Asymmetric synthesis is a field of vital importance in
current chemistry, and a considerable amount of effort
has been devoted in recent years. High enantio- and
diastereoselectivities are the principal objectives or pre-
requisites when a new synthetic methodology is devel-
oped, or chiral compounds such as naturally occurring
compounds and pharmaceuticals are synthesized. Since
the first report on the asymmetric photosensitization of
trans-1,2-diphenylcyclopropane by Hammond and Cole,1
many studies have been carried out on the enantio- and
diastereoselective photosensitized reactions.2 The optical
yields of photosensitized reactions, however, are still low
to moderate in general.
It was recently shown that asymmetric photochemical
reactions,3-5 proceeding through the electronically excited
* Address correspondence to Y.I. Phone: +81-6-6879-7920. Fax:
+81-6-6879-7923.
† This paper is dedicated to the memory of the late Professor Sang
Chul Shim of KAIST, deceased on Apr 10, 2002.
‡ KAIST.
In the present study, the validity of our methodology
to control the stereochemical outcome of photoreaction
by changing external factors was examined in the pho-
tosensitized diastereodifferentiating addition of methanol
to (R)-(+)-limonene (1).8 Among the extensive works on
the photochemical behavior of various cycloalkene
derivatives,9-12 Kropp et al.9e reported that m-xylene-
sensitized photoreaction of 1 in methanol affords a 1:1.6
mixture of polar addition product, i.e., diastereomeric cis-
§ Seonam University.
| ICORP and Osaka University.
(1) (a) Hammond G. S.; Cole, R. S. J . Am. Chem. Soc. 1965, 87, 3256.
(b) Murov, S. L.; Cole, R. S.; Hammond, G. S. J . Am. Chem. Soc. 1965,
87, 3256.
(2) For reviews, see: (a) Rau, H. Chem. Rev. 1983, 83, 535. (b) Y.
Inoue, Chem. Rev. 1992, 92, 741. (c) Everitt, S. R. L.; Inoue, Y. In
Organic Molecular Photochemistry; Ramamurthy, V., Schanze, K. S.,
Eds.; Marcel Decker: New York, 1999; p 71. (d) Inoue, Y.; Wada, T.;
Asaoka, S.; Sato, H.; Pete, J .-P. Chem. Commun. 2000, 251.
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Tetrahedron Lett. 1999, 40, 3173. (C) Bertrand, S.; Hoffmann, N.; Pete,
J .-P. J . Org. Chem. 2000, 2227. (d) Bertrand, S.; Hoffmann, N.;
Humbel, S.; Pete, J .-P. J . Org. Chem. 2000, 65, 8690.
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Scheffer, J . R.; Trotter, J . Am. Chem. Soc. 1996, 118, 1219. (c) J oy, A.;
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J . R.; Ramamurthy, V. J . Am. Chem. Soc. 2000, 122, 728.
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10.1021/jo025782o CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/13/2002
5718
J . Org. Chem. 2002, 67, 5718-5726

Photosensitized Addition of MeOH to (R)-(+)-Limonene
SCHEME 1
CHART 1
and trans-4-isopropenyl-1-methoxy-1-methylcyclohexane
(2 and 3), and exocyclic isomer 4, as shown in Scheme 1.
The study was carried out in methanol solution at room
temperature, and a low de of 23.1% in favor of 3 was
obtained. We investigated this photosensitized diaste-
reodifferentiating polar addition reaction under a variety
of conditions by varying the solvent polarity, irradiation
temperature, and structure and spin multiplicity of the
photosensitizers to enhance the diastereoselectivity of the
reaction.
4; see runs 1-69 in Table 1.13 The diastereomeric excess
(de ) ([3] - [2])/([3] + [2])) dramatically increased from
practically 0% de in methylene chloride-30% methanol
at 25 °C to ca. 96% de in diethyl ether-0.5 M methanol
at -75 °C. Interestingly, these triplet sensitizers, toluene
and o-, m-, and p-xylene, gave comparable de’s in the
same solvent at the same temperature.14
Resu lts a n d Discu ssion
P h otosen sitized P ola r Ad d ition of Meth a n ol to
(R)-(+)-Lim on en e. The photosensitized addition reac-
tions of methanol to (R)-(+)-limonene (1) were carried out
with varying temperature (25, 0, -40, -75 °C), solvent
polarity (methanol, methylene chloride, diethyl ether, and
pentane), methanol concentration (0.5 M to 100%), and
structure of the photosensitizers (5-13; see Chart 1 and
Table 1). Photosensitization with toluene and o-, m-, and
p-xylene (5-8) under a variety of conditions gave three
major products, i.e., cis- and trans-4-isopropenyl-1-meth-
oxy-1-methylcyclohexane (2 and 3) and exocyclic isomer
Singlet photosensitizations with benzenepolycarboxy-
lates 9-13 gave the same products, but the de’s obtained
were consistently higher by 3-15% than those obtained
in the triplet sensitization under comparable conditions,
irrespective of the solvent composition and temperature
employed; see runs 70-120 in Table 1. Furthermore, the
chemical yield and product de were dependent on the
structure of the sensitizer particularly in the singlet
sensitized reaction. It is interesting that, while all of the
triplet sensitizers 5-8 give practically the same de and
yield under comparable conditions, the singlet sensitiza-
tion leads to significant deviation in de and yield depend-
ing on the sensitizer structure. For example, methyl
benzoate (9) gave 31.6% de in methanol at 25 °C, but the
more bulky singlet sensitizer tetramethyl 1,2,4,5-ben-
zenetetracarboxylate (13) gave 44.1% de under the same
conditions. The singlet sensitized reactions often involve
exciplex formation and subsequent energy transfer.7
Hence, if the methanol addition proceeds within, or
immediately after the dissociation of, the exciplex inter-
mediate, such a singlet sensitized reaction should be
strongly affected by the structural features such as the
steric bulkiness of the sensitizer.
