Crystal structure prediction of aminols: Advantages of a supramolecular synthon approach with experimental structures

Article abstract of DOI:10.1021/ja042738c

The supramolecular synthon approach to crystal structure prediction (CSP) takes into account the complexities inherent in crystallization. The synthon is a kinetically favored unit, and through analysis of commonly occurring synthons in a group of related compounds, kinetic factors are implicitly invoked. The working assumption is that while the experimental structure need not be at the global minimum, it will appear somewhere in a list of computationally generated structures so that it can be suitably identified and ranked upward using synthon information. These ideas are illustrated with a set of aminophenols, or aminols. In the first stage, a training database is created of the 10 isomeric methylaminophenols. The crystal structures of these compounds were determined. The prototypes 2-, 3-, and 4-aminophenols were also included in the training database. Small and large synthons in these 13 crystal structures were then identified. Small synthons are of high topological but low geometrical value and are used in negative screens to eliminate computationally derived structures that are chemically unreasonable. Large synthons are more restrictive geometrically and are used in positive screens ranking upward predicted structures that contain these more well-defined patterns. In the second stage, these screens are applied to CSP of nine new aminols carried out in 14 space groups. In each space group, up to 10 lowest energy structures were analyzed with respect to their synthon content. The results are encouraging, and the predictions were classified as good, unclear, or bad. Two predictions were verified with actual crystal structure determinations.

Full text of DOI:10.1021/ja042738c

Published on Web 07/09/2005
Crystal Structure Prediction of Aminols: Advantages of a
Supramolecular Synthon Approach with Experimental
Structures
Archan Dey,† Michael T. Kirchner,† Venu R. Vangala,† Gautam R. Desiraju,*,†
Raju Mondal,‡ and Judith A. K. Howard*,‡
Contribution from the School of Chemistry, UniVersity of Hyderabad, Hyderabad 500046, India,
and Department of Chemistry, UniVersity of Durham, South Road, Durham DH1 3LE, U.K.
Received December 2, 2004; E-mail: gautam_desiraju@yahoo.com
Abstract: The supramolecular synthon approach to crystal structure prediction (CSP) takes into account
the complexities inherent in crystallization. The synthon is a kinetically favored unit, and through analysis
of commonly occurring synthons in a group of related compounds, kinetic factors are implicitly invoked.
The working assumption is that while the experimental structure need not be at the global minimum, it will
appear somewhere in a list of computationally generated structures so that it can be suitably identified and
ranked upward using synthon information. These ideas are illustrated with a set of aminophenols, or aminols.
In the first stage, a training database is created of the 10 isomeric methylaminophenols. The crystal structures
of these compounds were determined. The prototypes 2-, 3-, and 4-aminophenols were also included in
the training database. Small and large synthons in these 13 crystal structures were then identified. Small
synthons are of high topological but low geometrical value and are used in negative screens to eliminate
computationally derived structures that are chemically unreasonable. Large synthons are more restrictive
geometrically and are used in positive screens ranking upward predicted structures that contain these
more well-defined patterns. In the second stage, these screens are applied to CSP of nine new aminols
carried out in 14 space groups. In each space group, up to 10 lowest energy structures were analyzed
with respect to their synthon content. The results are encouraging, and the predictions were classified as
good, unclear, or bad. Two predictions were verified with actual crystal structure determinations.
Introduction
the corporate scientific community, and especially in the
pharmaceutical industry.4
Crystal structure prediction (CSP) has emerged as a problem
of outstanding importance in supramolecular science.1 While it
is stated simply enough as the prediction of the space group,
cell dimensions, and atomic fractional coordinates from the
chemical diagram of a small organic molecule, the hurdles
associated in so doing are numerous and the effort has been
termed as being of “formidable” difficulty in at least two recent
publications.2 General or particular solutions to CSP imply a
complete or partial understanding of the mechanism of crystal-
lization (molecule f crystal), and since this is a complex
phenomenon, CSP is rightly expected to be very difficult. CSP
is closely connected with polymorphism;3 accordingly, its value
as a predictive tool has always raised high expectations within
CSP has come of age during the past decade, with the
evolution of better force fields and increase in data processing
power,5 culminating in three blind tests organized by the
Cambridge Crystallographic Data Centre6 with the aim of
answering the question, “Can crystal structures be predicted?”
Now, seven years and eleven molecules later, the answer is not
much clearer: yes, no perhaps, sometimes.7 Generality is still
lacking, and there is a realization that while crystallization is
(4) (a) Beyer, T.; Price, S. L. CrystEngComm 2000, 3, 183. (b) Beyer, T.;
Day, G. M.; Price, S. L. J. Am. Chem. Soc. 2001, 123, 5086. (c) Smith, E.
D. L.; Hammond, R. B.; Jones, M. J.; Roberts, K. J.; Mitchell, J. B. O.;
Price, S. L.; Harris, R. K.; Apperley, D. C.; Cherryman, J. C.; Docherty,
R. J. Phys. Chem. 2001, B105, 5818. (d) Price, S. L. AdV. Drug DeliVery
ReV. 2004, 56, 301. (e) Ouvrard, C.; Price, S. L. Cryst. Growth Des. 2004,
4, 1119.
(5) Selected references include: (a) Karfunkel, H. R.; Gdanitz, R. J. J. Comput.
Chem. 1992, 13, 1171. (b) Perlstein, J. J. Am. Chem. Soc. 1992, 114, 1955.
(c) Holden, J. R.; Du, Z.; Ammon, H. L. J. Comput. Chem. 1993, 14, 422.
(d) Perlstein, J. J. Am. Chem. Soc. 1994, 116, 455. (e) van Eijck, B. P.;
Spek, A. L.; Mooij, W. T. M.; Kroon, J. Acta Crystallogr. 1998, B54, 291.
(f) Engel, G. E.; Wilke, S.; Konig, O.; Harris, K. D. M.; Leusen, F. J. J. J.
Appl. Crystallogr. 1999, 32, 1169. (g) Bond, A. D.; Feeder, N.; Teat, S. J.;
Jones, W. Tetrahedron 2000, 56, 6617. (h) Mooij, W. T. M.; van Eijck, B.
P.; Kroon, J. J. Am. Chem. Soc. 2000, 122, 3500. (i) Beyer, T.; Lewis, T.;
Price, S. L. CrystEngComm 2001, 4, 1. (j) Gavezzotti, A. CrystEngComm
2002, 4, 343. (k) Lewis, T. C.; Tocher, D. A.; Day, G. M.; Price, S. L.
CrystEngComm 2003, 5, 3. (l) Leusen, F. J. J. Cryst. Growth Des. 2003, 3,
189. (m) Dzyabchenko, A.; Scheraga, H. A. Acta Crystallogr. 2004, B60,
228. (n) Price, S. L. CrystEngComm 2004, 344. (o) Day, G. M.; Price, S.
L. J. Am. Chem. Soc. 2003, 125, 16434.
† University of Hyderabad.
‡ University of Durham.
(1) (a) Dunitz, J. D. Chem. Commun. 2003, 545. (b) Dunitz, J. D.; Scheraga,
H. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 14309.
(2) (a) Desiraju, G. R. Nat. Mater. 2002, 1, 77. (b) Price, S. L. Ency. Supramol.
Chem. (Atwood, J. L., Steed, J., Eds.) 2004, 371.
(3) Selected references that show the relationship between CSP and polymor-
phism include: (a) Jetti, R. K. R.; Boese, R.; Sarma, J. A. R. P.; Reddy,
L. S.; Vishweshwar, P.; Desiraju, G. R. Angew. Chem., Int. Ed. 2003, 42,
1963. (b) Cross, W. I.; Blagden, N.; Davey, R. J. Cryst. Growth Des. 2003,
3, 151. (c) Tremayne, M.; Grice, L.; Pyatt, J. C.; Seaton, C. C.; Kariuki,
B. M.; Tsui, H. H. Y.; Price, S. L.; Cherryman, J. C. J. Am. Chem. Soc.
2004, 126, 7071. (d) Lewis, T. C.; Tocher, D. A.; Price, S. L. Cryst. Growth
Des. 2004, 4, 979. (e) Hulme, A. T.; Price, S. L.; Tocher, D. A. J. Am.
Chem. Soc. 2005, 127, 1116.
9
10.1021/ja042738c CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 10545-10559
10545

A R T I C L E S
Scheme 1
Dey et al.
complex, the methods inherent to CSP are very complicated.8
Crystallization is a complex phenomenon because its outcome,
the crystal structure, is only indirectly related to molecular
structure as expressed as a collection of functional groups; the
crystal structure obtained depends not only on the nature of these
groups but also on their number and positioning.9 CSP is a
complicated exercise because the computational procedures are
arduous, the sources of error are numerous, and small variations
in the force field could cause major variations in the predictions.
Some of these problems are put together in a basket called
“kinetic factors”, and while observed polymorphs are often the
ones that appear faster rather than those that are the most stable,2
computer simulation of crystallization, say through molecular
dynamics, is beyond the realms of possibility.
It is in the context of addressing these inescapable kinetic
issues that experimental based approaches to CSP have origi-
nated.10,11 At the core of these approaches is the supramolecular
synthon, which is a structural entity smaller than the complete
crystal but which encapsulates a sufficient amount of critical
structural information so that it serves as model for the entire
crystal.12 The structural synthon is a kinetically favored unit,
and through analysis of commonly occurring or robust synthons
in a group of related compounds, kinetic factors are implicitly
invoked. Synthon based approaches to CSP acknowledge that
crystallization is a manifestation of complexity. Rather than try
to model thermodynamic and kinetic factors rigorously, one
attempts to identify important synthons from experimental
crystal structures and use them as positive (or negative) screens
in selecting (or rejecting) computationally derived structures.
