Compelled orientational control of the solid-state photodimerization of trans-cinnamamides: Dicarboxylic acid as a non-covalent linker

Article abstract of DOI:10.1016/S0040-4020(00)00505-6

The 2:1 hydrogen-bonded cocrystals 1a·ox, la·su, 1a·pht, 1a·fu, 1b·ox, 1c·ox, 1d·ox between trans-cinnamamides (1a-1d) and dicarboxylic acids (ox, su, gl, fu, pht) were prepared and characterized by IR and powder X-ray techniques. The crystal structures of 1a·pht, 1a·ox and 1a·fu were solved by single crystal X-ray diffraction. Phthalic acid (pht) caused β-type photodimerization of trans-cinnamamide (1a) in the cocrystal and functioned as a non-covalent linker like gauche 1,2-diamines in photodimerization of trans-cinnamic acids. Oxalic acid (ox) enforced 1a to take a bilayer structure that is suitable for β-type photodimerization. In the case of fumaric acid (fu), cross photodimerization with 1a occurred to give a cycloadduct 4. For the cocrystals 1a·pht and 1a·fu, pedal-like motion was assumed to occur prior to the dimerization. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00505-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6833±6844
Compelled Orientational Control of the Solid-State
Photodimerization of trans-Cinnamamides: Dicarboxylic Acid as
a Non-covalent Linker
b
b
Yoshikatsu Ito,a, Hiroyuki Hosomi and Shigeru Ohba
*
aDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 606-8501, Japan
bDepartment of Chemistry, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan
Received 17 November 1999; accepted 17 February 2000
AbstractÐThe 2:1 hydrogen-bonded cocrystals 1a´ox, 1a´su, 1a´pht, 1a´fu, 1b´ox, 1c´ox, 1d´ox between trans-cinnamamides (1a±1d) and
dicarboxylic acids (ox, su, gl, fu, pht) were prepared and characterized by IR and powder X-ray techniques. The crystal structures of 1a´pht,
1a´ox and 1a´fu were solved by single crystal X-ray diffraction. Phthalic acid (pht) caused b-type photodimerization of trans-cinnamamide
(1a) in the cocrystal and functioned as a non-covalent linker like gauche 1,2-diamines in photodimerization of trans-cinnamic acids. Oxalic
acid (ox) enforced 1a to take a bilayer structure that is suitable for b-type photodimerization. In the case of fumaric acid (fu), cross
photodimerization with 1a occurred to give a cycloadduct 4. For the cocrystals 1a´pht and 1a´fu, pedal-like motion was assumed to
occur prior to the dimerization. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
was demonstrated by formation of, e.g. a 2:1 hydrogen-
bonded cocrystal between benzamide and succinic acid.9
Recently, we have explored compelled orientational control
of the solid-state photodimerization of particular
compounds like trans-cinnamic acids and anthracene-
carboxylic acids.1±7 Our strategy is based on crystalline
double salt formation with diamines, which are used as a
supramolecular linker to connect two acid molecules in a
sort of pre-designed orientation. A series of diamines were
investigated. As a result of these studies, it was disclosed
that trans- and cis-cyclohexane-1,2-diamines or gauche 1,2-
diamines were useful linkers for preparing double salts of
unusual photoreactivity. Evidently, photoreactive overlap
con®gurations are more likely to happen to the gauche
conformation of 1,2-diamine.
Results and Discussion
A 2:1 mixture of trans-cinnamamide (1a) and each of
dicarboxylic acids, which are listed in Scheme 1, was
recrystallized from suitable solvent. Cocrystals of 1a with
oxalic acid (ox), succinic acid (su), phthalic acid (pht) and
fumaric acid (fu) (1a´ox, 1a´su, 1a´pht, 1a´fu) were success-
fully obtained (Table 1). Their melting points were sharp
and melted near mp of 1a. The molar ratio of the consti-
tuents was estimated by NMR and was determined by
elemental analysis to be 2:1 in all the cocrystals. The IR
frequencies of CONH2 and COOH groups for these
cocrystal, along with those for the component amide and
acid, are summarized in Table 2. The IR spectra of the
cocrystals were different from the superposition of the
spectra of their components throughout the whole region
(4000±600 cm21).
Upon photolysis in the solid state, trans-cinnamamide (1a)
and its derivatives undergo photodimerization to afford
exclusively the corresponding a-truxillamides,8 whereas in
solution only the trans±cis photoisomerization was
observed to occur as con®rmed by us. In this paper, orienta-
tional control of the [212] photodimerization of trans-
cinnamamides in the solid state by using a series of
dicarboxylic acids as a non-covalent intermolecular linker
will be described. The carboxamide group and the carboxyl
group can interact in the crystal via hydrogen bonding as
The identity of the cocrystal between 1a and glutaric acid
(gl) (1a´gl) is ambiguous. Although its C, H, N analysis was
correct as the 2:1 stoichiometry, its melting point was very
broad (Table 1) and the carbonyl stretching bands nearly
overlapped with the sum of those for 1a and gl (Table 2).
In the ®ngerprint region (1500±600 cm21), however, the
absorption peaks corresponding to gl were not discernible,
while those to 1a were clearly visible.
Keywords: cinnamamides; dicarboxylic acids; cocrystals; solid-state photo-
dimerization; hydrogen bond; dynamic disorder.
* Corresponding author. Tel.: 181-75-753-5654; fax: 181-75-753-5668;
e-mail: yito@sbchem.kyoto-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00505-6

6834
Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
Scheme 1.
