Self-assembly of enantiopure and racemic 2,2′,6,6′-tetrasubstituted biaryl tectons into hydrogen bonded chiral squares and infinite chiral square layers

Article abstract of DOI:10.1016/S0957-4166(01)00509-2

Both chiral and achiral hydrogen bonding o-,o-,o′-,o′-tetrasubstituted biaryls often exhibit unique self-assembling properties giving rise to chiral square cyclotetramers. The individual chiral squares self-assemble further with the formation of infinite layers which are either achiral or are chiral (homochiral). A priori analysis reveals various hydrogen bonding modes which may take part in the self-assembly, differing each from the other by structure and symmetry of the resulting squares and layers. Results of the theoretical analysis are compared with the experimental findings obtained from X-ray crystallographic analysis of three novel and two already known isosteric biaryl tectons, (S)-2a, (RS)-2a, 3a, (S)-5 and (RS)-5, respectively.

Full text of DOI:10.1016/S0957-4166(01)00509-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3035–3045
Self-assembly of enantiopure and racemic
2,2%,6,6%-tetrasubstituted biaryl tectons into hydrogen bonded
chiral squares and infinite chiral square layers
Petr Holy´,a Jirˇ´ı Za´vada,a,* Ivana C´ısarˇova´b and Jaroslav Podlahab
aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo na´m. 2,
166 10 Prague 6, Czech Republic
bDepartment of Inorganic Chemistry, Faculty of Natural Sciences, Charles University, Hlavova 2030,
128 40 Prague 2, Czech Republic
Received 5 November 2001; accepted 7 November 2001
Abstract—Both chiral and achiral hydrogen bonding o-,o-,o%-,o%-tetrasubstituted biaryls often exhibit unique self-assembling
properties giving rise to chiral square cyclotetramers. The individual chiral squares self-assemble further with the formation of
infinite layers which are either achiral or are chiral (homochiral). A priori analysis reveals various hydrogen bonding modes which
may take part in the self-assembly, differing each from the other by structure and symmetry of the resulting squares and layers.
Results of the theoretical analysis are compared with the experimental findings obtained from X-ray crystallographic analysis of
three novel and two already known isosteric biaryl tectons, (S)-2a, (RS)-2a, 3a, (S)-5 and (RS)-5, respectively. © 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
differentiation of the ortho substituents giving rise to
chiral molecules 2 (X"Y, C2 symmetry). If only one pair
of the distinct substituents (X or Y) is capable of hydrogen
bonding, discrete homochiral squares of D4 symmetry7
or homochiral helices8 result. However, if both pairs of
substituents (X as well as Y) are endowed with hydrogen-
bonding ability, infinite homochiral square layers should be
produced.
Supramolecular chemistry inspires the design of micro-
porous layers employing self-assembly of molecular
subunits (tectons) driven by non-covalent interactions as
the synthetic tool.1–3 Our recent discovery that biphenyl-
2,2%,6,6%-tetracarboxylicacid1a4 aswellasthecorrespond-
ing tetraamide 1b,5 and also the 1:1 adduct 1a·1b6
self-assemble with the formation of infinite 2D layers set
up from cyclotetrameric hydrogen-bonded square com-
partments (Fig. 1) opens interesting vistas in this direc-
tion.
Herein, we explore the formation of infinite homochiral
square layers organized by intermolecular carboxyl and
amide double hydrogen bonds. Towards this end, we have
designed 6,6%-dicarbamoylbiphenyl-2,2%-dicarboxylic acid
2a as a convenient chiral tecton and employed at the same
time its positional isomer 3a as the achiral counterpart.
In contrast to the individual molecules 1a and 1b that
possess D2d symmetry and are thus achiral, the self-assem-
bled cyclotetrameric squares possess D4 symmetry and are
chiral. Squares of opposite chirality (R or S) alternate,
however, in the resulting infinite network which is
accordingly again achiral.
X
X
X
X
X
X
Y
Y
X
Y
X
Y
In order to attain chirality of the overall network, the
individual self-assembling tectons must be made chiral.
The requisite chiralization of the parent achiral biaryl
tectons 1a and 1b can be accomplished by a pairwise
2
3
1
2a : X = COOH
1a : X = COOH
1b : X = CONH2
1c : X = COOMe
1d : X = COCl
3a : X = COOH
Y = CONH2
Y = CONH2
* Corresponding author. Fax: (+4202)-3333 1733; e-mail: zavada@
uochb.cas.cz
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00509-2

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P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
X
1a
1b
X
X
X
COOH =
CONH2 =
H
C
H
N
C
O
C
O H
H N
O
O
H
O
C
O H
H O
=
=
C
=
C
O
N H
O
H
R
S
R
S
S
R
R
S
S
R
S
R
C
A
B
Figure 1. Schematic representation of square layers in the crystal of tetraacid 1a (A), tetraamide 1b (B) and in the co-crystal 1a·1b
(C). Projection in direction of the biaryl axis indicates the orientation of substituents (wedges) directing downward from the upper
phenyl and upward from the lower phenyl. The complementary hydrogen bonded substituents always connect alternate (upper
versus lower) phenyl rings and, therefore, are visualized by two concordant wedges.