CSP today is more an exercise in reranking structures rather
than in predicting them because the force fields currently
available are good enough so that the experimental structure is
nearly always found in, say, the 500 structures that are closest
to the global minimum. The idea is that while the experimental
structure (kinetic polymorph) need not be the global minimum
(thermodynamic polymorph), it will appear somewhere in a list
of computationally generated structures so that it can be suitably
identified and ranked upward using synthon information.
In the solution of a complex problem, accuracy is usually
obtained at the expense of generality. The complexity inherent
in crystallization means that CSP strategies could become more
tractable if they are confined to groups of compounds that have
similar molecular structures.13,14 If such a group is understood
well from experimental and computational viewpoints, one
might consider evaluating another unknown member of the
group. If the similarities are satisfactory enough, one might
become confident enough to propose a crystal structure for the
new compound. Any such heuristic approach needs a sufficiently
large training database, and it has been estimated that, for a
general supramolecular synthon based interpretation of CSP
results, the Cambridge Structural Database (CSD) should contain
around a million refcodes.11c Because the CSD will not become
so large for several years, we sought to test this hypothesis and
generated our own small, but within itself exhaustive, database
of aminophenols, 1. We selected the simple aminols 2, 3, and
4 and all 10 possible methyl substituted derivatives 2a, 2b, 2c,
(6) (a) Lommerse, J. P. M.; Motherwell, W. D. S.; Ammon, H. L.; Dunitz, J.
D.; Gavezzotti, A.; Hofmann, D. W. M.; Leusen, F. J. J.; Mooij, W. T.
M.; Price, S. L.; Schweizer, B.; Schmidt, M. U.; van Eijck, B. P.; Verwer,
P.; Williams, D. E. Acta Crystallogr. 2000, B56, 697. (b) Motherwell, W.
D. S.; Ammon, H. L.; Dunitz, J. D.; Dzyabchenko, A.; Erk, P.; Gavezzotti,
A.; Hofmann, D. W. M.; Leusen, F. J. J.; Lommerse, J. P. M.; Mooij, W.
T. M.; Price, S. L.; Scheraga, H.; Schweizer, B.; Schmidt, M. U.; van Eijck,
B. P.; Verwer, P.; Williams, D. E. Acta Crystallogr. 2002, B58, 647.
(7) Gavezzotti, A. Acc. Chem. Res. 1994, 27, 309.
(8) For a distinction between the terms “complex” and “complicated”, see:
Ottino, J. M. Nature 2004, 427, 399.
(9) Desiraju, G. R. Science 1997, 278, 404.
(10) The reader will note that prediction of crystal structures using information
based on intermolecular interactions is not a new activity and that a notable
attempt was made in this direction long before CSP, as it is known today,
became fashionable. See: Leiserowitz, L.; Hagler, A. T. Proc. R. Soc.
London 1983, A388, 133.
(11) (a) Blagden, N.; Cross, W. I.; Davey, R. J.; Broderick, M.; Pritchard, R.
G.; Roberts, R. J.; Rowe, R. C. Phys. Chem. Chem. Phys. 2001, 3, 3819.
(b) Motherwell, W. D. S. Mol. Cryst. Liq. Cryst. 2001, 356, 559. (c) Sarma,
J. A. R. P.; Desiraju, G. R. Cryst. Growth Des. 2002, 2, 93. (d) Hofmann,
D. W. M.; Apostolakis, J. THEOCHEM 2003, 647, 17. (e) Hofmann, D.
W. M.; Kuleshova, L. N.; Antipin, M. Y. Cryst. Growth Des. 2004, 4,
1395. (f) Day, G. M.; Chisholm, J.; Shan, N.; Motherwell, W. D. S.; Jones,
W. Cryst. Growth Des. 2004, 4, 1327. (g) Desiraju, G. R. Curr. Sci. 2005,
88, 374.
(13) (a) Chin, D. N.; Palmore, G. T. R.; Whitesides, G. M. J. Am. Chem. Soc.
1999, 121, 2155. (b) Whitesides, G. M. Angew. Chem., Int. Ed. 2004, 43,
3632.
(14) This approach contradicts Kitaigorodskii who preferred a coarse method
provided it was general to a fine method which could be applied only to
selected systems. Kitaigorodskii, A. I. Molecular Crystal and Molecules;
Academic: New York, 1973; preface. We believe that CSP is so difficult
that truly general solutions are almost valueless, for example, a statement
that, in the predicted crystal structure, any molecule is surrounded by 12
others.
(12) (a) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311. (b) Nangia,
A.; Desiraju, G. R. Top. Curr. Chem. 1998, 198, 57.
9
10546 J. AM. CHEM. SOC. VOL. 127, NO. 30, 2005

Crystal Structure Prediction of Aminols
A R T I C L E S
Table 1. Crystallographic Data and Structure Refinement Parameters for the Compounds in This Study
2a
2b
2c
2d
3a
name
2-amino-3-
methylphenol
EtOH
149-152
orthorhombic
Iba2
21.6090(7)
7.4822(2)
8.2703(3)
90
2-amino-4-
methylphenol
EtOAc
135-137
orthorhombic
Pbca
7.5058(15)
7.7076(15)
22.691(5)
90
2-amino-5-
methylphenol
EtOAc+MeCN
157-159
monoclinic
P21/c
8.7860(5)
9.9708(5)
7.8700(4)
113.966(2)
4
2-amino-6-
methylphenol
MeOH+benzene
89.4
triclinic
P1h
8.0069(2)
8.0094(2)
20.3862(5)
84.7190(10)a
8
3-amino-2-
methylphenol
EtOAc
129-130
monoclinic
P21/n
6.6782(6)
8.1351(7)
11.9301(10)
101.661(2)
4
crystallization
mp [°C]
crystal system
space group
a [Å]
b [Å]
c [Å]
â [deg]
Z
8
8
V [Å3]
1337.17(7)
1.223
1312.7(4)
1.246
630.00(6)
1.298
1294.40(6)
1.264
634.76(10)
1.289
D
calc [mg/m3]
R1 [I > 2σ(I)]
0.0330
0.0390
0.0410
0.0375
0.0384
3b
3c
3d
4a
4b
name
3-amino-4-
methylphenol
EtOAc+MeCN
160.3
monoclinic
P21/n
7.5998(2)
18.3860(5)
9.9035(3)
110.1720(10)
8
3-amino-5-
methylphenol
EtOAc+hexane
137.7
monoclinic
P21/n
6.0239(1)
15.2605(3)
7.4566(2)
107.5570(10)
4
3-amino-6-
methylphenol
EtOAc
160-162
monoclinic
Pn
5.5990(10)
7.971(2)
7.700(2)
110.020(10)
2
4-amino-2-
methylphenol
EtOAc+MeCN
175.4
monoclinic
P21/c
4.4894(1)
10.4759(3)
14.3300(4)
93.1740(10)
4
4-amino-3-
methylphenol
EtOAc+EtOH
177-179
monoclinic
P21/n
4.6823(2)
11.5155(5)
12.0314(5)
96.884(2)
4
crystallization
mp [°C]
crystal system
space group
a [Å]
b [Å]
c [Å]
â [deg]
Z
V [Å3]
1298.93(6)
1.259
653.54(2)
1.252
322.88(13)
1.267
672.91(3)
1.216
644.04(5)
1.270
D
calc [mg/m3]
R1 [I > 2σ(I)]
0.0355
0.0353
0.0393
0.0393
0.0387
a R, â, and γ [deg] for 2d are 83.8860(10), 84.7190(10) and 89.1200(10), respectively.
3-Amino-5-methylphenol, 3c, was prepared in 70% yield according
to the literature.
2d, 3a, 3b, 3c, 3d, 4a, and 4b (Scheme 1). The crystal structures
of these aminols constitute a case of moderate complexity.
Conformational flexibility is limited, and this is a simplifying
feature, but the possibility of nonconventional interactions (N-
H‚‚‚π, C-H‚‚‚O, C-H‚‚‚π) raises the level of difficulty.
The discussion of the experimental and computational results
is as follows: (1) preparation and X-ray crystallography of the
aforementioned compounds; (2) analysis of the packing in the
experimental crystal structures and identification of important
synthons; (3) evaluation of COMPASS (COM), DREIDING
2.21 (DRE), Universal 1.02 (UNI) and pcff_300_1.01 (pcff)
force fields according to their ability to predict the experimental
structure in its observed space group; (4) exhaustive polymorph
prediction15 with Cerius2 for the experimental compounds with
the COM force field in at least six space groups to validate the
protocol for this family of molecules; (5) application of the
protocol to the CSP of nine new but related molecules; and (6)
testing of the predictions for two of the new compounds with
crystal structure determinations.
4-Amino-2-methylphenol, 4a. 2-Methyl-4-nitrophenol was obtained
from 2-methyl-4-nitroaniline by diazotization. Hydrolysis followed by
reduction afforded 4a.