Table 1. Solvents for recrystallization, melting points and analytical data for the cocrystals prepared from recrystallization of an amide (1a, 1b, 1c, or 1d) with
a dicarboxylic acid (ox, su, gl, fu, or pht)
Cocrystal
Recrystzn solvent
Crystal habit, mp, 8Ca
Calcd (%)b
H
Found (%)b
H
C
N
C
N
1a´ox
1a´su
1a´gl
iPrOH
iPrOH
C6H6
Colorless plates, 159±166.5
White needles, 150.5±151.5
Colorless plates1a small
62.49
64.06
64.78
5.25
5.87
6.14
7.29
6.79
6.57
62.46
64.16
64.59
5.29
5.95
6.08
7.32
6.86
6.47
amount of prisms, 88.5±124
Colorless needles, 142±143.5
Colorless needles, 164±166
Colorless prisms, 194±202
Colorless prisms, 207.5±211
Pale brown plates, 146±166
1a´pht
1a´fu
1b´ox
1c´ox
1d´ox
iPrOH
iPrOH
iPrOH
C6H6/i-PrOH
iPrOH
67.82
64.38
64.07
53.00
48.48
5.25
5.40
5.87
4.00
4.07
6.08
6.83
6.79
6.18c
7.07e
67.90
64.44
64.19
53.10
48.44
5.23
5.28
5.91
4.02
4.10
6.11
6.69
6.83
6.19d
6.93f
a Melting points for the components: 1a, 148±1508C; 1b, 189±1908C; 1c, 209±2108C; 1d, 152±1538C; ox (anhyd), 1908C dec; su, 187±1898C; gl, 95±988C;
fu, 299±3008C subl; pht, 2108C dec.
b The crystals were dried in vacuo at 358C for a few days. All samples gave correct C, H, N analyses (within ^0.3%) as (amide)2(dicarboxylic acid).
c Cl, 15.64.
d Cl, 15.66.
e S, 16.17.
f S, 16.31.
Table 2. FT IR frequencies in cm21 for CONH2 and COOH groups in KBr
trans-Cinnamamide
Dicarboxylic acid
COOH
Cocrystal
CONH2
CONH2 and COOH
1a
1664, 1608
ox (anhyd)
su
gl
pht
fu
1686a
1735, 1705
1701
1701, 1682
1684
1a´ox
1a´su
1a´gl
1a´pht
1a´fu
1b´ox
1c´ox
1d´ox
1682, 1639
1700, 1656, 1636
1704, 1663, 1608
1694, 1655, 1648
1697, 1651, 1628, 1572
1674, 1638
1b
1c
1d
1672, 1605
1676, 1613
1671, 1600
1677, 1637
1671, 1600
a ox (dihydrate) 1683 cm21
.
The above results on the melting point and the IR spectrum,
combined with the following powder X-ray studies (Fig. 2)
and photoreactivities (Table 3), indicate that cocrystals
1a´ox, 1a´su, 1a´pht and 1a´fu are crystalline complexes,
whereas 1a´gl may possibly be a mixture containing the
homocrystal of 1a and one polymorph of gl. The crystal
structures of 1a´ox, 1a´pht and 1a´fu could be determined
by single crystal X-ray diffraction.

Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
6835
Table 3. Products from solid-state photolyses of the cocrystals (except 1a´fu (50 h), irradiated for 20 h)
Cocrystals
Products (%)a,b
Recovery (%)
2
3
cis-1
Others
1
Acid
1a´ox
1a´su
1a´gl
1a´pht
1a´fu
1b´ox
6
42
8
Photostable
26
100
44
51
39
1
5
83
ne
100
100
100
45
ne
ne
ne
±
44
3
1
0
2
4
37
5
43
86
3
2
5
5
0
0
7
0
4, 50; ma, 5
Polymeric
1c´ox
1d´ox
0
18, 100, 100, or 97
1a, 1b, 1c, or 1dc
0
82, 0, 0, 3
a Products:
b Yields and recoveries were estimated by NMR and HPLC and calculated as follows: 100 (moles of dimer)/(moles of 2:1 cocrystal)% for a- and b-dimers
and 4, 50(moles of monomer)/(moles of 2:1 cocrystal)% for trans- and cis-cinnamamides, and 100(moles of acid)/(moles of 2;1 cocrystal)% for
dicarboxylic acids; neˆnot estimated.
c Homocrystals.
Attempts to cocrystallize trans-4-methylcinnamamide (1b),
trans-4-chlorocinnamamide (1c), and trans-b-(2-thienyl)-
acrylamide (1d) with the above dicarboxylic acids were
partly investigated. Cocrystallization with pht or with fu
all failed. In contrast, 2:1 cocrystals with oxalic acid
(1b´ox, 1c´ox, 1d´ox) were successfully obtained. Their
data for the recrystallization solvent, mp, elemental
analyses, and carbonyl frequencies are also summarized in
Tables 1 and 2. Judging from the fairly sharp mp and also
from the IR spectra that are distinct from those of the
components, cocrystals 1b´ox and 1c´ox are undoubtedly a
crystalline complex rather than a simple mechanical
mixture. From the data given above, the identity of cocrystal
1d´ox is uncertain, because its mp is broad (Table 1) and its
IR spectrum is close to that of 1d (Table 2). The powder as
well as single crystal X-ray studies, however, have demon-
strated that 1d´ox is also a crystalline complex (vide infra).
incident upon the sample is mainly or exclusively absorbed
by the component 1a. In the spectrum of 1a´fu, an in¯ection
is observed at ,343 nm, suggesting that the 1a molecule
and the fu molecule are interacting not only via hydrogen
bonds but also through a p±p interaction. In this case, as
described later, cross photodimerization occurred to give 4
(Table 3).