(7) (a) Inoue, Y.; Kunitomi, Y.; Takamuku, S.; Sakurai, H. J . Chem.
Soc., Chem. Commun. 1978, 1024. (b) Inoue, Y.; Takamuku, S.;
Kunitomi, Y.; Sakurai, H. J . Chem. Soc., Perkin Trans. 2 1980, 1672.
(c) Takamuku, S.; Sakurai, H.; Inoue, Y.; Hakushi, T. J . Chem. Soc.,
Perkin Trans. 2 1980, 1678. (d) Inoue, Y.; Yokoyama, T.; Yamasaki,
N.; Tai, A. J . Am. Chem. Soc. 1989, 111, 6480. (e) Inoue, Y.;
Shimoyama, H.; Yamasaki, N.; Tai, A. Chem. Lett. 1991, 593. (f) Inoue,
Y.; Yamasaki, N.; Yokoyama, T.; Tai, A. J . Org. Chem. 1992, 57, 1332.
(g) Inoue, Y.; Yamasaki, N.; Yokoyama, T.; Tai, A. J . Org. Chem. 1993,
58, 1011. (h) Inoue, Y.; Yamasaki, N.; Shimoyama, H.; Tai, A. J . Org.
Chem. 1993, 58, 1785. (i) Tsuneishi, H.; Hakushi, T.; Inoue, Y. J . Chem.
Soc., Perkin Trans. 2 1996, 1601. (j) Inoue, Y.; Tsuneishi, H.; Hakushi,
T.; Tai, A. J . Am. Chem. Soc. 1997, 119, 472. (k) Inoue, Y.; Matsushima,
E.; Wada, T. J . Am. Chem. Soc. 1998, 120, 10687. (l) Hoffmann, R.;
Inoue, Y. J . Am. Chem. Soc. 1999, 121, 10702. (m) Inoue, Y.; Ikeda,
H.; Kaneda, M.; Sumimura, T.; Everitt, S. R. L.; Wada, T. J . Am. Chem.
Soc. 2000, 122, 406.
(8) Kim, D. S.; Shim, S. C.; Wada, T.; Inoue, Y. Tetrahedron Lett.
2001, 42, 4341.
(9) (a) Kropp, P. J . J . Am. Chem. Soc. 1966, 88, 4092. (b) Kropp, P.
J .; Krauss, H. J . J . Am. Chem. Soc. 1967, 89, 5199. (c) Kropp, P. J . J .
Am. Chem. Soc. 1969, 91, 5783. (d) Kropp, P. J .; Krauss, H. J . J . Am.
Chem. Soc. 1969, 91, 7466. (e) Kropp, P. J . J . Org. Chem. 1970, 35,
2435. (f) Kropp, P. J . J . Am. Chem. Soc. 1973, 95, 4611. (g) Kropp, P.
J . Org. Photochem. 1979, 4, 1.
(10) (a) Marshall, J . A.; Wurth, J . M. J . Am. Chem. Soc. 1967, 89,
3788. (b) Marshall, J . A. Acc. Chem. Res. 1969, 2, 33. (c) Marshall, J .
A.; Hochstetler, A. R. J . Am. Chem. Soc. 1969, 91, 648. (d) Marshall,
J . A. Science 1970, 170, 137.
(11) (a) Bonneau, R.; J oussot-Dubien, J .; Yarwood, J .; Pereyre, J .
Tetrahedron Lett. 1977, 235. (b) Bonneau, R. F. d. V., Philippe C. R.
Hebd. Seances Acad. Sci., Ser. C 1977, 284, 631. (c) Bonneau, R. F. d.
V., P.; J oussot-Dubien, J . Nouv. J . Chim. 1977, 1, 31. (d) Bonneau, R.
J .-D., J .; Salem, L.; Yarwood, A. J . J . Am. Chem. Soc. 1976, 98, 4329.
(e) Schuster, D. I. B., R.; Dunn, D. A.; Rao, J . M.; J oussot-Dubien, J .
J . Am. Chem. Soc. 1984, 106, 2706.
(12) Aguiar, A. M.; Aguiar, H. J . Am. Chem. Soc. 1966, 88, 4901.
Shigemitsu, Y.; Arnold, D. R. J . Chem. Soc., Chem. Commun. 1975,
407.
Solven t P ola r it y a n d Tem p er a t u r e E ffect s. The
relationship between the solvent polarity and the product
de was investigated by using solvents of different polari-
ties, i.e. methanol, methylene chloride, and diethyl ether.
The de’s obtained upon triplet sensitization with m-
xylene in diethyl ether and methylene chloride at 25,
(13) For a review, see: (a) Verghese, J . Perfum. Essent. Oil Rec.
1968, 59, 439. (b) Kuczynski, L.; Kuczynski, H. Rocz. Chem. 1951, 25,
432.