2. Results and discussion
diester (S)-2d established on the basis of X-ray diffrac-
tion analysis.
2.1. Synthesis
2.2. X-Ray crystallographic analysis of the novel biaryl
Dianhydride 4, easily available9 from the parent tetra-
acid 1a, was chosen as the starting compound for
preparation of the target 2,2%,6,6%-tetrasubstituted
biphenyl compounds 2a and 3a. Reaction of 4 with
benzyl alcohol (Scheme 1) afforded two positionally
isomeric diester diacids as the sole products, which
could be easily separated by column chromatography,
converted into the corresponding dicarbamoyl diesters
and the ester groups smoothly cleaved by hydrogenoly-
sis. On comparison with the partial hydrolysis of the
corresponding tetraesters 1c (X=COOMe)10 or with
the partial alcoholysis of the corresponding tetra-
chloride 1d (X=COCl),11 both yielding complex
product mixtures, this novel approach greatly simplifies
the isolation/separation procedures.
tectons (S)-2a, (RS)-2a and 3a
2.2.1. Molecular structures. The molecular structures of
(S)-2a, (RS)-2a and 3a are depicted in Section 4. For
all the novel structures, the intramolecular bond angles
and distances are unexceptional. However, there are
large differences in the mutual dihedral angles of
phenyl planes (64.1–80.7°) and, especially, in the dihe-
dral angles of carboxyl and carbamoyl groups relatively
to the parent phenyl plane (9.8–60.7°). The geometry of
the hydrogen bonds is remarkably similar in all struc-
tures and the average values of their geometry (with
standard deviations of the mean in parentheses) are as
,
follows: OꢀH 0.96(6), H···O 1.66(5), O···O 2.595(7) A,
OꢀH···O 168(4)°; NꢀH 0.91(4), H···O 2.06(5), N···O
,
2.948(6) A, NꢀH···O 165(5)°.
Employment of the optically active benzylic alcohol,
(S)-1-phenylethanol, in the dianhydride 4 alcoholysis
(Scheme 1) provides additional advantages resulting
from diastereoselective course of the ring-opening reac-
tion. Absolute configuration of the resulting enantiomer
(S)-2a has been ascribed, unambiguously, by correla-
tion with the configuration of the diastereoisomeric
2.2.2. Self-assembly of the enantiopure tecton (S)-2a. In
contrast to the achiral tectons 1a, 1b and 1a·1b, each
allowing only one mode of intermolecular double
hydrogen bonding (Fig. 1, A–C, respectively), a priori
analysis suggests four possible modes of self-assembly

P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
3037
3a
(RS)-2a
(RS)-2c
iv
iv
3c
X = COOCH2Ph
Y = CONH2
X = COOCH2Ph
Y = CONH2
ii, iii
ii, iii
O
O
PhCH2OH, i
3b
+
(RS)-2b
X = COOCH2Ph
Y = COOH
O
O
X = COOCH2Ph
Y = COOH
O
O
4
(S)-PhCH(CH3)OH
i
3d
(S)-2d
X = COO-(S)-CH(CH3)Ph
Y = COOH
(R)-2d
+
+
X = COO-(S)-CH(CH3)Ph
X = COO-(S)-CH(CH3)Ph
Y = COOH
Y = COOH
ii, iii
iv
(S)-2e
(S)-2a
X = COO-(S)-CH(CH3)Ph
Y = CONH2
Scheme 1. Reagents and conditions: (i) py, DMAP; (ii) (COCl)2, CH2Cl2, DMAP; (iii) aq. NH4OH, dioxane; (iv) H2, Pd/C,
CH3OH/H2O.
(Fig. 2, D–G) for the homochiral tecton (S)-2a. The
first mode (D) rests on the combination of two homo-
functional double hydrogen bonds, carboxylꢀcarboxyl
and amideꢀamide, analogous to those found, individu-
ally, in 1a and 1b (Fig. 1, A and B, respectively). The
second mode (E) is based exclusively on the heterofunc-
tional (carboxylꢀamide) double hydrogen bond estab-
lished earlier6 in the molecular complex 1a·1b (Fig. 1,
C). The remaining two modes (F and G) consist of a
blend of the homo- and heterofunctional double hydro-
gen bonds. Notably, the alternative modes may also
differ by symmetry (see the symmetry symbols inside
the individual squares in Fig. 2). Irrespective of the
individual differences in hydrogen bonding and symmetry,
each of the four alternative modes D–G is set up from
homochiral squares and can accordingly afford infinite
homochiral layers.