The powder X-ray diffraction (PXD) for cocrystals 1a´ox,
1a´pht, 1a´gl, 1a´fu, 1a´su and 1d´ox were collected (Fig. 2).
The diffraction intensities for these cocrystals were much
weaker than those for the corresponding components (ox,
pht, gl, fu, su, 1a and 1d). This may imply that the crystal
structures of these cocrystals are loose. In fact, the X-ray
molecular structure for 1a´ox has proved to be disordered
and the photocycloaddition stereoselectivities for 1a´pht
and 1a´fu could only be rationalized by assuming the
dynamic torsional motions (vide infra).
Inspection of Fig. 2 shows that the PXD patterns for 1a´ox,
1a´pht, 1a´fu, 1a´su and 1d´ox cannot be represented as a
sum of those for the components, indicating that these
cocrystals are crystalline complexes. On the other hand,
the PXD pattern for 1a´gl is peculiar like its IR spectrum.
Note that the major peaks at 2uˆ20.70, 22.28, 23.58, 24.78,
25.58, 26.38, 28.10, 29.42, 33.66 and 37.508 observed for 1a
are still present for 1a´gl at 2uˆ20.66, 22.22, 23.46, 24.78,
25.48, 26.32, 28.00, 29.36, 33.58 and 37.568, respectively.
However, the strong peaks for gl at 2uˆ22.00, 24.04 and
27.328 are virtually missing for 1a´gl. It may be likely that
the lattice structure of homocrystal 1a is largely retained
after cocrystallization with gl, but the crystal packing for
the gl component in 1a´gl is different from that of homo-
crystal gl.
Pulverized samples of cocrystals 1a´ox, 1a´su, 1a´gl, 1a´pht,
1a´fu, 1b´ox, 1c´ox and 1d´ox were spread between two
Pyrex plates and irradiated with a 400 W high pressure
mercury lamp under an argon stream. During the irradiation,
the photolysis vessel was cooled from the outside with tap
The diffuse re¯ectance UV±Vis spectra for cocrystals
1a´ox, 1a´su, 1a´gl, 1a´pht, 1a´fu and for the crystals of
their constituents were measured (Fig. 1). It can be seen
from this ®gure that the Pyrex-®ltered light (.290 nm)

6836
Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
Figure 1. Diffuse re¯ectance spectra for cocrystals 1a´ox, 1a´su, 1a´gl, 1a´pht, 1a´fu and for their constituent crystals 1a, ox (anhyd), su, pht, and fu. The
spectrum for gl, which is almost the same as that of su, is not shown.
water. The photoproducts and their yields are summarized
in Table 3. As readily seen from the table, the unusual head-
to-head dimer of amides (i.e. b-truxinamide 3 rather than
a-truxillamide 2) was mainly produced by photolyses of the
hydrogen±bonded 2:1 complexes formed between the
amide and oxalic or phthalic acid 1a´ox, 1a´pht, 1b´ox,
1c´ox and 1d´ox, although the reaction was inef®cient for
1d´ox. Noticeably, the cocrystal of 1a with fumaric acid
1a´fu afforded a mixed dimer 4 as the predominant photo-
product (50% yield). The cocrystal with succinic acid 1a´su
was completely photostable. Finally, crystal 1a´gl, like
homocrystal 1a, gave a-truxillamide 2a as the main product.
The formation of the usual photodimer 2a from 1a´gl is
consistent with the above inference, where 1a´gl was
likened to a mixture comprised of the homocrystal of 1a
and a certain modi®cation of gl, on the basis of both the
IR spectrum and the PXD pattern.
compound 5 was subsequently converted to a trimethyl
ester 6 and the structure of 6 was established by single
crystal X-ray diffraction (see Experimental).
The crystal structures of cocrystals 1a´pht, 1a´ox and 1a´fu
and their packing diagrams are displayed in Figs. 3 and 4,
respectively. Inspection of the crystal packing for 1a´pht
(Fig. 4a) has revealed that the nearest amide molecules
are related in a head-to-head fashion via a supramolecular
linker pht as shown in Fig. 3a. The ethylene bonds in this
pair are anti and are not parallel with the C´´´C distances
Ê
3.82 and 4.85 A. Although such a twisted arrangement is not
ideal for photodimerization,10 the dimer, if formed from this
crystal structure, will be d-truxinamide, which was not
observed (Table 3). In order to accommodate the observed
product b-truxinamide 3a, therefore, a pedal-like dynamic
conformational change11,12 is thought to occur in the crystal
prior to cycloaddition into 3a (Scheme 3).13 This torsional
motion will bring about a parallel orientation that is favor-
able for the photodimerization. Although molecules of 1a
related by translation along the c-direction possess a perfect
arrangement for formation of 3a, the ole®ne bond separation
The structure of 4 was determined after it was hydrolyzed to
a tricarboxylic acid 5, which is unsymmetrical in stereo-
chemical con®guration (Scheme 2). A possible symmetrical
1
stereoisomer 5A could be eliminated by H NMR. The

Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
6837
Figure 2. X-Ray powder patterns for cocrystals 1a´ox, 1a´pht, 1a´gl, 1a´fu, 1a´su and 1d´ox and for the constituents ox (anhyd), pht, gl, fu, su, 1a and 1d.