(14) (a) Cundall, R. B. Prog. React. Kinet. 1964, 2, 165. (b) Ham-
mond, G. S.; Turro, N. J .; Leermakers, P. A. J . Phys. Chem. 1962, 66,
1144. (c) Testa, A. C. J . Org. Chem. 1964, 29, 2461. (d) Morrison, H.
Tetrahedron Lett. 1964, 3653. (e) Nozaki, H.; Nisikawa, Y.; Kamatani,
Y.; Noyori, R. Tetrahedron Lett. 1965, 2161.
J . Org. Chem, Vol. 67, No. 16, 2002 5719

Shim et al.
TABLE 1. Dia ster eod iffer en tia tin g P h otoa d d ition of Meth a n ol to (R)-(+)-Lim on en ea Sen sitized by 5-13 in Va r iou s
Solven ts a t 25, -40, a n d -75 °C
yieldd/%
2 + 3
entry
sensitizerb
solvent
[methanol]
30%
temp/°C
conversnc/%
4
dee/%
1
2
3
4
5
6
7
8
9
5
CH2Cl2
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
25
0
-40
-75
25
25
25
25
25
89.5
93.1
92.3
90.0
93.0
90.7
73.9
90.2
91.5
82.9
70.0
93.5
99.0
99.0
99.0
66.6
86.2
92.6
99.0
98.0
95.7
88.6
96.7
98.7
98.0
95.5
80.4
97.0
74.9
99.0
99.0
93.3
93.1
93.3
99.0
96.6
83.7
86.1
98.4
94.1
89.9
91.8
94.1
94.1
92.3
93.7
92.7
79.6
88.0
95.3
94.5
81.3
41.9
95.4
96.7
84.1
89.6
90.4
94.0
88.3
89.1
84.6
96.1
80.0
99.0
99.0
95.3
81.0
97.8
99.0
91.2
9.3
10.5
10.8
37.0
37.0
33.8
39.2
30.4
26.6
7.4
12.5
23.5
38.9
39.8
37.3
38.1
32.7
22.0
6.8
37.6
50.2
51.7
42.2
49.2
50.4
4.6
-0.7
2.7
7.4
29.4
36.4
44.3
68.8
80.5
91.6
2.4
CH3OH
Et2O
100%
0.5 M
30%
7.5
11.3
30.4
31.7
45.4
44.9
51.4
55.9
3.7
10
11
12
13
14
15
16
17
18
23
19
20
21
22
24
25
26
27
28
29
30
31
32
33
34
35
36
37
28
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
6
CH2Cl2
CH3OH
Et2O
2.4
6.8
28.2
37.1
45.8
70.6
79.6
90.6
8.4
-2.8
-1.7
2.3
0.5 M
5.7
7.6
7
CH2Cl2
50%
30%
33.2
33.9
46.2
48.8
48.2
36.8
33.4
30.5
20.8
40.4
29.3
42.8
40.9
29.5
29.2
36.8
33.9
30.0
28.3
31.2
28.4
25.8
22.3
22.8
19.0
22.3
18.4
17.7
16.3
14.7
10.0
16.9
11.7
7.0
8.1
13.8
19.2
30.5
7.2
8.3
20%
10%
5%
0.5 M
100%
-0.6
-2.4
-2.5
-2.5
28.1
30.3
36.6
46.7
29.2
29.9
33.8
40.6
30.2
30.5
33.0
41.3
31.0
32.1
41.5
51.0
31.7
33.2
49.3
65.7
43.3
45.8
60.0
77.4
52.4
63.8
74.3
86.3
65.6
69.2
75.5
79.5
92.1
0.5
9.5
10.4
15.5
32.8
24.9
32.6
27.4
40.3
37.4
41.4
40.4
48.9
46.6
40.0
39.8
46.4
51.6
40.5
33.4
47.0
57.8
35.5
30.8
32.8
52.5
33.2
27.2
47.0
27.0
23.5
25.1
55.6
52.8
50.7
47.3
18.2
8.9
CH3OH
Et2O
0
-40
-75
25
50%
40%
30%
20%
10%
5%
0
-40
-75
25
0
-40
-75
25
0
-40
-75
25
0
-40
-75
25
0
-40
-75
25
0
8.5
-40
-75
25
11.2
10.6
5.4
5.6
7.3
0.5 M
0
-20
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
9.6
9.2
8
CH2Cl2
CH3OH
Et2O
30%
37.8
46.5
50.9
37.5
51.4
53.0
5.4
6.2
7.8
46.9
37.9
17.2
26.3
32.9
37.8
35.0
51.4
28.9
24.8
15.7
18.8
2.7
7.7
100%
0.5 M
30%
29.5
37.9
46.9
59.1
80.9
87.1
0.6
9
CH2Cl2
-40
4.6
5720 J . Org. Chem., Vol. 67, No. 16, 2002

Photosensitized Addition of MeOH to (R)-(+)-Limonene
Ta ble 1 (Con tin u ed )
yieldd/%
2 + 3
entry
sensitizerb
solvent
CH3OH
[methanol]
100%
temp/°C
conversnc/%
4
dee/%
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
-40
-75
25
87.1
98.0
90.0
95.0
91.0
93.8
93.9
99.0
97.0
92.5
61.1
39.4
46.2
34.2
36.9
35.5
16.6
25.7
34.6
90.9
60.5
53.5
97.0
68.9
63.4
99.0
75.4
74.3
88.1
67.5
92.5
71.2
46.8
56.2
50.5
43.2
37.7
60.9
40.0
49.9
67.8
52.0
51.9
57.7
47.4
30.0
36.6
50.1
52.1
22.4
24.8
19.1
25.0
53.1
40.1
27.5
53.1
30.7
10.2
3.5
1.6
1.5
2.0
1.6
2.1
3.8
2.1
1.0
31.2
30.0
23.4
34.1
26.4
20.5
22.4
9.1
16.1
11.8
12.2
3.0
2.8
2.5
2.2
2.5
f
11.1
31.6
40.9
48.7
34.3
42.5
56.5
77.9
93.9
96.3
-2.6
5.2
18.9
39.1
48.6
57.9
f
Et2O
30%
0.5 M
30%
10
CH2Cl2
CH3OH
Et2O
100%
0.5 M
30%
f
f
f
f
11
CH2Cl2
CH3OH
Et2O
12.7
8.8
9.2
39.5
16.7
13.0
22.2
12.5
15.8
26.2
10.6
9.2
9.4
8.1
11.9
16.7
5.3
8.2
5.2
5.0
5.9
2.2
1.3
1.8
2.4
1.6
1.3
1.6
1.4
f
2.6
5.5
21.1
33.4
43.6
51.1
32.8
45.3
60.8
80.3
92.1
96.1
10.8
4.5
11.9
38.4
50.5
57.2
64.1
f
f
0
5.2
10.4
44.1
48.4
f
f
f
100%
30%
18.4
10.5
11.5
54.7
15.8
12.3
46.9
20.8
10.2
4.3
2.4
4.5
3.6
3.7
3.8
18.4
4.0
2.9
0.8
0.8
1.0
1.3
1.0
0.5
2.3
1.4
0.8
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
0.5 M
30%
12
CH2Cl2
CH3OH
