11814 J. Am. Chem. Soc., Vol. 119, No. 49, 1997
Palacin et al.
that, with the exception of TMeC6DKP and IndDKP, the planar
conformation permits more efficient packing of molecules (or
tapes) in the crystal than the lower energy boat conformation.
bonds. Further puckering of the DKP ring results in the type
of nonplanar tape observed in the crystalline solid of IndDKP.63
Comparison of the carbonyl stretching frequency in DKPs
suggests a difference of ∼15 cm-1 between the planar and boat
conformations, both in solution and in the polycrystalline solid.
This difference, if confirmed with more extensive data, may be
useful in discriminating between the planar and boat conforma-
tion of DKPs. Modeling of the vibrational properties of the
DKP ring in the boat conformation (simulations of planar DKPs
are available)64-67 may allow for unambiguous assignment of
conformation. The observed increase in the vibrational fre-
quency of the CdO stretching mode in the boat conformation
is consistent with similar behavior observed in lactams.68-70 It
is doubtful that this shift in frequency is related only to the
nonplanarity of the amide group, as claimed by Blaha,68,70 since
no straightforward relationship can be found in our data between
the torsion angle ω and the frequency of the CdO stretch.
The filling of space appears to be the driving force behind
the packing of the tapes. Adjacent tapes pack through a half-
period shift along the main axis of the tape, which brings the
substituent on one tape close to the amide dimer of the adjacent
tape. In all eight structures, the closest contact between adjacent
tapes occurs between substituents of one tape and the carbonyl
oxygen of an adjacent tape.
Discussion
The structure of the eight crystalline solids presented can be
analyzed in terms of successive levels of organization following
Kitaigorodskii’s Aufbau principle:4 DKPs reliably form one-
dimensional tapes; tapes pack into two-dimensional sheets by
interdigitation of substituents on adjacent tapes; sheets stack
into three-dimensional crystalline structures. The fact that all
eight DKPs form tapes in their crystalline solids, whether they
are planar or nonplanar tapes, suggests that the location of
substituents on the DKP ring limits their influence on the
formation of the tapes and allows systematic variation in the
structure of these substituents while preserving the common tape
motif. Moreover, the tape motif is preserved even when the
geometry of the DKP ring changes.
The question of conformation with regard to DKPs in solution
has been examined using NMR.38-42 For example, DKPs
bearing aromatic side chains generally adapt the boat conforma-
tion in solution. Our molecular-modeling studies of DKPs in
vacuum, as well as those of others, confirm that the boat
conformation is generally the more stable conformation.43-48
As shown by Ciarkowski, however, all possible conformations
of the DKP ring are found within a 6 kcal mol-1 range.44
Almost half of the published crystal structures of diketopip-
erazines contain the DKP ring in the boat conformation.49
Among them, 12 form nonplanar tapes similar to those observed
in the crystalline solids of C4DKP and TMeC6DKP.50-62 We
note, however, that the high degree of puckering observed in
C4DKP and TMeC6DKP has not been previously observed in
symmetrically substituted DKPs. The nonplanarity of the DKP
ring may be a way of increasing the strength of the hydrogen
Conclusions
We have selected derivatives of diketopiperazines, together
with cyclic ureas,23 as candidates for comparative work in the
solid state on the basis of a survey of the literature.18 In this
paper we systematically tested the ability of DKPs to form tapes
in the presence of nonpolar, achiral, cycloalkyl substituents that
represent a substantial range of size and shape. As evident from
the crystal structures presented, the hydrogen-bonded tape motif
is sufficiently stable that it survives large changes in the shape
and volume of the alkyl substituents. Although bulkier sub-
stituents may preclude the formation of the tapes, this effect
has not yet been demonstrated experimentally. These results,
along with those from previous studies, establish that DKPs
reliably form tapes in the presence of a large variety of
substituents: small or bulky, apolar or slightly polar, flexible
or rigid, and aliphatic or aromatic.
(38) Anteunis, M. J. O. Bull. Soc. Chim. Belg. 1978, 87, 627.
(39) Sammes, P. G. Fortschr. Chem. Org. Naturst. 1975, 32, 51.
(40) Deslauriers, R.; Grzonka, Z.; Schaumburg, K.; Shiba, T.; Walter,
R. J. Am. Chem. Soc. 1975, 97, 5093.
(41) Patino, N.; Condom, R.; Ayi, I.; Guedj, R.; Aumelas, A. J. Fluorine
Chem. 1992, 59, 47.