Ê
(7.52 A which is the length of the c-axis) is far too long for
the reaction to occur.
because of a somewhat long distance between the
nearest CvC bonds (C7´´´C7ˆC8´´´C8ˆC9´´´C9ˆC10´´´
Ê
C10ˆ4.96 A).
The X-ray structural features of 1a´ox are: (a) the presence
of disorder at the ethylene carbons (Fig. 3b); and (b) the
layered crystal structure (Fig. 4b).15 The occupancy for C7,
C8, C9 and C10 atoms was assumed 50%. The feature (b) is
considered to be another mode that can be utilized for the
compulsory reaction control. As pictured in Scheme 4, the
1a molecules are bilayered in a syn head-to-head orientation
and are thus in accord with the formation of b-truxinamide
3a. The photodimerization was not very ef®cient, however,
Fig. 3c shows an ortep diagram for 1a´fu. Scheme 5
depicts the nearest neighbor of 1a and fu in the crystal
packing: for example, the pair A and B in the packing
diagram Fig. 4c. The distances between the ethylene
Ê
carbons are 3.82 and 4.22 A. It is interesting that in order
to accommodate the stereochemical con®guration of the
observed product 4, a pedal-like conformational change in
either 1a or fu (see Scheme 5) is required like in the case of

6838
Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
Scheme 2.
1a´pht (see Scheme 3).13 There is an array of 1a and fu
molecules that are oriented properly to explain the stereo-
chemistry of 4: for example, A and C0 in Fig. 4c, where C0 is
generated by 21 cell translation of C along the a axis.
However, the ethylene carbons in this array are by far
Ê
apart, i.e. 7.39 and 7.51 A. Hence, the nearest separated
1a and fu molecules shown in Scheme 5 will be the reacting
partner. Furthermore, there is a good p-overlap between the
Figure 3. ortep drawings of cocrystals: (a) 1a´pht; (d) 1a´ox; and (c) 1a´fu.

Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
6839
Figure 4. Packing diagrams of cocrystals: (a) 1a´pht; (b) 1a´ox; and (c) 1a´fu, which are projected along the c-axis, the a-axis and the a-axis, respectively.
Scheme 3. A pedal-like dynamic conformational change in cocrystal 1a´pht and the solid-state photodimerization.

6840
Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
Scheme 4. A layered crystal packing of 1a´ox and the solid state photodimerization.
Ê
phenyl ring and the carbonyl group (O2´´´C11ˆ3.50 A,
is not unexpected, because the crystal packing for two-
component molecular crystals is often loose.1,2 The loose
crystal packing for 1a´ox, 1a´pht and 1a´fu was also indi-
cated from their weak PXD intensities, as described above.
Ê
O2´´´C12ˆ3.43 A,
C11´´´O2±C5ˆ898,
C12´´´O2±
C5ˆ898). This overlap should be responsible for the
343 nm in¯ection which appeared in the diffuse re¯ectance
spectrum of 1a´fu (Fig. 1). An attractive interaction between
the carbonyl and phenyl groups, referred to as CvO´´´p
interaction, was reported to exist and this interaction was
utilized for asymmetric dimerization and polymerization.17
Such a CvO´´´p interaction could not be recognized in the
X-ray structures of cocrystals 1a´ox and 1a´pht.
Although the R value was reduced to only 0.141 owing to
the poor quality of crystals, the crystal structure for 1d´ox
was found to be very similar to that of 1a´ox, as expected
from identical space group and similar lattice constants.20
For instance, there are double layers of 1d and the nearest
Ê
Ê
ethylene bonds are 4.97 A apart (cf. 4.96 A apart for 1a´ox).
However, the ethylene bond in 1d´ox is not disordered. For
1a´ox (Fig. 3b), disorder is present at the ethylene carbons,
indicating that 1a´ox possesses larger free space21 around
the ethylene bond than 1d´ox. This difference is apparently
re¯ected on the smaller photodimerization reactivity of
1d´ox (only 3% yield of 3d) as compared with that of
1a´ox (42% yield of 3a) (Table 3).22
The crystallographically determined lengths of the ethylenic
bond in 1a´ox, 1a´pht, and 1a´fu are ,1.28 (disordered),
1.316(2) and 1.318(2) (two 1a molecules in the asymmetric
Ê
Ê
unit), and 1.319(2) (1.283(2) A for the fu component) A,
respectively. For the 1a homocrystal, the length was
18
reported to be 1.331(4) A. For the fu homocrystal, it was
Ê
19
1.348 (a form) or 1.315 (b form) A. Consequently, the
Ê
ethylene bonds in 1a´pht and 1a´fu are considerably shorter
than the corresponding ones in the homocrystals. This fact
strongly suggests11 that there is dynamic disorder at the
ethylene bond in the hydrogen bonded cocrystals 1a´pht
and 1a´fu, in line with the pedal-like motion deduced
from the product stereochemistry (Schemes 3 and 5 and
cf. Ref. 13). Maybe 1a´ox is an extreme case, since here
the static disorder is present at the ethylene bond (Fig. 3b).
Facility of the dynamic or static disorder in these cocrystals
In conclusion, a compulsory control of solid-state photo-
dimerization like that by double salts of gauche 1,2-
diamine1±7 was also achieved by using pht as a hydrogen-
bonding intermolecular linker. Furthermore, a new mode of
control by ox was found. A key point of the latter control
was ascribed to the layered crystal structure enforced by ox.