Et2O
100%
0.5 M
30%
13
CH2Cl2
CH3OH
Et2O
100%
0.5 M
f
f
f
-20
-40
f
a
b
d
[Substrate] ) 5 mM. [Sensitizer] ) 2 mM; reaction scale 2 mL. c Loss of starting material determined by GC. Chemical yield
determined by GC on the basis of the initial concentration of substrate. e de ) ([3] - [2])/([3] + [2]). f Value not determined.
-40, and -75 °C are plotted against the methanol
concentration in Figure 1. The de profile at each tem-
perature shows a critical dependence on the solvent
polarity and methanol concentration particularly at low
methanol concentrations below 20%. At 25 °C, the de
increases only slightly from 28.1% in neat methanol to
31.7% in 20% methanol-ether, but rapidly to 43.3%,
52.4%, and then 65.6% with decreasing methanol content
to 10%, 5%, and finally 0.5 M (ca. 1.7%), respectively. As
can be seen from Figure 1 and Table 1, the irradiation
at lower temperatures gave significantly enhanced de’s
at all methanol concentrations examined. Thus, the de
curves (Figure 1) resemble each other, but are signifi-
cantly lifted upward and become appreciably gentle by
decreasing the temperature. Unexpectedly, the use of
apparently less polar methylene chloride as solvent led
to the complete losses of de (<3%) at low methanol
concentrations (<30%), although the photoreaction in
50% methanol-methylene chloride gave 8.4% de.
As expected from the highly ionic nature of the
intermediate involved in this polar photoaddition, the
solvent polarity significantly affected the product de. The
use of polar solvents is thought to be essential for high
chemical yields, which however often leads to low product
de, as exemplified in Table 1. To elucidate the nature of
the solvent effect and also to optimize the solvent system,
we carried out the m-xylene photosensitizations in polar
and nonpolar solvents at 25 °C (Table 2). Relatively high
de values of up to 53-54% were obtained in nonpolar
pentane and methylcyclohexane solutions containing 0.5
M methanol, while low de was obtained in polar solvents,
i.e., 9.6% de in 1,4-dioxane-30% methanol and 18.1% de
J . Org. Chem, Vol. 67, No. 16, 2002 5721

Shim et al.
F IGURE 1. Effect of methanol concentration on the product
de upon photoaddition of methanol to (R)-(+)-limonene (1)
sensitized by m-xylene (7) in ether at 25, -40, and -75 °C
and in methylene chloride at 25 °C.
F IGURE 2. Temperature effects on the product de obtained
upon sensitization with m-xylene (7) (9), methyl benzoate (9)
(2), and dimethyl phthalate (10) (b).
TABLE 2. Solven t Effects on P r od u ct
Dia ster eoselectivity u p on P h otosen sitiza tion of
(R)-(+)-Lim on en e (1) w ith m -Xylen e (7) a t Differ en t
Tem p er a tu r es
The photosensitized polar addition was investigated at
various temperatures between +25 and -75 °C, employ-
ing alkylbenzenes 5-8 and benzenepolycarboxylates
9-11 as sensitizers, and the results are shown in Tables
1 and 2. To analyze the temperature effect on the
differential activation parameters more quantitatively,
the natural logarithm of the relative formation rate of 3
and 2, ln(k3/k2) ) ln[(100 + de)/(100 - de)], is plotted
against the reciprocal temperature, 1/T, to give a good
straight line (average r2 ) 0.97) for all sensitizers and
solvents employed, as exemplified in Figure 2.
de/%
solvent
pentane
heptane
methylcyclohexane 0.00
hexane
diethyl ether
acetonitrile
methylene chloride 0.82
π* a [methanol] 25 °C -40 °C -75 °C
0.00
0.00
0.5 M
0.5 M
0.5 M
30%
53.3
56.5
53.6
33.0
31.0
18.1
-2.8
70.6
66.8
70.0
40.0
33.6
23.7
2.3
81.6
80.6
80.4
b
55.0
32.4
8.3
0.00
0.27
0.75
30%
30%
30%
Obviously, the singlet and triplet sensitizers afford
different lines particularly at low methanol contents, and
both the slope (-∆∆Hq/R) and intercept (∆∆Sq/R) become
greater as the solvent π* value decreases from 30%
methanol in methylene chloride to 30% methanol in
diethyl ether and then to 0.5 M methanol in diethyl ether.