Computational. All simulations were carried out with version 4.8
of the Cerius2 molecular modeling environment15 running on Silicon
Graphics workstations. The hypothetical crystal structures were gener-
ated with a polymorph predictor (PP) module. Molecular geometries
were optimized at the HF/6-31G** level using the program GAMESS-
02.16 For a PP, DRE, UNI, COM, and pcff force fields were used.17
Force field charges were used for COM and pcff, while, for DRE and
UNI, the charge-equilibrium method was used for the generation of
charges. Default options were used throughout with the fine search in
the Monte Carlo simulation and for clustering. All energy calculations
were performed without any modifications except for the use of Ewald
summation for van der Waals and Coulomb interactions. All calculations
were carried out with full body minimization. More details are given
in the Supporting Information.
X-ray Data Collection and Crystal Structure Determinations.
Diffraction quality single crystals of all compounds were obtained by
slow evaporation from solution (Table 1). The structure solution and
refinements were carried out using SHELXTL programs.18,19 In all cases
the OH and NH2 H-atoms were located in difference Fourier maps and
refined isotropically. For further details, see Table 1 and the Supporting
Information.
Experimental Section
Aminols (2a, 2b, 2c, 3a, 3d, and 4b) were commercially available.
Compounds 2d, 3b, 3c, and 4a were prepared according to the literature
(for details including references see Supporting Information).
2-Amino-6-methylphenol, 2d. 6-Methyl-2-nitrophenol was obtained
by selective nitration of 2-methylphenol followed by SnCl2‚2H2O
reduction.
(16) Schmidt, M. W.; Balridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M.
S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S. J.;
Windus, T. L.; Dupuis M.; Montgomery, J. A. J. Comput. Chem. 1993,
14, 1347.
(17) (a) Mayo, S. L.; Olafson, B. D.; Goddard, W. A., III. J. Phys. Chem. 1990,
94, 8897. (b) Rappe, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard, W.
A., III; Skiff, W. M. J. Am. Chem. Soc. 1992, 114, 10024. (c) Sun, H.;
Mumby, S. J.; Maple, J. R.; Hagler. A. T. J. Am. Chem. Soc. 1994, 116,
2978. (d) Sun, H. J. Phys. Chem. 1998, 102, 7338. (e) Jo´nsdo´ttir, S. OÄ .;
Welsh, W. J.; Rasmussen, K.; Klein, R. A. New J. Chem. 1999, 153.
3-Amino-4-methylphenol, 3b, was prepared from 4-methyl-3-
nitrophenol by reduction with Pd/C and N2H4‚H2O.
(15) Cerius2; Accelrys Ltd., 334 Cambridge Science Park, Cambridge CB4 0WN,
U.K. www.accelrys.com.
9
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A R T I C L E S
Dey et al.
Results and Discussion
However, even from among such possibilities, some interactions
are preferred. A CSD analysis of 64 aminols showed that
63 have O-H‚‚‚N hydrogen bonds (version 5.25, including
April 2004 updates).24 Of these, 55 have N-H‚‚‚O hydrogen
bonds; in the remaining 9 all but one have a N-H‚‚‚π hydrogen
bridge.25 Only 10 have an O-H‚‚‚O bond and only 4 have an
N-H‚‚‚N, this too only if there are multiple OH or NH2 groups
present. All this indicates that the O-H‚‚‚N hydrogen bond
is the most readily formed interaction in this family.26 An
N-H‚‚‚O hydrogen bond will then be facilitated by cooperat-
ivity. Accordingly, in 11 of the 13 aminols in our database these
two types of hydrogen bond form an infinite cooperative chain
O-H‚‚‚N-H‚‚‚O-H (synthon I). In the two other compounds,
the cooperative arrangement of O-H‚‚‚N and N-H‚‚‚O bonds
remains but the interactions form a closed loop, which we term
a square motif (synthon II). In these two compounds which
use synthon II to the exclusion of synthon I (2c, 3a), the four
aromatic rings surround the square motif, an arrangement that
better accommodates the methyl substituents (Figure 1). Similar
steric considerations lead to a square motif structure for the two
compounds that use synthon II along with I (4a, 4b).27 Synthons
I and II occurring in isolation or together constitute the simplest
and smallest recognition units for the supraminols, 1, and we
term them as small synthons. The presence of either or both
these synthons is almost compulsory within this family.
The synthon is a kinetic entity, and while we have no evidence
that these small synthons exist in solution for the aminols, recent
work from our group and elsewhere provide convincing
evidence for the existence of synthons in solution prior to
crystallization.28 Indeed, an implicit assumption in this entire
exercise is that the supramolecular synthon is important in all
stages of crystallization. Identification of synthons in solution
is difficult: each of the two examples cited above are very
special cases, but with more examples likely soon, the funda-
mental basis for synthon based CSP can only become better
established.
With the crystal structures of the 13 training molecules in
hand, the next step is their packing analysis. The structural
chemistry of the aminols has progressed in three distinct stages.
A decade ago, Ermer and Eling showed that complementarity
of O-H‚‚‚N and N-H‚‚‚O interactions leads to a saturation of
hydrogen bonding potential of the OH and NH2 functionalities
in aminol 4 and related compounds.20 Simultaneously and
independently, Hanessian described similar recognition schemes
in molecular complexes of diaminocyclohexanes and cyclohex-
ane diols (supraminols).21 A few years later, we showed that
the packing of aminols 2 and 3 cannot be explained similarly
and that the N-H‚‚‚π interactions in these structures occur
because of the need to optimize herringbone interactions.22 This
is an example of interaction interference. The levels of
complexity (interference between functional groups) were even
higher in our more recent study of homologated aminophenols
wherein phenyl rings bearing an OH and an NH2 substituent
respectively are separated by polymethylene chains of differing
lengths.23 Here, we showed that while 2, 3, and 4 are distinct
prototype structures, they have some commonalities at the
synthon level. The addition of a Me-substituent at various
positions on the aromatic ring further increases the levels of
difficulty in rationalizing and predicting crystal structures in
this family. This is because the supramolecular behavior of a
particular functional group in a molecule depends on its nature
and position and also on the nature and position of all other
functional groups, with the added stipulation that all portions
of a molecule including the hydrocarbon residues have su-
pramolecular functionality.9 Simplification of the resulting
structural complexity through the identification of a few
supramolecular synthons is therefore advantageous. In this
context, it is very significant that we determined the crystal
structures of all 10 isomeric methylaminophenols. This ensures
that all reasonable schemes of molecular recognition that involve
the OH, NH2, CH3, and Ph functionalities together are included,
to the maximum extent possible, in our training database.
Packing Description. Although the aminols in this study are
small and rigid, they display a variety of packing modes because
of the high ratio of functional groups to carbon skeleton. In
general, CSP of any trisubstituted benzene with three different
substituents is of moderate to high difficulty.11a Our analysis
of the packing of the 10 methylaminophenols and the 3
prototype compounds progresses from functional groups f
interactions f small synthons f large synthons f crystal
structure.
An alternative arrangement of N-H‚‚‚O and O-H‚‚‚N bonds
gives the cyclohexane type synthon III which forms a part
of the â-As network20 with its nearly tetrahedral arrangement
of the bonds around the O- and N-atoms. This is seen only
in 4. Between parallel hydrogen bonded networks are the
connector phenyl rings that form a herringbone arrangement
with C-H‚‚‚O and C-H‚‚‚π hydrogen bridges. We have
(24) (a) Allen, F. H.; Kennard, O. Chem. Des. Automat. News 1993, 8, 31. (b)
Allen, F. H.; Motherwell, W. D. S.; Raithby, P. R.; Shields, G. P.; Taylor,
R. New J. Chem. 1999, 23, 25. (c) Allen, F. H. Acta Crystallogr. 2002,
B58, 380. (d) Nangia, A. CrystEngComm 2002, 4, 93.
(25) Desiraju, G. R. Acc. Chem. Res. 2002, 35, 565.
(26) Selected references that describe the structural chemistry of supraminols
include: (a) Liminga, R.; Olovsson, I. Acta Crystallogr. 1951, 4, 100. (b)
Liminga, R. Acta Chem. Scand. 1967, 21, 1206. (c) Loehlin, J. H.; Etter,
M. C.; Gendreau, C.; Cervasio, E. Chem. Mater. 1994, 6, 1218. (d) Toda,
F.; Hyoda, S.; Okada, K.; Hirotsu. K. J. Chem. Soc., Chem. Commun. 1995,
1531. (e) Loehlin, J. H.; Franz, K. J.; Gist, L.; Moore, R. H. Acta
Crystallogr. 1998, B54, 695. (f) Roelens, S.; Dapporto, P.; Paoli, P. Can.
J. Chem. 2000, 78, 723. (g) O’Leary, B.; Spalding, T. R.; Ferguson, G.;
Glidewell, C. Acta Crystallogr. 2000, B56, 273. (h) Dapporto, P.; Paoli,
P.; Roelens, S. J. Org. Chem. 2001, 66, 4930. (i) Lewinski, J.; Zachara, J.;
Kopec, T.; Starawiesky, B. K.; Lipkowski, J.; Justyniak, I.; Kolodziejczyk,
E. Eur. J. Inorg. Chem. 2001, 5, 1123. (j) Vangala, V. R.; Mondal, R.;
Broder, C. K.; Howard, J. A. K.; Desiraju, G. R. Cryst. Growth Des. 2004,
5, 99. (k) Dey, A.; Desiraju, G. R.; Mondal, R.; Howard, J. A. K. Chem.
Commun. 2004, 2528.
(27) The square motifs may be isolated or connected with additional hydrogen
bonds to form ladders. See Bhogala, B. R.; Vangala, V. R.; Smith, P. S.;
Howard, J. A. K.; Desiraju, G. R. Cryst. Growth Des. 2004, 4, 647.