In order to determine which (if any) of the four alterna-
tive hydrogen bonding modes actually operates in the
self-assembled crystal, the tecton (S)-2a was subjected
to X-ray diffraction analysis. It was found that forma-
(S)- 2a
COOH =
, CONH2 =
C2
D4
C4
C2
C2
C4
D4
C2
C1
C1
C1
C1
C1
C1
C1
C1
D
E
F
G
Figure 2. Four theoretical modes of hydrogen bonding of the homochiral tecton (S)-2a visualized as described in Fig. 1.

3038
P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
tion of infinite homochiral square layers occurs in the
crystal (Fig. 3) via the hydrogen bonding mode F,
employing both homo- and heterofunctional double
hydrogen bonds. The individual homochiral 2D layers
are arranged in a staggered manner (similarly as the
achiral tectons 1ab, 1b and 1a·1b) and are intercon-
nected by intermolecular amideꢀamide single hydrogen
bonds (one direct and one solvent-mediated bond per
each square). The resulting 3D framework is rigidified
by complementary intramolecular amideꢀamide single
hydrogen bonds (one additional pair of bonds per
square).
diagonal alternation of the opposite enantiomers in the
square network. Each of the two distribution patterns
allows operation of four distinct hydrogen bonding
modes (Fig. 4; H–K and L–O, respectively) which are
analogous with those considered above for the enan-
tiopure tecton (S)-2a. They invariantly allow formation
of chiral squares, with the stipulation that squares of
opposite chirality in the racemic compound alternate
vertically and/or horizontally and the resulting layers
are accordingly achiral.
In a more complex analysis of the racemate, alternation
of higher homochiral aggregates of the hydrogen
bonded tectons in place of the individual chiral
molecules also has to be taken into account as another
viable pattern of the enantiomeric distribution. Alterna-
tion of opposite homochiral 2D layers resulting in a
single racemic crystal and stacking of homochiral layers
leading to a racemic mixture (a conglomerate12,13) of
homochiral crystals represent in this respect two possi-
ble scenarios.12–15 Accordingly, formation of infinite
homochiral square layers from racemic tectons cannot be
ruled out.
2.2.3. Self-assembly of the racemic tecton (RS)-2a. Con-
ceptually, self-assembly of the racemate (RS)-2a may
offer a greater number of hydrogen bonding modes
than the corresponding enantiopure tecton (S)-2a, as a
consequence of the variable distribution of opposite
enantiomers in the resulting supramolecular network.
At the simplest level of the a priori analysis, there are
two possible patterns of the enantiomeric distribution
differing each from the other by a horizontal/vertical or
Figure 3. Segment of an infinite chiral layer in the crystal of (S)-2a formed by intermolecular double hydrogen bonds. Disordered
water molecules and all hydrogens are omitted for clarity. Carbon atoms are not distinguished, oxygens and nitrogen atoms are
drawn as red and blue circles, respectively.

P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
3039
R
S
(RS)- 2a
+
COOH =
, CONH2 =
R
S
R
S
R
S
R
S
R
R
S
R
S
R
S
R
S
R
R
S
S
R
S
R
S
R
R
S
S
R
S
R
S
R
R
R
I
H
J
K
R
R
S
S
S
R
R
R
R
R
R
S
S
S
R
R
R
R
R
R
S
S
S
R
R
R
R
R
R
S
S
S
R
R
R
R
M
N
O
L
Figure 4. Eight theoretical modes of hydrogen bonding of the racemic tecton (RS)-2a corresponding either to the horizontal/ver-
tical (H–K) or to the diagonal alteration of enantiomers (L–O) visualized as described in Fig. 1.
Of the aforementioned alternatives, X-ray diffraction
analysis established (Fig. 5) that a simple horizontal/
vertical alternation of the molecular tectons (S)- and
(R)-2a, linked by the homofunctional car-
boxylꢀcarboxyl and amideꢀamide double hydrogen
bonds (mode H) accounts for the single-crystal self-
assembly of the racemate (RS)-2a into achiral layers. A
closer examination of the crystal structure of (RS)-2a
shows that the individual 2D layers are stacked in a
staggered manner and are interconnected by inter-
molecular amideꢀamide single hydrogen bonds. The
resulting 3D framework is rigidified by intramolecular
amideꢀamide single hydrogen bonds, similarly as noted
above for the enantiopure tecton (S)-2a.
important properties, (a) chirality of the biaryl axis,
and (b) two pairs of distinct ortho-, ortho%-substituents
capable of participation in the formation of intermolec-
ular hydrogen bonds.