Consequently, high product de can be achieved by using
low π* solvents at low reaction temperatures, for which
the enthalpic and entropic terms are jointly responsible
as discussed below.6,7
Activa tion P a r a m eter s. From the Eyring treatment
of the temperature-dependent de, we can calculate the
differential activation enthalpy and entropy (∆∆Hq and
∆∆Sq) of diastereodifferentiation for each combination of
sensitizer and solvent, by using eq 1,
a
π* ) solvent polarizability parameter as a measure of the
ability of solvent to stabilize a charge or dipole by virtue of its
dielectric effect. Not determined.
b
in acetonitrile-30% methanol. The global profile of the
de values obtained in the diverse solvents does not
correlate with those of the dielectric constant, dipole
moment, or solvent polarity parameters (such as ET or
Z) of solvents, but nicely coincides with the trend of the
charge stabilization capability parameter (π*), with the
exception of 1,4-dioxane (π* ) 0.55).15 Thus, the product
de at 25 °C in 30% methanol solution gradually increases
in general with decreasing π* values of pure solvents in
the order -3% de in methylene chloride (π* ) 0.82) to
18% de in acetonitrile (0.75), 28% de in pure methanol
(0.60), 31% de in diethyl ether (0.27), and 53-54% de in
0.5 M methanol solution in pentane and methylcyclo-
hexane (0.00).
ln(k3/ k2) ) -∆∆Hq/RT + ∆∆Sq/R
(1)
The acid-catalyzed addition of methanol to limonene
1 was carried out in the dark in 0.5 M methanol-diethyl
ether at 25 °C in the presence of 0.1 M sulfuric acid to
test the protonated intermediate. A complex mixture was
obtained,11d,16 but the product de was practically zero.
This result is in sharp contrast to the high de of 65.6%
obtained photochemically in neutral diethyl ether con-
taining 0.5 M methanol (run 56), and clearly indicates
that the thermal protonation gives quite different, poor
diastereoselectivity.
which is similar to that derived for the photosensitized
enantiodifferentiation.7 The ∆∆Hq and ∆∆Sq values thus
obtained are listed in Table 3. In all cases examined, both
of the ∆∆Hq and ∆∆Sq values are negative and there
exists the compensatory enthalpy-entropy relationship,
giving a linear ∆∆Hq-∆∆Sq plot with a relatively good
correlation coefficient (r2 ) 0.91). This indicates that a
single diastereodifferentiation mechanism is operative
and the process is governed simultaneously by the two
(16) (a) Inoue, Y.; Ueoka, T.; Kuroda, T.; Hakushi, T. J . Chem. Soc.,
Chem. Commun. 1982, 1076. (b) Greenberg, A.; Liebman, J . F. Strained
Organic Molecules; Academic: New York, 1978, Chapter 3. (c) Kresge,
A. J .; Chiang, Y.; Fitzgerald, P. H.; McDonald, R. S.; Schmid, G. H. J .
Am. Chem. Soc. 1971, 93, 4907.
(15) (a) Inoue, Y.; Takamuku, S.; Sakurai, H. J . Chem. Soc., Perkin
Trans. 2 1977, 1635. (b) Inoue, Y.; Ueoka, T.; Kuroda T.; Hakushi, T.
J . Chem. Soc., Perkin Trans. 2 1983, 983. (c) Inoue, Y.; Ueoka, T.;
Hakushi, T. J . Chem. Soc., Perkin Trans. 2 1984, 2053.
5722 J . Org. Chem., Vol. 67, No. 16, 2002

Photosensitized Addition of MeOH to (R)-(+)-Limonene
TABLE 3. Differ en tia l Activa tion P a r a m eter s for
Dia ster eod iffer en tia tin g P h otoa d d ition of Meth a n ol to
(R)-(+)-Lim on en e Sen sitized by 5-12 in Meth a n ol or
Meth a n ol-Dieth yl Eth er Mixtu r e a t 25 °C
100% MeOH
30% MeOH
0.5 M MeOH
sensitizer ∆∆Hq a ∆∆Sq b ∆∆Hq a ∆∆Sq b ∆∆Hq a ∆∆Sq b
5
6
7
8
9
10
11
12
-0.11
-0.13
-0.17
-0.13
-0.13
-0.15
-0.14
-0.16
-0.16
-0.48
-1.05
-0.41
-0.32
-0.32
-0.34
-0.32
-0.46
-0.39
-0.45
-0.42
-0.61
-2.38
-1.51
-3.13
-2.42
-3.16
-0.16
-0.18
-0.77
-0.85
-0.23
c
-1.55
c
-0.54
c
-2.29
c
a
b
In kcal/mol. In cal/(mol K). c Not determined.