(28) (a) Parveen, S.; Davey, R. J.; Dent, G.; Pritchard, R. G. Chem. Commun.
2005, 1531. (b) Banerjee, R.; Bhatt. P. M.; Kirchner, M. T.; Desiraju, G.
R. Angew. Chem., Int. Ed. 2005, 44, 2515.
Hydrogen bonding is the major interaction type, and the
hydrogen bonds may be classified as strong or weak; those
involving only O- and N-atoms as donors and/or acceptors are
better from both kinetic and thermodynamic viewpoints, owing
respectively to their long-range nature and their strength.
(18) The crystal structure of aminol 2b has been determined earlier; see:
Kashino, S.; Tomita, M.; Haisa, M. Acta Crystallogr. 1988, C44, 730.
(19) SHELXTL, version 5.1; Bruker AXS Inc.: Madison, WI, 2001.
(20) Ermer, O.; Eling, A. J. Chem. Soc., Perkin Trans. 2 1994, 925.
(21) Hanessian, S.; Saladino, R. In Crystal Design. Structure and Function;
Desiraju, G. R., Ed.; Perspectives in Supramolecular Chemistry; Wiley:
New York, 2003; Vol. 7, pp 77-151.
(22) Allen, F. H.; Hoy, V. J.; Howard, J. A. K.; Thalladi, V. R.; Desiraju, G.
R.; Wilson, C. C.; McIntyre, G. J. J. Am. Chem. Soc. 1997, 119, 3477.
(23) Vangala, V. R.; Bhogala, B. R.; Dey, A.; Desiraju, G. R.; Broder, C. K.;
Smith, P. S.; Mondal, R.; Howard, J. A. K.; Wilson, C. C. J. Am. Chem.
Soc. 2003, 125, 14495.
9
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Crystal Structure Prediction of Aminols
A R T I C L E S
Figure 1. Crystal structures with synthon II.
described this structure in detail elsewhere;22,23 in the present
context, it suffices to say that the steric demands imposed by it
rule it out for 4a and 4b.
O-H‚‚‚N, C-H‚‚‚O, and N-H‚‚‚π bonds. The near structural
equivalence of 2b and 2 is because the H(4) atom in 2 is used
neither in hydrogen bonding nor in a crowded location.
Therefore it may be replaced by an Me-group with little change
in the packing.30 Aminol 2d is related but it has Z′ ) 4 (in P1h).
Therefore it is not used in the CSP and is not discussed further.
In 2c, the square motif II is surprising, and synthon VI might
have been expected. However, 2c has exceptional packing; it
has the highest density of all the Me-substituted aminols and
the shortest C-H‚‚‚π hydrogen bond (d ) 2.58 Å).
The tape herringbone synthon VII, obtained by extending
trimer V, is found in 3b, 3c, and 3d between translated
molecules (7.5 Å). The tapes interact with the three donor groups
along the edge forming O-H‚‚‚N, C-H‚‚‚O, and N-H‚‚‚π
bonds to the face of the next tape. 3 is a more complex variation,
and the supramolecular functionality of the N-H groups is
exchanged so that the N-H‚‚‚π becomes an N-H‚‚‚O and vice
versa. Synthons III-VII constitutes more elaborate patterns of
molecular recognition for the aminols, and we call them large
synthons (Scheme 2). These patterns are not seen always and
A sterically undemanding motif is obtained in the common
N-H‚‚‚O dimer synthon IV which originates from the archetype
2. Synthon V, the trimer may be visualized as originating from
II.29 The structures with II have a small intermolecular O-C-
C-N torsion angle (4a, 61°; 4b, 82°; 3a, 62°; 2c, 14°). In the
9 others, this angle is between 130° and 162°. Effectively, the
π-system of the N-acceptor molecule opens up to allow for
synthon V that incorporates a third molecule that associates with
the two others with N-H‚‚‚O and N-H‚‚‚π bridges (Figures 2
and 3). Synthon V is found in 7 of these 9 structures (2, 2b,
2d, 3, 3b, 3c, 3d).
Combination of some of these synthons into larger units such
as the dimer herringbone (VI) and the tape herringbone (VII)
leads to more geometrical detail with concomitant loss of
generality. Still, VI is found in three structures (2, 2b, 2d), and
N-H‚‚‚O dimers (IV) interact in an edge-to-face manner with
(29) We have described recently how a synthon may “evolve” from another,
and it is in this context that II and V are related. See Banerjee, R.; Desiraju,
G. R.; Mondal, R.; Howard, J. A. K. Chem.sEur. J. 2004, 10, 3373.
(30) Thomas, N. W.; Ramdas, S.; Thomas, J. M. Proc. R. Soc. London 1985,
A400, 219.
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J. AM. CHEM. SOC. VOL. 127, NO. 30, 2005 10549

A R T I C L E S
Dey et al.
Figure 2. Crystal structures with synthon V.
there are variations between structures, but all in all, they
represent favorable situations.
data, but the parameters are optimized empirically to yield good
agreement with experiment.
The identification of small and large synthons in the 13
structures in our training database is an essential part of the
synthon based CSP exercise. The small synthons are of high
topological but low geometrical value. Synthon I, for instance,
is found in 11 out of 13 structures but in different geometrical
arrangements. The large synthons are more defining in geo-
metrical terms but lack generality and therefore predictive value;
synthon V is found in barely half the cases. The absence of
small synthons can therefore be used in negative tests to
eliminate all those computationally derived structures that are
chemically unreasonable. Large synthons lend themselves
readily to positive tests, essentially ranking upward predicted
structures that contain these larger and geometrically well-
defined patterns. Each type of synthon therefore plays its part
in CSP.
The aminols posed some special problems: (1) The crystal
packing and the intramolecular torsion angles C-C-N-H and
C-C-O-H are implicitly linked. Retaining experimental angles
in a rigid body PP run would lead readily to the experimental
structure, while gas phase optimized angles might not necessarily
lead to a good solid state packing. Noting, however, the needs
for the “real” CSP that would follow, we decided to forego the
rigid body assumption. We were well aware that the results
might be worse with respect to reproducing known structures
but (and keeping the new compounds in mind) felt that an ability
to model the torsion angles even somewhat satisfactorily would
be a real asset in a force field. This procedure also led to the
discovery of an unsatisfactory atom typing in UNI and DRE,
which gave experimentally unobserved planar NH2 groups. (2)
It is known that the charges are not updated during minimization.
In the rigid body assumption this is unproblematic, but with
rotation of hydrogen bonds to electronegative N- and O-atoms,
the charge distribution and (more so) the dipole moments will
change, affecting the quality of the results. (3) We did not use
a multipole model for the modeling of electrostatic interactions,
although it is superior to point charges.31 Despite these problems,
we felt confident in proceeding further since the force fields
already worked quite well. With improvements in the compu-
Evaluation and Selection of the Force Field. The most
important decision in CSP is the choice of an appropriate force
field.17 The commercial package we used offers several, and
we decided to test how well they were able to reproduce the 12
experimental crystal structures in the experimental space groups.
Four force fields were evaluated (DRE, UNI, pcff, and COM).
Among these, DRE and UNI are generic force fields, intended
to be broadly applicable. COM and pcff are based on ab initio
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10550 J. AM. CHEM. SOC. VOL. 127, NO. 30, 2005

Crystal Structure Prediction of Aminols
A R T I C L E S
Figure 3. Crystal structures with synthons IV and V.
tational methods, parametrization of the force field, and fine-
tuning of the run-time parameters, better results should be
obtainable, but this is beyond the scope and the purpose of the
present work.
force fields, experimental structures are more likely to be
predicted closer to the global minimum but that, in the final
analysis, resolution of kinetic issues cannot come through such
efforts.
Table 2 shows the unit cell parameters and energies for the
minimized experimental structure and the lowest energy pre-
dicted structure using DRE, COM, and pcff force fields32 for
two representative compounds, 2c and 4b. The Supporting
Information Table SI2 contains data on all 12 aminols, and
Figure SI3 presents the information pictorically. If the lowest
energy structure is not the same as the experimental structure,
both unit cells are given. Structures predicted with the UNI force
field are not given because it performed consistently worse than
the others. To maintain generality and accuracy in the “real”
CSP that would follow, we decided to use just one force field
for all compounds33 and to compare predicted structures with
minimized experimental structures rather than with the experi-
mental structures themselves. The use of minimized experi-
mental structures as benchmarks deviates a little from conven-
tional CSP wherein experimental cell parameters have to be
accurately predicted.6 Differences between the experimental and
the minimized experimental structure reflect inadequacies in the
force field. Synthon based CSP is slightly different from a purely
computational approach in that one does not try to fine-tune
force fields beyond a point and attempts to make up for this
inadequacy by using elements of pattern recognition. We leave
efforts to improve force fields to theoretical chemists. From an
experimentalist’s viewpoint, it may be said that, with improving
An overall indication of agreement between experimental and
predicted structures is provided by simulated powder diffraction
patterns. Figures 4 and SI4 show that COM predicted structures
(for 4b) reproduce the powder patterns, while DRE and pcff
fail. Comparisons of cell parameters alone are not necessarily
conclusive, as Cerius2 does not perform a cell reduction. We
therefore used PLATON34 in Tables 2 and SI2, which compares
experimentally minimized and predicted values for the 12
molecules with three force fields. After cell reduction, all cell
parameters, volume, and total energy are comparable for 4b
with COM. The cell parameters predicted by DRE are close to
the experimentally minimized structure but the packing is
different, while pcff clearly gives an incorrect structure. A final
assertion was made after a visual inspection of the crystal
packing in each case. DRE works well for 4 and its derivatives.