CONH2
CONH2
O
N
HOOC
HOOC
HOOC
HOOC
O
N
(S)-2a
(S)-5
2.3.1. Comparison of the enantiopure tectons (S)-2a ver-
sus (S)-5. As has already been pointed out, the enan-
tiopure biphenyl tecton (S)-2a employs a blend of the
homo- and heterofunctional double hydrogen bonds in
the self-assembly via the hydrogen bonding mode F.
Whereas, the corresponding bipyridyl tecton (S)-5
exploits16 the heterofunctional ꢀNꢀO···HOOCꢀ single
hydrogen bond, which is analogous with the hydrogen
bonding mode E. Reasons for this difference can be
explained as follows.
2.2.4. Self-assembly of the achiral isomer 3a. 2,2%-Dicar-
bamoylbiphenyl-6,6%-dicarboxylic acid 3a is the achiral
counterpart of the chiral tecton 2a. A priori stereo-
chemical analysis suggests that the achiral tecton 3a
allows formation of the chiral squares by two alterna-
tive hydrogen bonding modes, exploiting either the
homofunctional (carboxylꢀcarboxyl and amideꢀamide)
or the heterofunctional (carboxylꢀamide) double hydro-
gen bonds (Fig. 6; P and Q, respectively). The latter of
the two alternative modes (Q) actually operates in the
crystal 3a (Fig. 7).
In the self-assembly of the biphenyl tecton (S)-2a both
the participating (carboxyl and amide) functional
groups serve simultaneously17,18 as an acceptor as well
as a donor in the hydrogen bond, thus allowing ‘a free
choice’ among the four alternative hydrogen bonding
modes D–G (Fig. 2). As a contrast, only one of the
functional groups (carboxyl) in the bipyridyl tecton 5
can serve the dual acceptor–donor role, the other
(amine oxide) group being solely hydrogen bond accep-
2.3. Comparison with earlier crystallographic results
The present study has been stimulated by our earlier
investigation16 of
a
related biaryl tecton, 2,2%-
bipyridine-3,3%-dicarboxylic acid-1,1%-dioxide 5, which
together with the novel tecton 2a have in common two

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P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
Figure 5. Segment of an infinite achiral layer in the crystal of (RS)-2a formed by intermolecular double hydrogen bonds.
Disordered water molecules and all hydrogens are omitted for clarity. Carbon atoms are not distinguished, oxygens in carboxyls
are drawn as red circles, disordered oxygen/nitrogen atoms in carbamoyl groups are shown as red/blue-halved circles.
2.3.2. The racemic tectons (RS)-2a versus (RS)-5. The
corresponding racemates (RS)-2a and (RS)-5 exploit
3a
different hydrogen bonding modes in the single-crystal
COOH =
, CONH2 =
self-assembly. The homofunctional (carboxylꢀcarboxyl
and amideꢀamide) double hydrogen bonds operate in
the self-assembly of the former whereas the heterofunc-
tional (carboxylꢀamine oxide) single hydrogen bonds
are engaged16 in the self-assembly of the latter
racemate.
Notably, the distribution pattern of the opposite enan-
tiomers found in the single crystals of the two race-
mates is also different. As has already been noted, a
regular horizontal/vertical alternation of enantiomeri-
cally opposite molecular tectons occurs in the crystal of
the biphenyl racemate (RS)-2a and the resulting indi-
vidual infinite square layers are accordingly achiral. In
a striking contrast, in the corresponding crystal of
(RS)-5 the individual infinite square layers are
homochiral, being set up from tectons that are enan-
tiomerically uniform. Within a single racemic crystal of
Q
P
Figure 6. Two theoretical modes of hydrogen bonding of the
achiral tecton 3a visualized as described in Fig. 1.
tor. Thus, the bipyridyl tecton 5 is relegated to the
formation of square layers via the heterofunctional
hydrogen bonds.

P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
3041
Figure 7. Segment of an infinite achiral layer in the crystal of 3a formed by intermolecular double hydrogen bonds, details as in
Fig. 3.
the tecton (RS)-5, enantiomeric separation accordingly
occurs on the level of the alternating homochiral 2D
layers. Only a few similar cases have been reported in
literature to date.12–15
ity of the enantiomeric distribution must be also
taken into account.
Results of the theoretical analysis were compared
with the experimental findings obtained from X-ray
crystallographic analysis of five isosteric biaryl tec-
tons, (S)-2a, (RS)-2a, 3a, (S)-5, and (RS)-5, distin-
guished by chirality, by enantiomeric homogeneity, or
by hydrogen bonding ability of the individual sub-
stituents.