F IGURE 4. Fluorescence spectra of tetramethyl 1,2,4,5-
benzenetetracarboxylate (13) excited at 270 nm in methanol
solution in the presence of varying concentrations of limonene
1: 0, 7.5, 15, 22.5, and 30 mM (from top to bottom).
F IGURE 3. Fluorescence spectra of m-xylene (7) excited at
280 nm in methylene chloride-30% methanol solution in the
presence of varying concentrations of limonene 1: 0, 7.5, 15,
22.5, 30, 37.5, and 45 mM (from top to bottom).
factors (∆∆Hq and ∆∆Sq) with equal significance.7 In
polar solvents, the |∆∆Hq| and |∆∆Sq| values are well less
than 0.2 kcal/mol and 1 cal/(mol K), respectively. In
contrast, much larger |∆∆Hq| and |∆∆Sq| values of 0.4-
0.7 kcal/mol and 1.5-5.6 cal/(mol K) were obtained in less
polar 0.5 M methanol-diethyl ether, which enable us to
obtain de’s in such a low polarity solvent at low temper-
atures as high as 96%.
F lu or escen ce Qu en ch in g. To elucidate the excited
state and mechanism involved in this photosensitized
polar addition, fluorescence quenching experiments were
carried out with representative triplet and singlet sen-
sitizers 7 and 13 in nondegassed pentane, methanol, and
methylene chloride at 25 °C. The sensitizer fluorescence
was quenched effectively in each case by adding substrate
1. Typical quenching behaviors of 7 and 13 in three
solvents are shown in Figures 3 and 4. A very weak, but
appreciable, new emission was observed at longer wave-
lengths upon fluorescence quenching of 13 by 1 (Figure
4), which may be attributed to the exciplex fluorescence.
According to the Stern-Volmer equation for fluores-
cence quenching (eq 2), the relative fluorescence intensity
(IF°/IF) in the presence and absence of substrate is plotted
F IGURE 5. Stern-Volmer plots for the fluorescence quench-
ing of 7 by 1 in pentane-0.5 M methanol (9), 7 by 1 in
methanol solution (b), 7 by 1 in methylene chloride-30%
methanol (1), and 13 by 1 in methanol solution ([).
TABLE 4. F lu or escen ce Qu en ch in g P a r a m eter s
Obta in ed for Sen sitizer s 7 a n d 13 in th e P r esen ce of
(R)-(+)-Lim on en e (1)
kQτ0/
τ0/
kQ/
sensitizer
7
solvent
[methanol]
M-1
ns
109 M-1 s-1
n-C5H12
CH3OH
CH2Cl2
CH3OH
0.5 M
100%
30%
17.9
14.4
6.0
11.8
9.7
8.6
1.52
1.48
0.70
14.4
13
100%
7.2
0.5
From the Stern-Volmer constant (kQτ0) obtained as a
slope of the plot and the fluorescence lifetime (τ0)
determined independently by the single-photon-counting
technique, the apparent quenching rate constant (kQ) for
each sensitizer in each solvent can be calculated. The
results are summarized in Table 4.
The quenching rate constant (kQ) obtained for m-xylene
sensitizer (7) is smaller by a factor of 10-20 than that
for benzenetetracarboxylate sensitizer 13, the latter of
which is almost comparable to the diffusion-controlled
rate constant in methanol (kdiff ) 1.8 × 1010 M-1 s-1).
These rate constants clearly indicate that the singlet
IF°/IF ) 1+ kQτ0[Q]
(2)
as a function of the concentration of added 1 to afford an
excellent straight line for each combination of the sen-
sitizer and solvent examined, as shown in Figure 5.
J . Org. Chem, Vol. 67, No. 16, 2002 5723

Shim et al.
SCHEME 2
CHART 2. MM2-Op tim ized Str u ctu r es of (Z)- a n d
(E)-Lim on en es
and 3 or undergoes deprotonation to exocyclic isomer 4
(Scheme 2). In polar solvents, this mechanism is quite
reasonable because the carbocation 15 can be stabilized
in such solvents. However, the diastereoselectivity, at-
tained upon the initial photoisomerization step, must be
diminished or completely reset to zero in 15, and the
subsequent methanol attack will occur from both sides
of the carbocation, probably at similar rates, ultimately
giving the final products in a low de. On the contrary,
the mechanism incorporating the carbocation 15 is not
realistic in nonpolar solvents, since the free carbocation
is no longer stabilized through the ion-dipole interaction
or solvation, and hence such high de’s (of up to 96%) are
not expected to be obtained from the addition to 15. It
should be noted that the product de obtained in low-
polarity solvents, such as diethyl ether, critically depends
on the structure of the, particularly singlet, sensitizer
employed. Thus, the substitution pattern of the sensitizer
obviously affects the product de; i.e., p-xylene and
terephthalate give appreciably lower de’s than the cor-
responding o- and m-analogues.
To rationalize all of the above observations in less polar
solvents, the pair of strongly hydrogen bonded species
(R)- and (S)-16 are proposed as plausible intermediates
(Scheme 2). They are diastereomeric to each other and
preserve the original de of 14 generated photochemically.