It was also able to generate experimental structures for 3, 3a,
and 3c (with some deviation). It does not work at all for 2 and
its derivatives. Force field pcff works well for 2 and (with the
exception of 2c) is the best for this group. It also predicts 3 and
3c but does not work with 4 and its derivatives. COM was
uniformly better, and except for 4 all the structures were
correctly predicted. While 2b, 2c, and 3a were found with higher
energy structures (0.267, 1.248, and 1.453 kcal/mol above the
global minimum), this force field was able to predict the
maximum number of structures with greatest accuracy and
retained the topology of the synthons after minimization (see
Figure SI5). Accordingly, we used COM for all further work.
While this force field is acceptable,35 the extent to which further
improvements are desirable may be seen from Table SI6 which
(31) Mooij, W. T. M.; Leusen, F. J. J. Phys. Chem. Chem. Phys. 2001, 3, 5063.
(32) 2d is excluded here and elsewhere for reasons stated above.
(33) The use of a single force field for all predictions stems from practical
considerations. Although better agreements might be obtained with different
force fields in individual cases (say DRE for 4), we prefer to sacrifice
accuracy for generality. The selected force field would be used for the test
compounds, and comparisons between the training and test compound
structures would be more meaningful if the same force field were used
throughout.
(34) Spek, A. L. 2002 PLATON, A Multipurpose Crystallographic Tool; Utrecht
University, Utrecht, The Netherlands.
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A R T I C L E S
Dey et al.
Scheme 2. Supramolecular Synthons in This Study
Table 2. Evaluation of Force Fields for Aminols 2c and 4ba
experimental
predicted
energy
kcal/mol/
molecule
energy
kcal/mol/
molecule
reduced cell parameters
(Å, deg)
V
(Å3)
reduced cell parameters
(Å, deg)
V
(Å3)
FF
2c
DRE
COM
8.034, 8.295, 10.513, 112.95
7.338, 9.054, 10.084, 112.88
645.13
617.23
4.981
-36.010
1st, 4.734, 11.197, 12.220, 93.84
1st, 5.768, 9.318, 11.194, 91.03
8th, 7.738, 9.054, 10.084, 112.9
1st, 5.121, 8.377, 15.228, 94.14
1st, 5.548, 9.799, 12.390, 92.56
1st, 5.244, 9.928, 11.983, 93.10
1st, 7.411, 7.595, 11.792, 105.55
646.32
601.58
617.21
651.48
672.91
622.90
639.41
28.192
-37.249
-36.011
-24.162
-22.453
-46.485
-35.520
pcff
7.497, 9.034, 10.459, 114.88
5.456, 10.985, 11.776, 96.13
5.245, 9.925, 11.983, 93.09
4.909, 10.732, 12.328, 95.99
644.62
701.80
622.92
645.97
-25.309
-21.491
-46.485
-36.057
4b
DRE
COM
pcff
a For cases where the global minimum unit cell is not the same as the experimental cell and a local minimum structure corresponding to the experimental
can be found, both are given with the ranking of the latter. A similar table pertaining to all training database compounds is given in Table SI2.
compares the reduced cell parameters for experimental and
minimized structures.
Compilation of the CSP Protocol. With an appropriate force
field in hand, the expectation was that if CSP of a known crystal
structure was satisfactory, the force field would not lead one
completely astray for an unknown but related crystal structure.
The CSP protocol is based on the use of COM to reproduce
the experimental crystal structures of the training database
compounds. Such an exercise is ideally done in a number of
space groups (and the experimental space group if it is not in
the list of selected space groups). We selected P21, P21/c,
C2/c, Pca21, Pna21, and Pbca because they are the most
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Crystal Structure Prediction of Aminols
A R T I C L E S
approach comes into its own. The chemist may compile a
protocol that will rerank the predicted structures on the basis
of chemical information. The question then becomes, “What
minimum protocol would lead to a maximum number of correct
predictions?” Once the protocol is proven to work acceptably
within the database, it may be applied to new compounds.
In our protocol, the absence of small synthons in the predicted
structures is used as a negative indicator, and the presence of
large synthons, as a positive one. The O-H‚‚‚N-H‚‚‚O-H
connectivity, either as an infinite chain (I) or as a square motif
(II), is a sine qua non in this family.37 Computationally predicted
structures containing only O-H‚‚‚O and/or N-H‚‚‚N bonds
must therefore be treated cautiously. Among the large synthons,
III is uncommon in the database but we cannot rule it out in
new compounds. Again, VI and VII are common in our
database, but one should be prepared to see simpler versions of
them (IV and V) in new compounds. Accordingly, we carried
out a detailed evaluation of the low energy structures vis-a`-vis
their synthon content. The information is given in Table 3 for
the representative 2b (for all 12 compounds are in the Supporting
Information Table SI7).
The 10 lowest energy structures for 2b are in three space
groups and are close in energy and net volume. All 10 structures
contain synthon I, and none can be rejected outright. The fifth,
sixth, eighth, and ninth structures do not contain a large synthon,
and so they were given lower priority. The six others contain
dimer synthon IV. Of these, five also have synthon V. The tenth
(with IV but not V) lacks an N-H‚‚‚π interaction and was
down-ranked. The five remaining structures (first, second, third,
fourth, seventh) were further considered. The first, second, and
fourth lack the C-H‚‚‚O interaction necessary for synthon VI;
in the third a C-H‚‚‚O is present but in a distorted orientation
(2.652 Å, 141.8° and 2.796 Å, 165.4°). Only in the seventh
ranked structure is distortion of (the large) synthon VI com-
pletely absent, leading to its reranking as the predicted packing.
Such a prediction is confirmed by comparison with minimized
experimental cell parameters and fractional coordinates, which
match to the second decimal place. Our final ranking for these
10 low energy structures is therefore 7, 3, (1,2,4), 10, (5,6,8,9)
wherein groups such as (1,2,4) and (5,6,8,9) represent sets within
which the differences are only with respect to higher order
packing features. The 10 lowest energy structures for each of
the 11 other compounds were analyzed similarly. The results
are summarized briefly:
Figure 4. X-ray powder patterns of crystal structure of 4b simulated with
different force fields. Experimentally minimized structures: a, DRE; b,
COM; c, pcff. Predicted structures: a′, DRE; b′, COM; c′, pcff. For similar
illustrations for all training aminols, see Figure SI4 in the Supporting
Information.
common. Triclinic space groups were excluded because none
of the 12 training compounds adopt them.36 Because crystal-
lization is subject to kinetic factors, the experimental structure
need not correspond to the global energy minimum.
Table 3 gives the 10 lowest energy structures for aminol 2b
as a representative example. Table SI7 gives the corresponding
information for all 12 experimental compounds. Figure 5 is an
energy-volume (EV) graph for the 12 compounds. For half
the compounds (3, 3b, 3c, 3d, 4a, 4b), the experimental packing
is also the global minimum. For the others (2, 2a, 2b, 2c, 3a,
4), the situation is less clear-cut and other structures are favored
in the CSP. The worst result was obtained for 2c, where the
experimental packing is #13 in energy ranking. However, and
in totality, these results are promising, and one might say that
polymorphism is uncommon for aminophenols (for polymorph
screening, see the Supporting Information). The confidence with
which this statement can be made increases with the energy
gap between the lowest energy packing and the second one. If
one of the predicted structures is well separated from the rest
(2a, 3, 3b, 3c, 4, 4b), it can be considered to be the most stable
polymorph. This is ideal, but the global minimum is often close
to many nearby structures (3a, 3d) so that no discrimination is
possible (2, 2b, 2c, 4a). The fact that polymorphs predicted as
stable for 2a and 4 are not found experimentally shows the
importance of kinetic factors; of course, compounds such as
4a might pose problems with any method. We stress that such
issues cannot be resolved by faster computation or better force
fields and suggest that it is here that the supramolecular synthon
2: The structures are close in energy and density. The fourth
structure does not have large synthons and was down ranked.
The first (and third as a stacking variation) have synthons I,
IV, and V, but the dimer herringbone is distorted. In the second
(experimental structure) and the fifth and seventh, which are
stacking variations, this distortion is completely absent. Con-
sidering the distortion as unacceptable, the correct packing is
predicted.
2a: The experimental structure (Iba2) is found only tenth
ranked, but a packing in Pca21 with the same secondary structure
has an equivalent packing and is fifth in energy. The third was
down ranked, while the fourth was discarded. The square motif
in the second structure allows it to retain precedence, and we
(35) Rationalization as to why COM performs the best is obtained by considering
the weaker N-H‚‚‚π types of hydrogen bonds, which are ubiquitous in
the 2- and 3-aminophenols. In COM all hydrogen bonds are implicitly
parametrized in the electrostatic terms and so the weak edge-to-face
hydrogen bonds that are characteristic of the tape and dimer structures are
modeled better. In contrast, the â-As sheets contain only strong hydrogen
bonds that elude the parametrization of COM. The success of DRE with
aminol 4 is also understood, as these interactions are parametrized in this
force field.
(37) Synthon II is unique in that it need not be incorporated into any larger
synthon. It can be linked to itself (ladder motif) or not at all. Therefore it
may also serve as a positive discriminant when it appears in a predicted
packing.