3. Conclusion
Hydrogen bonding o-,o-,o%-,o%-tetrasubstituted chiral
as well as achiral biaryls exhibit unique self-assem-
bling properties, giving rise to chiral square cyclotet-
ramers. The individual chiral squares self-assemble
further to form of infinite open square layers which
are either achiral or are chiral (homochiral). Biaryls
which are achiral yield achiral layers. Biaryls which
are chiral and enantiomerically uniform give
homochiral layers. Racemic biaryls exhibit intermedi-
ate behaviour, affording either achiral or chiral
(homochiral) square layers, depending on the nature
of the biaryl substituents.
4. Experimental
4.1. General
Melting points were determined on a Kofler appara-
1
tus and are uncorrected. H NMR spectra were mea-
sured on a Varian Unity XL-200 spectrometer (200
MHz, FT mode). Mass spectra were recorded on a
ZAB-EQ (VG Analytical) instrument. Thioglycerol/
glycerol and 2-hydroxyethyl disulfide matrices were
used for FAB techniques. Silica gel 60 (0.063–0.200
mm, Fluka) was used for column chromatography.
TLC analyses were done on aluminium sheets silica
gel 60 F254 (Merck) with UV detection.
A priori analysis shows that several hydrogen bond-
ing modes can compete in the self-assembly, giving
rise to alternative supramolecular chiral squares and
infinite layers. In the case of racemic tectons variabil-

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P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
4.2. Preparation of dibenzyl esters and their
transformations
(100). Anal. calcd for C30H24N2O6: C, 70.86; H, 4.76;
N, 5.51. Found C, 70.60; H, 4.90; N, 5.41%.
4.2.4. 2%,6%-Dicarbamoylbiphenyl-2,6-dicarboxylic acid
3a. Palladium on carbon (10% Pd/C, 50 mg) was
added to a solution of dicarbamoyldiester 3c (250 mg,
0.492 mmol) in 60% aq. methanol (150 mL) and the
suspension was stirred under H2 atmosphere at rt
overnight. The catalyst was filtered off and washed
with 50% aq. methanol (2×50 mL). The combined
filtrate and washings were evaporated to dryness and
the residue was crystallized from hot water. Yield 150
mg (93%), mp 346–348°C. 1H NMR spectrum
(DMSO-d6) l 13.35 (br s, 2H), 7.79 (d, J=7.6 Hz,
2H), 7.42–7.66 (m, 8H). MS FAB spectrum (m/z, %
rel.): 329 (MH+, 2), 235 (13), 201 (23), 187 (25), 181
(12), 171 (95), 159 (34), 149 (15), 110 (36), 91 (100).
Anal. calcd for C16H12N2O6: C, 58.54; H, 3.68; N,
8.53. Found C, 58.39; H, 3.74; N, 8.38%.
4.2.1. Reaction of dianhydride 4 with benzyl alcohol. A
mixture of dianhydride 4 (1.00 g, 3.4 mmol), benzyl
alcohol (1.00 g, 9.25 mmol), dry pyridine (8 mL) and
4-dimethylaminopyridine (100 mg, 0.82 mmol) was
heated to 110°C under stirring for 6 h. After cooling,
the mixture was treated with aq. HCl (2 M, 100 mL)
and extracted with ethyl acetate (4×30 mL). The com-
bined extracts were washed with 10% aq. sodium car-
bonate (3×30 mL). The washing was acidified with
conc. HCl to pH 1, the pasty precipitate was taken
up in ethyl acetate (4×20 mL), dried with MgSO4 and
evaporated in vacuo. The semi-solid residue (1.52 g)
was separated into the individual products by column
chromatography (silica gel, eluent toluene:ethyl ace-
tate:acetic acid 80:19:1) followed by crystallization
from a toluene–heptane mixture.
Biphenyl-2,2%,6,6%-tetracarboxylic acid 2%,6%-dibenzyl
ester 3b: yield 759 mg (44%), mp 218–220°C. Anal.
calcd for C30H22O8: C, 70.58; H, 4.34. Found C,
70.38; H, 4.44%. 1H NMR spectrum was in accord
with the reported data.11
4.2.5. 6,6%-Dicarbamoyl-(RS)-biphenyl-2,2%-dicarboxylic
acid (RS)-2a. Prepared analogously from the dicar-
bamoyldiester (RS)-2c (220 mg, 0.433 mmol). Yield
1
128 mg (90%), mp 307–309°C (dec.). H NMR spec-
trum (DMSO-d6) l 12.48 (br s, 2H), 7.89 (dd, J=7.6
Hz, J=1.5 Hz, 2H), 7.80 (br s, 2H), 7.54 (dd, J=7.6
Hz, J=1.5 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.27 (br
s, 2H). MS FAB spectrum (m/z, % rel.): 329 (MH+,
2), 274 (4), 257 (5), 232 (3), 202 (13), 181 (12), 149
(6), 126 (9), 110 (100), 91 (38), 75 (54), 57 (61). Anal.
calcd for C16H12N2O6: C, 58.54; H, 3.68; N, 8.53.