The backside attack of methanol to (R)- and (S)-16 affords
adducts 3 and 2, respectively, along with the deprotona-
tion product 4. It is crucial that there is no common
intermediate or interconversion process involved in the
mechanism, which is compatible with the distinctly
different de’s observed for each sensitizer. This mecha-
nism can justify the effects of solvent polarity and
reaction temperature on the de value (Table 2).17 The
high π* value of methylene chloride or acetonitrile will
stabilize the carbocation 15 and result in a low de value,
whereas the low π* value of diethyl ether or pentane will
prefer the charge-dispersed intermediate 16 and lead to
a high de value. At low temperatures, the hydrogen-
bonding interaction is strengthened and the attack to the
less hindered (R)-16 is more favored, both of which
accelerate the formation of the major product 3, giving a
higher de value.
sensitization with 13 is extremely efficient while the
corresponding process with xylene 7 is 10-20 times less
efficient and therefore the triplet sensitization is more
favored, although the singlet path cannot be completely
ruled out particularly at high substrate concentrations.
Mech a n ism . From the fluorescence quenching experi-
ments and the different de values obtained upon sensi-
tization with alkylbenzene 7 and benzenepolycarboxylate
13, intervention of two discrete mechanisms is proposed
for the singlet- and triplet-photosensitized methanol
addition to limonene.
In the triplet sensitization, the first step is the geo-
metrical photoisomerization16 of limonene to the highly
strained trans-isomer, which is followed by protonation
of the resulting reactive intermediate by methanol. This
mechanism was supported by the studies on photoi-
somerization of cycloheptene and 1-phenylcyclohexene,
which clearly demonstrate the intervention of a highly
strained ground-state intermediate possessing a lifetime
much longer than that expected for an electronically
excited state.16 In the present case, the photosensitized
geometrical isomerization of cis-limonene 1 as the first
step of the photoaddition produces two diastereomeric
trans-limonenes, (R)- and (S)-14, as reactive intermedi-
ates, as illustrated in Scheme 2. MM2 calculations
revealed that (R)- and (S)-14 have different steric ener-
gies (SEs) of 38.4 and 41.0 kcal/mol, which are 32-35
kcal/mol higher than that of 1 (SE ) 5.9 kcal/mol) (Chart
2). (R)- and (S)-14 isomers possessing different steric
energies and dipole moments are produced photochemi-
cally in different ratios depending on the solvent polarity
and irradiation temperature.
In the singlet sensitization, relatively higher de values
were obtained in general compared to the triplet-
sensitized reactions, particularly in less polar solvents
(17) We cannot rigorously exclude the involvement of a trace amount
of photoproduced hydrogen chloride in the formation of photoproducts
upon irradiation in methylene chloride, which may lead to the low de
values.
The second step is the protonation of highly strained
trans-isomers 14, producing a common intermediate (15),
which is in turn attacked by methanol to give adducts 2
5724 J . Org. Chem., Vol. 67, No. 16, 2002

Photosensitized Addition of MeOH to (R)-(+)-Limonene
SCHEME 3
demonstrated that the diastereoselectivity of the photo-
addition reaction can be critically controlled and fine-
tuned by several internal/external factors such as sen-
sitizer structure, solvent polarity, and reaction tempera-
ture, and also that the product de can be enhanced from
almost zero to >96% by optimizing these entropy-related
factors. The idea of “entropy control” was originally
proposed for the enantiodifferentiating photoisomeriza-
tion, involving weakly interacting exciplex intermedi-
ates,7 but is now shown to be applicable also to the
photochemical diastereodifferentiation in a more explicit
way, giving very high de’s. Probably, the same methodol-
ogy utilizing the entropy-related factors can be used
rather widely not only for photochemical but also for
thermal reactions and even for biochemical reactions, as
far as the weak interactions are involved in the critical
step or intermediate.
Exp er im en ta l Section
Gen er a l P r oced u r es. High-resolution mass spectra were
determined. Fluorescence lifetimes were measured with a 1
× 10-5 M solution of sensitizer in deaerated pentane, metha-
nol, and methylene chloride by means of the time-correlated
single-photon-counting method on an instrument equipped
with a pulsed H2 light source. The light source from the lamp
was made monochromatic by a 10-cm monochromator, and the
emission from the sample solution was detected through a
filter.
such as diethyl ether. The fluorescence of singlet sensi-
tizer 13 was quenched very efficiently by limonene
despite its spectroscopic (“vertical”) singlet energy being
higher than that of 13, indicating the intervention of a
singlet exciplex. The singlet-sensitized enantiodifferen-
tiating photoisomerization of cis-cyclooctene with opti-
cally active benzenepolycarboxylates is known to give the
chiral trans-isomer in good to excellent ee’s, which are
much higher than those obtained in the triplet sensitiza-
tion with optically active alkyl aryl ethers.7 Such high
ee’s are reasonably accounted for in terms of the intimate
chiral sensitizer-substrate interactions in the exciplex
intermediate (Scheme 3). In the present case, we can also
expect similar, or even more, intimate interactions
between the singlet sensitizer and limonene in nonpolar
solvents, since the latter is more electron rich than
unsubstituted cyclohexene. However, as the reaction
medium becomes polar, the radical ionic character of the
exciplex increases and the chiral sensitizer-substrate
interactions become weaker, leading to a lower de in 14.