The crystal structure±reactivity relationship is well investi-
gated and it is believed that the reactivity and the product

Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
6841
Scheme 5. A pedal-like dynamic conformational change in cocrystal 1a´fu and the mixed photodimerization.
stereochemistry are precisely predictable from the crystal
structure.24 Our study suggests that this is not always the
case when there is a dynamic disorder. It seems that this
situation is particularly ubiquitous for mixed molecular
crystals, because their crystal packings are often loose.1,2
Torsional vibrations may bring about orientations or con-
®gurations that are more favorable for the reaction.
Materials
trans-Cinnamamide (1a), trans-4-chlorocinnamamide (1c),
oxalic acid (ox) (anhydrous and dihydrate), malonic acid,
succinic acid (su), glutaric acid (gl), adipic acid, fumaric
acid (fu), maleic acid, phthalic acid (pht), (^)-trans-1,2-
cyclohexanedicarboxylic acid, cis-1,2-cyclohexanedi-
carboxylic acid, and 1,1-cyclobutanedicarboxylic acid
were commercially available. trans-4-Methylcinnamamide
(1b) and trans-b-(2-thienyl)acrylamide (1d) were prepared
according to the literature method.8,25 Prior to measuring the
diffuse re¯ectance or PXD spectra, 1a, ox (dihydrate), su,
gl, fu, and pht were recrystalized from EtOH, water, water,
water, water, and EtOH, respectively, while ox (anhydrous)
was used as received.
Experimental
General procedures
1H NMR spectra were measured on a Varian Gemini-200,
JEOL EX-270J, or JEOL JNM-A400 spectrometer. The
solvent employed is DMSO-d6, unless otherwise speci®ed.
IR spectra were recorded in a JASCO FT/IR-5M or
SHIMADZU FTIR-8100A spectrometer. Mass spectra
were obtained in a JEOL JMS-DX 300 or JEOL JMS-SX
102A spectrometer. Diffuse re¯ectance spectra were
gathered with a SHIMADZU UV-2400PC spectrometer
equipped with a diffuse-re¯ectance attachment and a
BaSO4 powder was used as a standard of re¯ectivity.
Powder X-ray diffraction (PXD) patterns were obtained
with a MAC Science MX Labo diffractometer equipped
Cocrystallization
A hot solution containing 1.472 g (10.0 mmol) of 1a in
iPrOH (15 mL) was mixed with a hot solution containing
0.831 g (5.0 mmol) of pht in iPrOH (15 mL) and the
mixture was ®ltered immediately. Upon cooling to room
temperature, colorless needles crystallized out of the ®ltrate
and were collected by ®ltration to afford 1.59 g (69%) of
1a´pht. This was dried in vacuo at 358C for a few days.
Other cocrystals were similarly prepared from mixing
2 equiv. of amides 1a±1d with 1 equiv. of dicarboxylic
acids ox (dihydrate), su, gl, and fu in appropriate solvent
(Table 1).
Ê
with CuKa radiation (1.5406 A). Data were collected
between 20 and 708 in 2u at a scan rate of 48/min. HPLC
analyses were performed with a SHIMADZU LC-5A
chromatograph and a UV detector (®xed at 217 nm) by
using a Cosmosil 5C18-AR column (4.6 mm i.d.£150 mm)
and were eluted with a mixture of methanol and water, a
mixture of methanol and 20 mM acetate buffer (pH 3.6), or a
mixture of methanol and 10 mM phosphate buffer (pH 2.6).
Small-scale irradiation of cocrystals
Cocrystals of 1a´ox, 1a´su, 1a´gl, 1a´pht, 1a´fu, 1b´ox, 1c´ox

6842
Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
or 1d´ox (15±20 mg) were crushed and spread between two
Pyrex plates. This sandwiched sample was placed in our
solid-state photolysis vessel.1,2 Irradiation was carried out
with a 400 W high-pressure mercury lamp under an argon
atmosphere for 20 h. During the irradiation, the vessel was
cooled from outside by running water. After the irradiation,
the reaction mixture was dissolved in MeOH or DMSO-d6
(62); IR (KBr) 3394, 3358, 1664, 1516, 1421, 1406, 1245,
811, 722 cm21
.
1
(d) From the H NMR analysis of the photolysate from
1c´ox, 3c: 1H NMR (200 MHz) d 3.61 (2H, quasi-d,
Jˆ6 Hz, cyclobutyl), 4.19 (2H, quasi-d, Jˆ6 Hz, cyclo-
butyl), 7.00 and 7.16 (8H, AB, Jˆ8.4 Hz). This photolysate
was directly hydrolyzed with conc HCl as described above.
The dimer 3c was led cleanly to the previously known p, p0-
dichloro-b-truxinic acid.4,26
1
for HPLC and H NMR analyses, respectively. Yields thus
estimated are summarized in Table 3.
Similar irradiation of homocrystals 1a±1d gave cleanly the
corresponding a-truxillamides 2a±2d, as was previously
reported.8
(e) The pale brown photolysate from 1d´ox (80 mg, 45 h
irradiation) was recrystallized ®rst with 10 mL of 1:1
chloroform±MeOH, then with 7 mL of 5:2 EtOH±MeOH.