Found C, 58.54; H, 3.85; N, 8.28%.
(RS)-Biphenyl-2,2%,6,6%-tetracarboxylic acid 6,6%-diben-
zyl ester (RS)-2b: yield 523 mg (30%), mp 231–232°C.
Anal. calcd for C30H22O8: C, 70.58; H, 4.34. Found
1
C, 70.61; H, 4.29%. H NMR spectrum was in accord
with the reported data.11
4.2.2. 2%,6%-Dicarbamoylbiphenyl-2,6-dicarboxylic acid
dibenzyl ester 3c. Oxalyl chloride (1.455 g, 11.46
mmol) and 4-dimethylaminopyridine (20 mg, 0.16
mmol) were added to a solution of dibenzyl ester 3b
(400 mg, 0.783 mmol) in dry dichloromethane (10
mL) and the mixture was stirred at rt for 12 h. After
evaporation of the volatiles, the residue was dissolved
in dioxane (20 mL) and added dropwise into a stirred
solution of conc. aq. NH4OH (5 mL) in dioxane (5
mL). After 1 h stirring, the mixture was taken to
dryness and the crude product was crystallized from
4.3. Preparation of (S)-1-phenylethyl esters and their
transformations
4.3.1. Reaction of dianhydride
4 with (S)-(−)-1-
phenylethanol. Performed analogously as the reaction
with benzyl alcohol (Section 4.2.1) starting from dian-
hydride
4
(1.18 g,
4
mmol) and (S)-(−)-1-
phenylethanol (1.22 g, 10 mmol).
Biphenyl-2,2%,6,6%-tetracarboxylic acid 2%,6%-bis-[(S)-1-
phenylethyl] ester 3d: yield 905 mg (42%), mp 188–
190°C. 1H NMR spectrum (DMSO-d6) l 8.05 (d,
J=7.9 Hz, 2H), 8.01 (d, J=7.9 Hz, 2H), 7.52 (t,
J=7.9 Hz, 2H), 7.05–7.35 (m, 10H), 5.66 (q, J=6.4
Hz, 2H), 1.06 (d, J=6.4 Hz, 6H). MS FAB spectrum
(m/z, % rel.): 561 (MNa+, 10), 539 (MH+, 8), 435 (8),
331 (50), 313 (100), 269 (10), 251 (22). Anal. calcd for
C32H26O8: C, 71.37; H, 4.87. Found C, 71.21; H, 4.82.
1
aq. ethanol. Yield 370 mg (92%), mp 215–217°C. H
NMR spectrum (DMSO-d6) l 7.97 (d, J=7.9 Hz,
2H), 7.42–7.56 (m, 3H), 7.20–7.38 (m, 11H), 7.03 (br
s, 2H), 6.97 (br s, 2H), 4.99 (s, 4H). MS FAB spec-
trum (m/z, % rel.): 509 (MH+, 9), 309 (8), 278 (21),
250 (9), 231 (30), 184 (9), 154 (76), 137 (100), 109
(34), 91 (23). Anal. calcd for C30H24N2O6: C, 70.86;
H, 4.76; N, 5.51. Found C, 70.68; H, 4.85; N, 5.38%.
4.2.3. 6,6%-Dicarbamoyl-(RS)-biphenyl-2,2%-dicarboxylic
acid dibenzyl ester (RS)-2c. Prepared analogously
from the racemic dibenzyl ester 2b (420 mg, 0.823
mmol). Yield 395 mg (94%), mp 187–189°C. 1H
NMR spectrum (DMSO-d6) l 7.76 (br s, 2H), 7.84
(dd, J=7.6 Hz, J=1.5 Hz, 2H), 7.56 (dd, J=7.6 Hz,
J=1.5 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.24–7.36
(m, 8H), 7.10–7.21 (m, 4H), 5.03 (d, J=12.5 Hz, 2H),
4.88 (d, J=12.5 Hz, 2H). MS FAB spectrum (m/z, %
rel.): 509 (MH+, 22), 419 (2), 251 (4), 181 (14), 91
(S)-Biphenyl-2,2%,6,6%-tetracarboxylic acid 6,6%-bis-[(S)-
1-phenylethyl] ester (S)-2d: yield 603 mg (28%), mp
184–186°C. 1H NMR spectrum (DMSO-d6) l 8.05
(dd, J=7.8 Hz, J=1.4. Hz, 2H), 8.01 (dd, J=7.8 Hz,
J=1.4 Hz, 2H), 7.52 (t, J=7.8 Hz, 2H), 7.05–7.30
(m, 10H), 5.65 (q, J=6.4 Hz, 2H), 1.04 (d, J=6.4
Hz, 6H). MS FAB spectrum (m/z, % rel.): 561
(MNa+, 15), 539 (MH+, 12), 435 (9), 331 (60), 313
(100), 269 (15), 251 (15). Anal. calcd for C32H26O8: C,
71.37; H, 4.87. Found C, 71.36; H, 4.86%.