(42) Rajappa, S.; Natekar, M. V. AdV. Heterocycl. Chem. 1993, 57, 187.
(43) Ramani, R.; Sasisekharan, V.; Venkatesan, K. Int. J. Peptide Protein
Res. 1977, 9, 277.
Our results also indicate that the tape motif can accommodate
either the planar or boat conformation of the DKP ring. Trends
from molecular modeling in vacuum suggest that when the boat
conformation is favored over the planar conformation by <2
kcal/mol, then the planar conformation may appear in the crystal;
when the boat is favored over the planar conformation by >2
kcal/mol, then the boat conformation appears in the crystal. This
information may be useful in predicting the conformation of
new derivatives of DKPs in the solid state.
The XPD patterns of crystals grown under different conditions
(see Supporting Information) provide further evidence in support
of using DKPs as a basis for a systematic study of physical-
organic chemistry of the solid statesonly one example showed
polymorphism. One explanation for the low frequency of
polymorphism may be that the hydrogen-bond donor and
(44) Ciarkowski, J. Biopolymers 1984, 23, 397.
(45) Bielinski, H.; Ciarkowski, J. Biopolymers 1986, 25, 795.
(46) Kolodziejczyk, A.; Ciarkowski, J. Biopolymers 1986, 25, 771.
(47) Jankowska, R.; Ciarkowski, J. Int. J. Pept. Protein Res. 1987, 30,
61.
(48) Gdaniec, M.; Liberek, B.; Kolodziejczyk, A.; Jankowska, R.;
Ciarkowski, J. Int. J. Pept. Protein Res. 1987, 30, 79.
(49) The N-substituted DKPs have not been taken into account here.
(50) Sletten, E. J. Am. Chem. Soc. 1970, 92, 172.
(51) Gorbitz, C. H. Acta Chem. Scand. 1987, B41, 83.
(52) Lin, C. F.; Webb, L. E. J. Am. Chem. Soc. 1973, 95, 6803.
(53) Mez, H. C. Cryst. Struct. Commun. 1974, 3, 657.
(54) Cotrait, M.; Ptak, M.; Busetta, B.; Heitz, A. J. Am. Chem. Soc 1976,
98, 1073.
(55) Tanaka, I.; Iwata, T.; Takahashi, N.; Ashida, T.; Tanihara, M. Acta
Crystallogr. 1977, B33, 3902.
(56) Varughese, K. I.; Lu, C. T.; Kartha, G. Int. J. Protein Res. 1981,
18, 88.
(57) Suguna, K.; Ramakumar, S.; Kopple, K. D. Acta Crystallogr. 1984,
C40, 2053.
(58) Ajo, D.; Casarin, M.; Bertoncello, R.; Busetti, V.; Ottenheijm, H.
C. J.; Plate, R. Tetrahedron 1985, 41, 5543.
(59) Kojima, Y.; Yamashita, T.; Nishide, S.; Hirotsu, K.; Higuchi, T.
Bull. Chem. Soc. Jpn. 1985, 58, 409.
(60) Gdaniec, M.; Liberek, B. Acta Crystallogr. 1986, C42, 1343.
(61) Symersky, J.; Blaha, K.; Langer, V. Acta Crystallogr. 1987, C43,
303.
(64) Karplus, S.; Lifson, S. Biopolymers 1974, 10, 1973.
(65) Gupta, M. K.; Gupta, V. D. Indian J. Biochem. Biophys. 1978, 15,
407.
(66) Cheam, T. C.; Krimm, S. Spectrochim. Acta 1984, 40A, 481.
(67) Cheam, T. C.; Krimm, S. Spectrochim. Acta 1988, 44A, 185.
(68) Smolikova, J.; Koblicova, Z.; Blaha, K. Collect. Czech. Chem.
Commun. 1973, 38, 532.
(62) Valle, G.; Guanteri, V.; Tamburro, A. M. J. Mol. Struct. 1990, 220,
19.
(63) The only other example of a racemic DKP tape is with a racemic
mixture of 2,5-diazabicyclo[2.2.2]octane-3,6-dione (ref 15).
(69) Vicar, J.; Smolikova, J.; Blaha, K. Collect. Czech. Chem. Commun.
1973, 38, 1957.
(70) Smolikova, J.; Tichy, M.; Blaha, K. Collect. Czech. Chem. Commun.
1976, 41, 413.