The mother liquor was evaporated and the residue was
recrystallized from 11 mL of 10:1 benzene±EtOH. A pale
brown solid (16 mg) containing 3d in ca. 30% (1H NMR)
precipitated. 3d: 1H NMR (CD3OD, 270 MHz) d 3.80 (2H,
quasi-d, Jˆ6 Hz, cyclobutyl), 4.51 (2H, quasi-d, Jˆ6 Hz,
cyclobutyl), 6.81±6.89 (2H, m), 7.16 (1H, d with each peaks
slightly split, Jˆ5 Hz). This spectrum was very similar to
that of the corresponding dicarboxylic acid previously
prepared.4,27
Isolation and characterization of b-truxinamides
(a) Cocrystal 1a´ox (51 mg) was irradiated for 20 h as
described above. The slightly colored photolysate, which
1
contained 3a with 29% yield (estimated by H NMR and
HPLC), was taken up in 2 mL of water and was stirred at
458C for 1 h. After cooling in a refrigerator, an insoluble
pale yellow solid was collected by ®ltration. This was stirred
into 2 mL of acetonitrile and an insoluble solid was ®ltered
off to afford 5 mg (13% yield) of 3a as a white crystalline
Isolation of heterodimer 4. Cocrystal 1a´fu (101 mg) was
irradiated for 90 h as described above. The resultant pale
yellow powder, which contained the product 4 with 50%
yield (1H NMR and HPLC), was fractionally recrystallized
from water (2 mL), then acetonitrile±water, and ®nally
acetonitrile (5 mL). As a result of these recrystallization
procedures, fumaric and maleic acids, b-truxinamide 3a,
a-truxillamide 2a, and cis-1a could be entirely removed
and ®nally 18 mg of a mixture of 4 and 1a was isolated as
a solid. This mixture was further recrystallized from 7 mL
of 4:3 acetonitrile±ether and then 7 mL of 4:3 acetonitrile±
benzene to afford 4 mg (6%) of t-3-carbamoyl-c-4-phenyl-r-
1
solid: mp 246±2528C (dec); H NMR (200 MHz) d 3.64
(2H, quasi-d, Jˆ6.5 Hz, cyclobutyl), 4.20 (2H, quasi-d,
Jˆ6.5 Hz, cyclobutyl), 6.88±7.18 (10H, m, aromatic); MS
(EI) m/z (rel intensity) 277 (42, M1z2NH3), 205 (63), 180
(31, [PhCHvCHPh]1z), 147 (21, M1z/2), 131 (100); IR
(KBr) 3430, 3402, 1665, 1605, 1414, 698 cm21. The stereo-
chemistry of the cyclobutane ring of 3a was determined on
1
the basis of the characteristic H NMR chemical shift and
coupling pattern of the cyclobutyl protons, which were simi-
lar to those of the corresponding cinnamic acid photodimer.
In fact, upon heating 2 mg of 3a in 0.4 mL of conc HCl at
958C for 1 h, 3a was hydrolyzed to b-truxinic acid3,26 in
81% yield (HPLC).
1,t-2-cyclobutanedicarboxylic acid
4 as white small
1
needles: mp 187±1908C; H NMR (CD3OD, 400 MHz) d
3.74±3.78 (1H, dd, Jˆ10.1 and 6.1 Hz, H2N±COCH),
3.79±3.83 (1H, dd, Jˆ10.1 and 6.1 Hz, H2NCOCHCH-
COOH), 3.89±3.3.93 (1H, dd, Jˆ10.7 and 6.1 Hz,
PhCHCHCOOH), 4.09±4.13 (1H, dd, Jˆ10.7 and 6.1 Hz,
PhCH), 7.19±7.32 (5H, m, aromatic); 13C NMR (CD3OD,
100 MHz) d 41.12 (CH), 43.97 (CH), 45.61 (CH), 46.14
(CH), 128.10 (CH), 128.71 (CH), 129.37 (CH), 140.45
(C), 174.84 (CO), 175.16 (CO), 176.69 (CO); IR (KBr)
3425 and .2500 (CONH2 and COOH), 1706 (COOH),
1665 (CONH2), 1648 (CONH2), 1602, 1424, 1301, 1223,
(b) Cocrystal 1a´pht (53 mg) was irradiated for 50 h as
described above. The resultant white powder, which
1
contained 3a with 37% yield (estimated by H NMR and
HPLC), was recrystallized from 5.5 mL of 10:1 aceto-
nitrile±methanol to furnish 10 mg (31%) of 3a as white
needles.
The cyclobutane ring protons for 3b±3d also exhibited the
1H NMR pattern characteristic of the b-type photodimer.
Attempts to purify b-truxinamides 3c and 3d were not
1179, 741, 699 cm21
.
1
carried out. Their H NMR data were derived from the
mixtures.
Hydrolysis of 4. (a) Heterodimer 4 (2 mg) in conc. HCl
(0.5 mL) was heated at 958C for 1 h. The reaction mixture
was evaporated in vacuo. The residue was essentially pure
c-4-phenyl-r-1,t-2,t-3-cyclobutanetricarboxylic acid 5 (1H
NMR and HPLC).