P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
3043
(R)-Biphenyl-2,2%,6,6%-tetracarboxylic acid 6,6%-bis-[(S)-
1-phenylethyl] ester (R)-2d: yield 43 mg (2%), mp 168–
170°C. 1H NMR spectrum (DMSO-d6) l 8.03 (d,
J=7.8 Hz, 4H), 7.53 (t, J=7.8 Hz, 2H), 7.00–7.28 (m,
10H), 5.64 (q, J=6.4 Hz, 2H), 1.07 (d, J=6.4 Hz, 6H).
MS FAB spectrum (m/z, % rel.): 539 (MH+, 12), 435
(8), 417 (7), 352 (40), 331 (50), 313 (100). Anal. calcd
for C32H26O8: C, 71.37; H, 4.87. Found C, 71.28; H,
4.89%.
calcd for C16H12N2O6: C, 58.54; H, 3.68; N, 8.53.
Found C, 58.39; H, 3.91; N, 8.38%.
4.4. X-Ray diffraction analysis
Single crystals of compounds (S)-2a, (RS)-2a and 3a
were grown from their aqueous solutions by slow cool-
ing. Single crystals of the diester (S)-2d were obtained
by a slow diffusion of hexane into the toluene solution.
Crystal data, measurement and refinement details for
compounds listed above are summarized in Table 1.
4.3.2.
6,6%-Dicarbamoyl-(S)-biphenyl-2,2%-dicarboxylic
acid bis[(S)-1-phenylethyl] ester (S)-2e. Prepared from
diester (S)-2d (300 mg, 0.557 mmol) analogously as
described above for dibenzyl derivative 3c. Yield 275
(S)-2a monohydrate contains two crystallographically
independent molecules which differ significantly in their
relative conformation, see inset of Fig. 8. The water
molecule is held in a void of the structure by secondary
hydrogen bonds and is disordered over two positions
with the fixed relative occupancy of 75:25; since the two
positions are mutually closely spaced, the hydrogen
bonding scheme is essentially unaffected by the disor-
der. The carbon-bonded hydrogen atoms were fixed in
theoretical positions and assigned temperature parame-
ters 1.2 of their parent carbons, the other hydrogen
atoms were refined isotropically (except of those of the
minor position of the disordered water which were not
found).
1
mg (92%), mp 167–169°C. H NMR spectrum (DMSO-
d6) l 7.89 (dd, J=7.6 Hz, J=1.5 Hz, 2H), 7.75 (br s,
2H), 7.57 (dd, J=7.56 Hz, J=1.5 Hz, 2H), 7.46 (t,
J=7.6 Hz, 2H), 7.32 (br s, 2H), 7.20–7.30 (m, 10H),
5.66 (q, J=6.8 Hz, 2H), 1.28 (d, J=6.8 Hz, 6H).
spectrum (m/z, % rel.): 537 (MH+, 27), 433 (14), 329
(100), 312 (40), 269 (13), 251 (53). Anal. calcd for
C32H28N2O6: C, 71.63; H, 5.26; N, 5.22. Found C,
71.46; H, 5.36; N, 5.18%.
4.3.3.
6,6%-Dicarbamoyl-(S)-biphenyl-2,2%-dicarboxylic
acid (S)-2a. Prepared from (S)-2e (250 mg, 0.466 mmol)
analogously as described above for the positional iso-
mer 3a. Yield 139 mg (91%), mp 320°C (dec.), [h]D20
In the crystal of (RS)-2a hemihydrate both carbamoyl
groups exhibit rotational disorder about their bonds to
the aromatic carbons which makes impossible to distin-
1
−32.8 (c 0.25, 50% aq. methanol). H NMR and MS
FAB spectra are in accord with those of (RS)-2a. Anal.