(36) We note that the 13th compound with Z′ ) 4 (2d) adopts a triclinic space
group.
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A R T I C L E S
Dey et al.
Table 3. Ten Lowest Energy Crystal Structures for Aminol 2ba,b
energy
kcal/mol/
molecule
net
volume
Å3
space
group
cell parameters
Å/deg
rank
rerank
structural description
1
3
P21/c
-36.018
153.13
9.013, 5.776, 11.774, 87.84
Synthons I, IV, and V present, lacks C-H‚‚‚O
for synthon VI, therefore disfavored.
Variation of structure 1 in stacking of layers.
Synthons I, IV and V present, C-H‚‚‚O
different to synthon VI, therefore disfavored.
Variation of structure 1 in stacking of layers.
Synthon I without any large synthons.
Similar to 2a in packing.
2
3
3
2
P21/c
P21/c
-35.973
-35.908
154.71
157.15
8.946, 5.755, 13.161, 65.96
8.595, 5.805, 12.735, 81.59
4
5
3
5
Pbca
Pbca
-35.678
-35.559
158.76
150.43
5.834, 8.501, 25.607
7.635, 28.655, 5.500
6
7
5
1
Pbca
Pbca
-35.552
-35.411
149.71
157.96
7.582, 28.720, 5.500
7.917, 21.757, 7.335
Variation of structure 5 in stacking of layers.
Experimental: synthons I, IV, V, and VI
present without distortion.
8
9
10
5
5
4
Pca21
Pbca
P21/c
-35.357
-35.288
-35.263
152.00
151.71
148.79
5.432, 14.585, 7.674
25.625, 5.870, 8.069
14.493, 5.520, 7.549, 99.80
Variation of structure 5 in stacking of layers.
Synthon I without any large synthons.
Synthons I and IV present, lacks N-H‚‚‚π for
synthon V and VI therefore disfavored.
a For similar data on all 12 compounds in the database, see Table SI7. b The structure in bold font is the experimental structure.
would have predicted this structure in a blind test. The many
different and unexpected patterns for this compound suggest
that there might be problems in packing (perhaps because of a
1,2,3 juxtaposition of substituents). The choice remains difficult,
and no simple synthon protocol can predict the crystal structure
correctly (and probably no simple computational procedure
either).
2c: The experimental packing is the thirteenth in the EV
diagram and has synthon II. The fourth ranked structure also
has I and II, but it is unusual in that the OH and NH2 groups
point toward each other. The 11 other structures have disfavored
arrangements with a multitude of stacking patterns. If the fourth
is discarded, the protocol leads to the correct structure although
it is 1.2 kcal/mol down in ranking. We had a strong suspicion
that the experimental structure of 2c is a kinetic polymorph,
and we recrystallized it from various solvents (EtOH, EtOAc,
1:1 EtOAc-MeCN) and by sublimation but no other polymorph
was obtained. It should be noted that the experimental structure
has a short C-H‚‚‚π interaction of only 2.575 Å and a C‚‚‚C
close contact of 3.236 Å, which are difficult to reproduce
computationally. We feel that 2c is a special case.
3d: A variation of the experimental structure, with a distorted
tape herringbone, is the best-ranked. The next best is a structure
that resembles 3. The third has a square motif, while the fourth
is a variation of the experimental packing. The fifth shows only
synthon I, while the sixth and eighth are stacking variations of
the square motif in the third. The seventh, ninth, and tenth are
rejected because of missing small synthons. The outcome of
this prediction depends on how much distortion is acceptable
for synthon VII. But the best-ranked structure is the one closest
to the experimental packing.
4: The experimental packing is not reproduced with COM.
But the first, fifth, and ninth ranked structures have the
cyclohexane synthon III and show a structural variation of the
experimental packing, which is a cubic ZnS structure rather than
wurtzite. Of the remaining structures only the second has a
plausible structure with a square motif. The rest may be rejected.
4a: The first and third have N-H‚‚‚O linked square motif
synthons as does the experimental packing, but they differ by
the conformation of the OH group which unexpectedly points
toward the Me-group. The remaining structures are rejected or
disfavored because they miss small or large synthons.
3: The experimental structure was found to be the best ranked,
and its selection would have been unproblematic using any type
of CSP. The fourth is a possibility.
4b: The best ranked structure is the experimental one. Of
the remaining nine only the third and eighth ranking has
plausible packing with a square motif.
3a: The experimental packing is found ranked fifth. The
fourth can be discarded, and two others are suspect because
the C-C-O-H torsion angle is inclined toward the Me-group.
However, we would have predicted the lowest energy structure
containing II with N-H‚‚‚O connections and is 1.5 kcal/mol
more stable than the experimental structure. A short H‚‚‚H
contact below 2.2 Å in the experimental structure hints that
computational methods might be unreliable. Such a difficulty
has been noted for the rigid imide molecule in CSP2001.6b
3b: The experimental structure is the best ranked. The second
and fifth are unfavorable because they have no synthon larger
than I. The third and fourth have a square motif II and a tape
herringbone, respectively. The calculation was done with Z′ )
2, and structures ranked second, third, and fifth can be
transformed into higher symmetry space groups with Z′ ) 1.
3c: The experimental structure is the best ranked and is
followed closely by two structures that differ in their layer
stacking.
How does one evaluate the level of success? For seven
compounds (out of 12), the lowest energy structure is the
experimental packing (3, 3b, 3c, 4b) or a distortion thereof (3d,
4, 4a). In all cases, our protocol would also have given the same
result. In the five other compounds, the experimental structure
is not the lowest energy structure. For 2 and 2b, the second
and seventh structures respectively were reranked correctly with
the synthon protocol. For 2c and 3a the fourth and first would
have been predicted by us, whereas the thirteenth and fifth would
have been correct. However, in both cases the experimental
structure was the second after our reranking (#13f#2, #5f#2).
For 2a the second ranked packing with a square motif would
have been predicted by our protocol, while the fifth, with a
stacking variation of the experimental packing, and the tenth,
with the experimental packing in an uncommon space group,
would have been reranked to second and third place. These
results are encouraging because in all cases the experimental
structure appears among the three best-ranked solutions.
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10554 J. AM. CHEM. SOC. VOL. 127, NO. 30, 2005

Crystal Structure Prediction of Aminols
A R T I C L E S
Figure 5. Plots of lattice energy (kcal/mol/molecule) versus net volume (Å3) for 12 experimental crystal structures. Color codes blue and red indicate
experimental and rejected structures, respectively.
Of course, one could be critical and state that, in the five
cases where synthon based interpretation of CSP results became
necessary, the correct structure only appeared as the #1 structure
in two of them. One could also say that this CSP was not truly
“blind”. It could even be argued that in 7 of the 12 cases,
synthon based CSP was unnecessary because computational CSP
gave the correct answer. To this, it may be countered that if
one were told only that computational CSP gave the correct
answer in 7 out of these 12 cases, it would be Virtually
impossible to say (without the synthon information) which 7
were thus predicted correctly. To summarize, these predictions
are only the first step (dry run) for the “real” CSP still to follow.
If the protocol had not been so tuned to give correct (or nearly
correct) predictions for the training structures, the next (and
final) step would surely give many incorrect results (summary
table for 12 aminols, see Table SI8.)
Use of the Protocol in Polymorph Prediction. The Synthon
Approach. In the selection of appropriate aminols for this
exercise, two caveats are pertinent: (1) the molecules chosen
should resemble the molecules in the training database, but one
could also extend the molecular similarity beyond a certain limit
to test the robustness of the protocol; (2) the aminols should be
“blind” in the best sense of the word, and their crystal structures,
unknown. We carried out CSP on approximately 20 such
molecules. For each of these, CSP was carried out in 14 space
groups (P1h, P21, Pc, P2/c, P21/c, C2, Cc, C2/c, P212121, Pca21,
Pna21, Pbca, Pbcn, and Iba2). In each case, the starting point
is the ab initio optimized molecular structure. As previously,
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J. AM. CHEM. SOC. VOL. 127, NO. 30, 2005 10555

A R T I C L E S
Dey et al.
Scheme 3. Test Molecules for CSP
classified as the same (or mostly not describable at all) by the
synthons of the database group points to molecular structures
that are beyond the scope of the synthon protocol. In cyclo-
hexane 6, might the conformational issues be important?
Experimental results from the Hanessian group21 show that both
axial and equatorial conformations may be found in the same
structure, but we did not include this aspect in our modeling
because the complexity level would rise unacceptably. For all
these reasons, we classify both these predictions as “unclear”.
While this paper was being refereed, we were able to determine
the crystal structure of 6; our synthon based prediction was
correct, and the details are discussed later in this paper.
Methyl f Ethyl Exchange. For 7 the EV diagram is
moderately crowded. The eighth and tenth can be rejected, and
the first, fourth, and ninth only show synthon I. In the second,
sixth, and seventh structures, a dimer synthon IV is found, which
is unusual for 3-aminophenols because it leads to a close
H‚‚‚H contact across the inversion center. Also, while the
packing generally has the dimer herringbone arrangement, it
lacks the N-H‚‚‚π interaction that is necessary for synthon VI.
The remaining structures, namely the third and fifth with synthon
II, were reranked as #1 and #2. We would term this prediction
as “bad” because we were compelled to opt for a low-density
structure that does not have enough by way of larger synthons,
in the absence of any meaningful alternative.
the rigid body approximation was not used. Therefore only the
relative energies of various predicted structures are comparable.