(c) The photolysate from 1b´ox (50 mg, 40 h irradiation)
was recrystallized twice with i-PrOH (®rst 3 mL, then
2 mL) to remove polymeric materials (11 mg). The residue
was then recrystallized from MeCN (1 mL) to afford,
although still a little contaminated with the polymer, 5 mg
(b) In order to obtain more 5, 20 mg of a mixture of 4 and 1a
(molar ratio, ca. 1:1) in conc. HCl (3 mL) was heated at
908C for 5 h. The reaction mixture was evaporated and the
residue was recrystallized with 2 mL of 1:1 methanol±water
and then with 5 mL of ether. Relatively insoluble cinnamic
acid and other insoluble materials were removed. The
resultant soluble part (16 mg) was again recrystallized
1
of 3b as pale yellow crystals: mp 188±2028C; H NMR
(200 MHz) d 2.11 (6H, s), 3.56 (2H, quasi-d, Jˆ6 Hz,
cyclobutyl), 4.11 (2H, quasi-d, Jˆ6 Hz, cyclobutyl), 6.87
(10H, AB with almost vanishing end peaks, Jˆ8 Hz,
aromatic); MS (EI) m/z (rel intensity) 305 (3), 233 (12),
208 (7, [MePhCHvCHPhMe]1z),161 (100, M1z/2), 145

Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
6843
Figure 5. ortep drawing of compound 6.
from CHCl3 (5 mL) to give 9 mg of 5 as white plates: mp
205±2088C; H NMR (CD3OD, 400 MHz) d 3.72±3.79
successfully analyzed by single crystal X-ray diffraction
(Fig. 5).
1
(2H, m), 3.82±3.87 (1H, m), 4.22±4.27 (1H, m, PhCH),
7.19±7.32 (5H, m, aromatic); 13C NMR (CD3OD,
100 MHz) d 41.55 (CH), 44.28 (CH), 44.87 (CH), 45.80
(CH), 128.11 (CH), 128.52 (CH), 129.34 (CH), 140.04
(C), 174.64 (CO), 175.36 (CO), 175.71 (CO); MS (EI) m/z
(rel intensity) 219 (17, M1z2COOH), 200 (18), 174 (45,
M1z22COOH), 172 (56), 148 (97, [PhCHvCHCOOH]1z),
147 (80), 129 (100, M1z23COOH), 128 (93), 103 (44), 77
(50, Ph1); IR (KBr) 3500±2500 (COOH), 1724 (COOH),
X-Ray crystal structure determination
X-ray intensities were measured on Rigaku AFC-5 or AFC-
7R diffractometer with graphite monochromatized MoKa
Ê
radiation (lˆ0.71073 A). The structures were solved by
direct methods and were re®ned using crystan-gm or
texsan software.28
1709 (COOH), 1409, 1272, 1204, 743, 698 cm21
.
ꢀ
Crystal data. 1a´pht: triclinic, P1, aˆ9.562(1), bˆ
Ê
17.402(2), cˆ7.522(1) A, aˆ90.82(1), bˆ105.71(1), gˆ
75.50(1)8, Vˆ1164.6(3) A , Zˆ2, Dxˆ1.313 g/cm3,
Ê 3
In a separate experiment, the photolysate from 539 mg of
1a´fu (irradiated for 170 h, containing 4 with ca. 75%
Rˆ0.043. 1a´ox: monoclinic, P21/n, aˆ4.961(5), bˆ
1
yield by H NMR) was heated in 25 mL of conc. HCl at
Ê
Ê 3
30.536(9), cˆ6.471(3) A, bˆ101.62(5), Vˆ960.2(11) A ,
Zˆ2, Dxˆ1.330 g/cm3, Rˆ0.052. 1a´fu: monoclinic, P21/
958C for 3 h. The resulting brown to yellow precipitate
was ®ltered off, the ®ltrate was evaporated to dryness,
and then the yellow residue (440 mg) was recrystallized
from 18 mL of 5:1 water±methanol. After ®ltration, a
yellow solid (390 mg) was obtained from evaporation of
the mother liquor and this was re¯uxed in CHCl3 (50 mL)
for 1 h. Tricarboxylic acid 5 (175 mg, 51% yield on the
basis of 1a´fu) was obtained as an insoluble pale yellow
solid.
Ê
n, aˆ11.503(1), bˆ5.297(1), cˆ16.888(1) A, bˆ94.09(1),
Ê 3
3
Vˆ1026.4(2) A , Zˆ2, Dxˆ1.328 g/cm , Rˆ0.050. 6:
monoclinic, P21/c, aˆ5.789(2), bˆ17.576(2), cˆ
Ê
Ê 3
15.667(2) A, bˆ99.85(2), Vˆ1570.6(6) A , Zˆ4, Dxˆ
1.295 g/cm3, Rˆ0.061.
Acknowledgements
Esteri®cation of 5. Into a solution containing 10 mg
(0.038 mmol) of 5 in 2 mL of 1:1 methanol±benzene was
added a 10% hexane solution of (trimethylsilyl)diazo-
methane (1 mL, ca. 0.8 mmol). The mixture was kept at
room temperature for 4 h under stirring. After evaporation,
the residue was subjected to preparative TLC (Merck
Kieselgel 60 F254, 10:1 CHCl3±acetone) to afford 8 mg
(69%) of trimethyl c-4-phenyl-r-1,t-2,t-3-cyclobutanetri-
carboxylate 6. This was crystallized from 0.6 mL of
5:1 hexane±acetonitrile to afford 4 mg of colorless prisms:
This work was supported by the grant-in-aid for Scienti®c
Research from the Japanese Government (Nos. 10440215,
10132229, 11119229). The authors also acknowledge Ms
Ryoko Yoshihara for her assistance in X-ray work.
References
1. Ito, Y. Synthesis 1998, 1±32.
2. Ito, Y. Mol. Supramol. Photochem. 1999, 3, 1±70.
3. Ito, Y.; Borecka, B.; Scheffer, J. R.; Trotter, J. Tetrahedron Lett.
1995, 36, 6083±6086.