Table 1. Crystal data, measurement and refinement detailsa
Compound
(S)-2a
(RS)-2a
3a
(S)-2d
Empirical formula
Crystal system
Space group
C16H14N2O6.5
Orthorhombic
P21221 (no. 18)
11.4170(1)
13.0690(2)
20.4990(3)
C16H13N2O6.5
Monoclinic
P21/c (no. 14)
10.1500(4)
11.5400(4)
13.0890(4)
103.340(2)
4
C16H12N2O6
Orthorhombic
Pna21 (no. 33)
10.643(1)
13.512(2)
10.337(1)
C32H26O8
Monoclinic
P21 (no. 4)
8.8730(1)
31.8750(3)
9.7690(1)
94.0010(6)
4
,
a (A)
,
b (A)
,
c (A)
i (°)
Z
8
4
3
,
V (A )
3058.63(7)
1.469
1491.76(9)
1.502
1486.5(3)
1.467
2756.20(5)
1.298
Dcalcd (g cm−3
)
Temperature (K)
Crystal size (mm)
150(2)
0.3×0.5×0.55
0.116
−13, 13
−16, 16
−26, 26
36664
150(2)
0.25×0.25×0.45
0.119
−12, 12
−13, 13
−15, 15
19515
150(2)
0.25×0.3×0.3
0.115
0, 12
−16, 16
0, 12
150(2)
0.25×0.3×0.35
0.093
−11, 11
−40, 40
−12, 12
41995
v (mm−1
h Range
k Range
l Range
)
Reflections measured
2704
Independent reflections (Rint
)
6534(0.027)
5879
545
2627(0.027)
2521
234
1388(0.037)
1225
265
11952(0.037)
9952
735
Observed reflections [I\2|(I)]
No. of parameters
GOF
1.060
1.231
1.034
1.022
R, wR (observed data)
0.040, 0.091
0.064, 0.145
0.026, 0.064
0.055, 0.135
a Data in common: Nonius KappaCCD and CAD4-MACHIII diffractometers for (S)-2a, (RS)-2a, (S)-2d and 3a, respectively, Mo Ka,
u=0.71073, direct methods (SIR-9219), full-matrix least-squares refinement on F2 (SHELXL-9720); see text for further details of individual
structures.

3044
P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
mutually and, therefore, the net result is the 180°
rotational disorder of the whole double carbamoyl
hydrogen bridge. The water molecule is again hold in a
void by secondary hydrogen bonds. Hydrogen atoms
were treated as above except of the disordered ones
which were fixed in calculated positions.
In the crystal of 3a all hydrogen atoms were refined
isotropically; the molecular structure is shown in Fig.
10.
In the crystal of (S)-2d there are again two crystallo-
graphically independent molecules of remarkably differ-
ent conformation (see inset of Fig. 11). One phenyl
group of one molecule is heavily disordered over two
positions modelled with the fixed 80:20 occupancy.
Hydrogen atoms were treated as for (S)-2a.
Crystallographic data (excluding structure factors) for
the structures (S)-2a, (RS)-2a, 3a and (S)-2d have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
173042, CCDC 173043, CCDC 173044 and CCDC
173045, respectively. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
Figure 8. Perspective view of one of the two independent
molecules of (S)-2a with atom labelling (40% probability
ellipsoids, hydrogen atoms as spheres of arbitrary size). An
overlay of the two molecules with one phenyl ring as reference
is given in the inset.
Acknowledgements
guish their oxygen and nitrogen atoms. The disorder
was modelled in 50:50 fixed occupancy with two hydro-
gen atoms of half occupancy assigned to each disor-
dered N/O atom (Fig. 9). Fortunately, the disorder
does not affect the overall hydrogen bonding scheme
since the two disordered groups are hydrogen-bonded
The financial support provided by the Grant Agency of
the Czech Republic to the authors (project No. 203/00/
0138) and to the Center for Molecular and Crystal
Structures (No. 203/99/M037) is gratefully acknowl-
edged. This work was performed within the framework
of the research project Z-4055905.
Figure 9. Perspective view of one molecule of (RS)-2a with
atom labelling (40% probability ellipsoids, hydrogen atoms as
spheres of arbitrary size). Hydrogen atoms of disordered
carbamoyl groups are omitted.
Figure 10. Perspective view of one of the two independent
molecules of 3a with atom labelling (50% probability ellip-
soids, hydrogen atoms as spheres of arbitrary size).

P. Holy´ et al. / Tetrahedron: Asymmetry 12 (2001) 3035–3045
3045
Figure 11. Perspective view of one molecule of (S)-2d (unaffected by disorder) with atom labelling (40% probability ellipsoids,
hydrogen atoms as spheres of arbitrary size). Overlay of the two molecules is given in inset.
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