From these 20 molecules, a subset of nine is presented (Scheme
3; see also Scheme SI12 for the remaining 11 test molecules).
These constitute, to our mind, a fair and concise pick of good,
unclear, and bad results for synthon based CSP. The nine
structures are discussed with reference to structural information
in Table 4 and the EV diagrams in Figure 6. Detailed structural
information is given in Table SI9.
It might be recollected that the difference in crystal packing
for aminols 2b and 2c is not really understandable. While the
4-substituted 2b has the dimer herringbone VI, the 5-substituted
2c has a different and unusual packing with a short C‚‚‚C
separation. 2b is analogous to 2. It is argued that the H(4) atom
in 2 does not play any specific role in the packing and that
HfMe exchange causes no structural change. On similar steric
grounds, 2c could also just as easily have adopted a similar
structure. Why does it not do so? The ethyl analogues 8 and 9
were selected to further examine this question. Aminol 8 has a
crowded EV diagram although there is a big gap of 0.531 kcal/
mol after the three best-ranked packings. All predicted structures
are somewhat unsatisfactory. For 9 the EV diagram is less
crowded. The third structure has no large synthons, and the fifth
and seventh have only an infinite chain. All the remaining, but
one, are of the distorted herringbone dimer type. The solitary
exception is the ninth which has only a square motif. The cell
parameters are more telling in that they are nearly equal to those
of 2c (2c: 7.337, 9.054, 10.084 Å, 112.84°; 9: 7.533, 9.985,
10.145 Å, 111.66°; the second axis is the axis within the MefEt
exchange). This similarity hints that 9 will pack with synthon
II like 2c and maintains the analogy between methyl and ethyl
derivatives, while the true packing for 8 (similar to that of 2b?)
might still be hidden in a higher energy structure, as in 2b.
Variation of the Aromatic System. The EV diagram for 5
is crowded, in terms of both energy and net volume. Six of the
seven best-ranked structures do not show a small synthon and
may be rejected. The second, which is the exception, features
only an infinite chain. The eighth also has infinite chains, but
running parallel and linked by N-H‚‚‚O, as has been previously
described as being of the narsarsukite type.27 The ninth is a
variant of the eighth, and the chains run antiparallel and give
synthon II. Neither arrangement was seen in the database group.
The tenth surprisingly shows a tape herringbone synthon with
only a slightly distorted orientation, which might even be
expected since the N-H‚‚‚π would be more oriented toward
the electron rich sulfur. This tenth packing was reranked as #1,
followed by the narsarsukite packings. A possible issue here is
that the S-atom could act as an additional hydrogen bond
acceptor. The second ranked structure has such hydrogen
bonding. We feel, however, that N-H‚‚‚S hydrogen bonds to
thioether-S (as opposed to thione-S) is not so important, and
there is some precedent for this.38 As for 6, the EV diagram is
very crowded with the exception of the second packing, which
is also separated by its lower density. Despite this, we reranked
it #1 because it has an N-H‚‚‚O linked square motif such as
that found in 4a and 4b. The fourth, which is a variation of the
second with the infinite chains running parallel, was reranked
#2. All other packings display only the infinite chain and no
larger synthons, and the seventh, which is close to the â-As
structure with a very long N-H‚‚‚O (d, 3.06 Å), was reranked
#3. That the EV diagrams are crowded in a small energy window
for both 5 and 6 points to an unspecific force field or
computational procedure. That many predicted packings are
These predictions are in the “unclear” category, and they raise
a general problem of synthon based interpretation of CSP results.
If the test molecule is sufficiently dissimilar to those in the
training database, it is clear that all the larger synthons in the
latter will not replicate themselves faithfully in the former. But
one does not know a priori the actual degree of molecular
similarity/dissimilarity. So does one assume that the molecules
are similar and, therefore, search for large synthons in the blind
CSP, not find them, and then rule out a (correct) packing of
the actually dissimilar molecule? Or does one assume that the
molecules are dissimilar and, therefore, accept a structure only
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10556 J. AM. CHEM. SOC. VOL. 127, NO. 30, 2005

Crystal Structure Prediction of Aminols
A R T I C L E S
Table 4. Ten Lowest Energy Crystal Structures for Aminols 9 and 12a,b
energy
kcal/mol/
molecule
net
volume
Å3
space
group
cell parameters
Å/deg
rank
rerank
structural description and prediction
1
2
C2/c
-37.005
182.44
9.151, 6.682, 24.589, 76.10
Synthon I, IV, V, and VI lacking CH‚‚‚O
but with aliphatic CH‚‚‚π.
Variation of structure 1 in stacking of layers.
Rejected because small synthons not found.
Variation of structure 1. More tilt between
dimers.
2
3
4
3
0
4
C2/c
Pca21
C2/c
-36.573
-36.164
-36.093
181.12
182.34
189.54
9.160, 6.677, 24.276, 90.38
4.652, 15.491, 10.121
9.100, 5.879, 29.370, 74.80
5
6
6
5
Pca21
C2/c
-35.654
-35.563
180.45
180.36
5.353, 16.406, 8.219
35.157, 6.675, 6.150, 99.13
Synthon I without large synthons.
Synthons I and IV present, lacks N-H‚‚‚π for synthon V
and VI, therefore disfavored.
7
8
9
6
5
1
5
P212121
C2/c
P21/c
P21/c
-35.561
-35.535
-35.519
-35.513
175.04
179.83
177.32
184.52
4.652, 25.196, 5.973
Synthon I without large synthons.
Variation of structure 6.
Synthon II.
6.379, 6.916, 34.345, 108.29
9.985, 10.145, 7.533, 111.66
7.171, 6.302, 17.104
10
Variation of structure 6.
1
2
3
1
3
3
P21/c
P212121
P21
58.753
59.362
59.455
186.40
186.27
188.56
16.435, 5.537, 9.173, 116.72
7.872, 5.447, 17.376
7.930, 5.534, 8.777, 78.26
Synthon II, similar to 3a and 4b.
Synthon I without large synthons.
Synthon I without large synthons.
Variation of structure 2 in stacking of layers.
Variation of structure 1.
Synthon I without large synthons.
Rejected because small synthons not found.
Synthon I without large synthons.
Variation of structure 5.
4
5
6
7
2
3
0
3
P21/c
59.462
59.486
59.556
59.602
185.59
186.72
185.43
189.88
15.807, 5.305, 9.032, 78.55
17.714, 5.361, 7.865
9.560, 5.374, 14.437
17.820, 7.895, 5.398
Pna21
P212121
Pna21
8
9
10
3
3
3
Pbca
P21/c
P21/c
59.779
60.080
60.083
189.47
190.52
190.82
9.068, 18.327, 9.120
7.951, 5.268, 20.822, 119.08
7.854, 18.302, 5.310, 90.07
Synthon I without large synthons.
Synthon I without large synthons.
Synthon I without large synthons.
a For similar data on all 9 compounds in the database, see Table SI8. b The structure in bold font is the preferred predicted structure.
Figure 6. Plots of lattice energy (kcal/mol/molecule) versus net volume (Å3) for CSP of 9 test structures. Blue and red codes indicate plausible and rejected
structures.
on the basis of smaller synthons, to find that the correct packing
in the (actually similar) molecule is at a higher energy and
therefore hidden? In both cases, one arrives at an incorrect
answer. In the particular case of MefEt exchange, one might
9
J. AM. CHEM. SOC. VOL. 127, NO. 30, 2005 10557

A R T I C L E S
Dey et al.
Table 5. Comparison of Cell Parameters and Lattice Energies for Experimental Verification of Aminols 12 and 6
energy
cell parameters
(Å/deg)
volume
(Å3)
reduced cell
volume
(Å3)
(kcal/mol/
molecule)
aminol
parameters (Å/deg)
12
experimentally
minimized
predicted
experimentally
minimized
predicted
9.173, 5.537, 14.788, â ) 96.92
745.92
5.537, 9.173, 14.788, γ ) 96.92
745.6
58.754
16.435, 5.537, 9.173, â ) 116.72
5.163, 11.476, 11.335, â ) 92.87
745.61
670.85
5.537, 9.173, 14.788, γ ) 96.92
5.163, 11.335, 11.476 γ ) 92.87
745.6
670.8
58.753
-73.069
6
12.134, 11.583, 5.180, â ) 100.78
715.27
5.181, 11.583, 12.135, γ ) 100.78
715.3
-72.752
assume that the molecules in the training and test databases are
not really similar and that one should be content to see
similarities at the level of the small synthons.
this prediction to be “good”. We have noted earlier in this
section that the HfMe exchange in going from 2 to 2b does
not change the essential packing. The cell parameters of 10 and
13 support this hypothesis.39 A summary of all nine test
molecules is given in Table SI10.
Phenyl f Naphthyl Exchange. Naphthalene 10 is analogous
to 2 in that many elements of the molecular structure are
retained; only the aromatic system is enlarged. The fourth, fifth,
and sixth structures may be rejected, and the seventh does not
show any synthon larger than the infinite chain. The first three
are very similar to each other in that they display the expected
dimer herringbone, although the motif is distorted in a manner
that would be unusual, if one goes by the training database.
The second is not as good because the C-H‚‚‚O is missing.
The eighth, ninth, and tenth have an unusual OH group
conformation and form dimers with O-H‚‚‚O hydrogen bonds.
As they are also higher in energy by 1.5 kcal/mol, they were
not considered. It is easy to accept #1, and one might confidently
classify this prediction as “good”.