1
mp 88±948C; H NMR (CDCl3, 200 MHz) d 3.29 (3H, s),
3.70 (3H, s), 3.75 (3H, s), 3.8 1±4.02 (3H, m), 4.28±4.40
(1H, m, PhCH), 7.16±7.37 (5H, m, aromatic); MS (EI) m/z
(rel intensity) 306 (11, M1z), 275 (16), 246 (44), 214 (41),
187 (35), 162 (100, [PhCHvCHCOOMe]1z), 131 (96), 113
(42); IR (neat) 1742, 1728, 1436, 1314, 1301, 1274, 1216,
1204, 1172, 1018, 754, 701 cm21. This compound was
4. Ito, Y.; Borecka, B.; Olovsson, G.; Trotter, J.; Scheffer, J. R.
Tetrahedron Lett. 1995, 36, 6087±6090.
5. Ito, Y.; Olovsson, G. J. Chem. Soc., Perkin Trans. 1 1997, 127±
133.
6. Ito, Y. Mol. Cryst. Liq. Cryst. 1996, 277, 247±253.

6844
Y. Ito et al. / Tetrahedron 56 (2000) 6833±6844
7. Ito, Y.; Fujita, H. J. Org. Chem. 1996, 61, 5677±5680.
8. Hung, J. D.; Lahav, M.; Luwisch, M.; Schmidt, G. M. J. Isr.
J. Chem. 1972, 10, 585±599.
(b) Bednowitz, A. L.; Post, B. Acta Crystallogr. 1966, 21, 566±
571.
20. Crystal data of 1d´ox: monoclinic, P21/n, aˆ4.968(3),
Ê
Ê 3
9. Huang, C.-M.; Leiserowitz, L.; Schmidt, G. M. J. J. Chem. Soc.,
Perkin Trans. 2 1973, 503±508; Leiserowitz, L. Acta Crystallogr.
B 1976, 32, 775±801.
bˆ28.435(18), cˆ6.592(4) A, bˆ104.80(5), Vˆ900.3(9) A , Zˆ
2, Dxˆ1.462 g/cm3.
21. (a) Cohen, M. D. Angew. Chem., Int. Ed. Engl. 1975, 14, 386±
393. (b) Gavezzotti, A. J. Am. Chem. Soc. 1983, 105, 5220±5225.
(c) Marubayashi, N.; Ogawa, T.; Hirayama, N. Bull. Chem. Soc.
Jpn 1998, 71, 321±327. (d) Ito, Y.; Matsuura, T. Tetrahedron Lett.
1988, 29, 3087±3090. Ito, Y.; Ito, H.; Ino, M.; Matsuura, T.
Tetrahedron Lett. 1988, 29, 3091±3094.
10. Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647±678.
11. (a) Ogawa, K.; Sano, T.; Yoshimura, S.; Takeuchi, Y.;
Toriumi, K. J. Am. Chem. Soc. 1992, 114, 1041±1051.
(b) Ogawa, K.; Harada, J.; Tomoda, S. Acta Crystallogr. B 1995,
51, 240±248. (c) Harada, J.; Ogawa, K.; Tomoda, S. Acta
Crystallogr. B 1997, 53, 662±672.
22. The yields of a-truxillamide 2 from the solid-state photo-
dimerization of homocrystals 1a, 1c, 1d (18, 100, 97%,
respectively) is consistent with the separation of the nearest
12. Galli, S.; Mercandelli, P.; Sironi, A. J. Am. Chem. Soc. 1999,
121, 3767±3772.
23
13. We have recently proved unequivocally by crystallographic
analysis of the crystal-to-crystal phototransformation of 1a´pht
and 1a´fu that the pedal-like motion prior to cycloaddition is
true.14 It is possible, however, that this motion preferentially occurs
at defect sites, which may be regarded as the effect of dynamic
defects on reactions.
Ê
neighbor CvC bonds (4.11, 3.63, 3.76 A, respectively). As a
result, the intrinsic reactivity of 1d appears normal.
23. Hosomi, H.; Ito, Y.; Ohba, S. Acta Crystallogr. B 2000, (in
press).
24. Ihmels, H.; Scheffer, J. R. Tetrahedron 1999, 55, 885±907.
25. Mason, C. D.; Nord, F. F. J. Org. Chem. 1951, 16, 1869±1872.
26. Cohen, M. D.; Schmidt, G. M. J.; Sonntag, F. I. J. Chem. Soc.
1964, 2000±2013.
14. Hosomi, H.; Ito, Y.; Ohba, S. In preparation.
15. Single crystals of benzamide form hydrogen-bonded bilayers16
but those of 1a do not.18
27. Lahav, M.; Schmidt, G. M. J. J. Chem. Soc. (B) 1967, 239±243.
28. (a) Edwards, C.; Gilmore, C. J.; Mackay, S.; Stewart, N. 1996.
crystan-gm Version 6.3.3; Computer Program for the Solution
and Re®nement of Crystal Structures, MAC Science, Japan.
(b) Molecular Structure Corporation. texsan, Single Crystal
Structure Analysis Software, Version 1.9. MSC, 3200 Research
Forest Drive, The Woodlands, TX 77381, USA; 1998.
16. Edgar, R.; Schultz, T. M.; Rasmussen, F. B.; Feidenhans'l, R.;
Leiserowitz, L. J. Am. Chem. Soc. 1999, 121, 632±637.
17. Addadi, L.; Lahav, M. Pure Appl. Chem. 1979, 51,
1269±1284.
18. Iwamoto, T.; Kashino, S.; Haisa, M. Acta Crystallogr. C 1989,
45, 1110±1112.
19. (a) Brown, C. J. Acta Crystallogr. 1966, 21, 1±5.