In highly polar solvents, the reaction proceeds through
a very loose exciplex, which is similar to intermediate
15, and the stereochemical outcomes from the singlet and
triplet sensitizations become similar, equally giving low
de’s, as described above. Another evidence of an exciplex
intermediate in singlet sensitization is the change of the
chemical yield and reaction conversion by changing the
structure of the sensitizers. As shown in Table 1, pho-
tosensitization with methyl benzoate (9) gives 99%
conversion in 30% methylene chloride at 25 °C, but that
with bulky sensitizers, such as tetramethyl 1,2,4,5-
benzenetetracarboxylate (13), gives 67.8% conversion
upon irradiation for the same time and under the same
reaction conditions. This result indicates that the singlet-
sensitized reactions proceed through an exciplex inter-
mediate and the exciplex formed plays a critical role in
controlling the diastereomeric differentiation. Tempera-
ture and solvent polarity effects are also readily rational-
ized by the exciplex formation as described above.
The diastereomeric excess of the photoproduct was deter-
mined by gas chromatograpy over a 30-m capillary column
(PEG) at 50-120 °C.
Ma ter ia ls. Pentane was stirred over concentrated sulfuric
acid until the acid layer no longer turned yellow, washed with
water, neutralized with aqueous sodium bicarbonate, dried
over sodium sulfate, and distilled. Diethyl ether was refluxed
over potassium hydroxide and distilled from sodium. Methanol
was fractionally distilled from magnesium turnings. Methylene
chloride was refluxed over calcium hydride and distilled from
magnesium turnings. (R)-(+)-Limonene was purified by distil-
lation, followed by column chromatography on activated
alumina. Toluene and o-, m-, and p-xylene were shaken with
concentrated sulfuric acid and then with water, dried over
P2O5, distilled over sodium, and finally purified by column
chromatography on activated alumina. Methyl benzoate was
purified by fractional distillation. Dimethyl phthalate, dim-
ethyl isophthalate, and dimethyl terephthalate were purified
by recrystallization from methanol. Tetramethyl 1,2,4,5-ben-
zenetetracarboxylate was prepared from the corresponding
dianhydride and methanol and was purified by column chro-
matography over silica gel and the subsequent recrystallization
from methanol.
P h otolysis. All the irradiations were performed in
a
temperature-controlled water (25 °C), methanol-2-propanol
(0 and -40 °C), or methanol-ethanol (-75 °C) bath. The light
source employed was a conventional 300 W high-pressure
mercury arc lamp fitted with a Vycor sleeve. A solution (2 mL),
containing limonene 1 (5 mM), sensitizer 5-13 (2 mM), and
dodecane (5 mM) added as an internal standard, was irradi-
ated under an argon atmosphere in a quartz tube (1 cm i.d.)
placed near the lamp surface, the whole system being im-
mersed in the cooling bath.
For product isolation and identification, a preparative-scale
irradiation was run. A methanol solution (300 mL) of 1 (0.5
M) was irradiated at 25 °C for 2 h. The photolyzed solution
was evaporated to give a residue, from which products 2-4
were isolated by preparative gas chromatography.
Con clu sion
Da ta for cis-4-Isop r op en yl-1-m eth oxy-1-m eth ylcyclo-
h exa n e (2): H NMR (CDCl3, 400 MHz) δ 4.66 (s, 2H), 3.21
(s, 3H), 1.86 (t, 1H, J ) 12 Hz), 1.74 (s, 2H), 1.70 (s, 2H), 1.69
J . Org. Chem, Vol. 67, No. 16, 2002 5725
1
In this study on the photosensitized diastereodiffer-
entiating addition of methanol to limonene, we have

Shim et al.
(s, 3H), 1.45 (t, 2H, J ) 15 Hz), 1.31 (t, 2H, J ) 15 Hz), 1.16
(s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 149.7, 108.4, 74.5,
48.4, 44.6, 36.2, 28.4, 21.1, 20.5 ppm; HRMS (M+) m/z calcd
for C11H20O 168.1514, found 168.1554.
1H, J ) 6 Hz), 2.03 (m, 4H), 1.69 (s, 3H), 1.29-1.23 (m, 4H)
ppm; 13C NMR (CDCl3, 100 MHz) δ 150.1, 149.3, 108.4, 106.9,
45.0, 34.8, 33.0, 20.8 ppm; HRMS (M+) m/z calcd for C10H16
136.1252, found 136.1255.
Da t a for tr a n s-4-Isop r op en yl-1-m et h oxy-1-m et h yl-
1
cycloh exa n e (3): H NMR (CDCl3, 400 MHz) δ 4.66 (s, 2H),
3.19 (s, 3H), 1.86(t, 1H, J ) 12 Hz), 1.74(s, 2H), 1.70 (s, 2H),
1.69 (s, 3H), 1.45 (t, 2H, J ) 15 Hz), 1.31(t, 2H, J ) 15 Hz),
1.16(s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 149.7, 108.4,
74.5, 48.4, 44.6, 36.2, 28.4, 21.1, 20.5 ppm; HRMS (M+) m/z
calcd for C11H20O 168.1514, found 168.1554.
Ack n ow led gm en t. This work was supported by the
Center for Molecular Design and Synthesis (KOSEF)
and School of Molecular Science (BK-21).
Da ta for 1-Isop r op en yl-4-m eth ylen ecycloh exa n e (4):
1H NMR (CDCl3, 400 MHz) δ 4.66 (s, 2H), 4.59 (s, 2H), 2.31(t,
J O025782O
5726 J . Org. Chem., Vol. 67, No. 16, 2002