Experimental Verification. At the end of the study, it was
felt appropriate to verify two of the blind predictions with
experimental structure determinations. The two compounds
selected were naphthalene aminol, 12, and cyclohexane aminol,
6, because they are commercially available. For compound 12
the computationally predicted structure is also the structure
predicted via the synthon approach (Table 5; see also Figure
SI11). However, even in such cases (#1 f #1), the double
confirmation of the prediction is welcome. The synthon ap-
proach is not superfluous, but rather it strengthens a prediction
that could be called into question for a variety of reasons.40
When we determined the crystal structure, we found that the
experimental structure41 was identical to the experimentally
minimized crystal structure; in other words, the prediction was
correct. As for compound 6, the experimental structure deter-
mination itself posed problems because the crystals were
hygroscopic and nearly intractably twinned. However, when we
determined the crystal structure (in response to a referee
comment),42 we were gratified to note that our prediction was
correct (Table 5, Figure SI11). More significantly, and this
argues in favor of synthon based analysis in CSP, our predicted
structure was originally ranked #2 in terms of energy but then
upgraded by us to the #1 position in our synthon based
reranking. The reader will also note (and appreciate) that our
predicted packing has the lowest density, and this too is
counterintuitive. Perhaps we were too self-critical when we
originally classified this prediction as “unclear”, and it is possible
that the COM force field is already at a point where it may be
used reliably for synthon based CSP of all aminols.
Similarly, 11 is analogous to the prototype 3. Structures
ranked second, fourth, fifth, sixth, ninth, and tenth only show a
linear chain. The first and second have an additional trimer
synthon V and pack similar to 3. Another combination of I and
V is found in the eighth but without any similarities to known
structures. The outstanding packing in this prediction has rank
#7 and displays an adaptation of the tape herringbone that is
suited to the larger displacement of functional groups in 11
relative to 3. In addition to the known interactions, it features
an additional and excellent C-H‚‚‚π bond of the H(4)-atom
while H(3) is incorporated into the C-H‚‚‚O bond. This
prediction is tempered by a large energy gap of 2.3 kcal/mol,
but we still feel confident enough to rerank #7 to #1, with the
first and third to follow, adding that polymorphism might
become an issue. Again, one might classify this prediction as
“good”. In compound 12, the sixth is rejected and seven others
have only a linear chain. The first ranked structure and the fourth
which is a variation have a square motif. Both are similar to 3a
and 4b. The energy gap between #1 and #2 is 0.609 kcal/mol.
This leads to a rather confident prediction of the first ranked
structure. Since we confirmed this prediction with an experi-
mental crystal structure determination, we do not classify it as
“good”, “unclear”, or “bad”.
(38) Allen, F. H.; Bird, C. M.; Rowland, R. S.; Raithby, P. R. Acta Crystallogr.
1997, B53, 696.
(39) Predicted cell parameters of 10 and 13 are: 10, #1: C2/c 5.851 Å, 8.888
Å, 14.892 Å, 97.07°, 101.33°, 90.00°, 753.4 Å3. 10, #2: Pbca 5.845 Å,
8.883 Å, 29.879 Å, 1551.2 Å3. 13, #1: Pbca 5.922 Å, 8.697 Å, 33.007 Å,
1699.8 Å3. 13, #2: C2/c 5.832 Å, 8.794 Å, 17.407 Å, 97.51°, 99.64°, 90.00°,
872.3 Å3.
(40) We feel at the present time that any CSP result may be called into question,
and this has nothing to do with the quality of the effort that is being put
into this problem worldwide but rather is inherent to the complexity and
difficulty of the problem.
(41) Crystal data for 12: (C10H9NO), M ) 159.18, pale pink blocks, mp 204-
207 °C, monoclinic, a ) 12.415(2) Å, b ) 4.1719(7) Å, c ) 15.511(3) Å,
â ) 108.804(3)°, V ) 760.5(2) Å3, T ) 100(2) K, space group P21/n, Z′
) 1, µ ) 0.091 mm-1, λ ) (Mo KR) ) 0.710 73 Å, 5450 total reflections
of which 1497 were independent, 1214 observed [I > 2σ(I)], 121
parameters, R1 [I > 2σ(I)] ) 0.0564, wR2 ) 0.1533.
Aminol 13 is the naphthyl analogue of 2b, and its study might
verify the near isostructural relationship between 2 and 2b. It
has a fair EV diagram with the first and second ranked packings
clearly separated from the rest. These two are also ranked highest
synthonwise because they contain I, IV, V, and VI; the fourth
and tenth can be rejected outright, while the third, sixth, seventh,
and ninth show only a linear chain I. The fifth and eighth also
have only synthon I, but the arrangement of molecules is as
close as a vicinal aminol can get to the tape herringbone synthon.
Therefore they are ranked higher at #3 and #4. We consider
(42) Crystal data for 6: (C6H13NO), M ) 115.17, colourless blocks, mp 111
°C, monoclinic, a ) 5.259(2) Å, b ) 11.954(5) Å, c ) 11.730(4)(3) Å, â
) 95.486(8)°, V ) 734.1(5) Å3, T ) 298(2) K, space group P21/n, Z′ ) 1,
µ ) 0.070 mm-1, λ ) (Mo KR) ) 0.710 73 Å, twinned crystal, 3661 total
reflections, 3683 data, 1853 observed [I > 2σ(I)], 91 parameters, R1 [I >
2σ(I)] ) 0.0660, wR2 ) 0.1697.
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Crystal Structure Prediction of Aminols
A R T I C L E S
Conclusions
The following points emerge from this study, specific to the
aminols: (1) Polymorphism is not so common in this family of
compounds. We had long suspected this to be the case,23-25,29
but the present study confirmed it repeatedly. This could be
because all the important hydrogen bond donors and acceptors
are situated in flexible functional groups (OH, NH2). Therefore
fine-tuning of all hydrogen bonds is possible in the packing. In
particular, this fine-tuning can take place within the kinetically
favored synthon I. Therefore the kinetic and thermodynamic
polymorphs are more likely to be one and the same leading to
an absence of polymorphism. (2) Changing the connector group
between OH and NH2 causes significant changes in the synthon
profile, especially the change from an aromatic connector to
an aliphatic one, but the prediction is still secure. (3) A MefEt
substitutional change, considered to be one of the simplest
changes in molecular chemistry, has deep-seated supramolecular
consequences. (4) A phenylfnaphthyl substitutional change,
in contrast, is easy to handle and predict in supraminols.
Our experiences with these substitutional exchanges is
suggestive. Why does a MefEt change lead to unpredictable
changes at the supramolecular level, but why is the phenylfnaph-
thyl change much more robust? Our inability to answer such
questions illustrates that the grammar of supramolecular chem-
istry is, at a fundamental level, different from that of molecular
chemistry. Put another way, the molecular f supramolecular
transition represents a change to systems of higher complexity
and emergence, and the supramolecular synthon concept is one
of the ways in which such complexity may be approached.
The supramolecular synthon concept recognizes the com-
plexities inherent in crystallization. Likewise, the synthon
approach to CSP recognizes that the kinetic issue is not easily
resolved with exhaustive computation. In synthon based CSP,
the better the information, the more reliable will be the CSP.
Further, one could also consider whether there is any need for
more fine-tuning of atom potentials, leaving aside the question
of whether it is possible or even meaningful. Finally, we note
that as the amount of structural information in crystallographic
databases increases, structural prediction would gradually move
toward fingerprinting.
The following general points emerge from this study: (1)
Synthon based interpretation of CSP results is a valuable adjunct
to computational CSP because it biases the results of the latter
in chemically reasonable ways. (2) In synthon based CSP, the
force field is a working rubric that achieves accuracy without
sacrificing generality, to the extent possible. The force field
should not be so coarse that the results are erroneous, but it
also need not be calibrated so fine that precise agreements are
obtained only for a limited number of structures. (3) As an
experimental method, this sort of CSP is advantageous and
especially suited to cases where CSP is needed for one or a
small number of chemically related compounds. This is typical
of the pharmaceutical industry, where the researcher is more
concerned with whether a particular compound will show
additional polymorphs rather than whether a general solution
for CSP will be found across a broad range of chemical space.
(4) The analysis of several, or in the present case all, members
of a family of structurally related compounds might be compared
to a polymorphism screening, in that the packing landscape43
has been exhaustively surveyed.11c As with the use of different
solvents or methods of crystallization, molecular level variations
within a family will favor or disfavor certain arrangements of
molecules but the crystal structures are related or at least
connected. An observed crystal structure of one of the members
of the family is a putative structure of another. (5) There is an
urgent case for crystallographers to deposit unpublished crystal
structures in the CCDC, so that the size of the CSD increases
as rapidly as possible. This would obviate the need to synthesize
and characterize the training set compounds prior to the CSP
as we have done here. However, we do not foresee an early
resolution of this difficulty.
Acknowledgment. A.D. and V.R.V. thank the CSIR for
SRFs. M.T.K. thanks the AvH Foundation for a Lynen fellow-
ship. R.M. thanks the CCDC and University of Durham for
funding. G.R.D. thanks the CSIR and DST for continuing
support of his research programs. J.A.K.H. thanks the EPSRC
for a Senior Research Fellowship. The Hyderabad group thanks
the UGC (UPE, CMSD) and DST (FIST, IRPHA) programs
for the purchase of advanced equipment and computational
hardware and software.
Supporting Information Available: Detailed Experimental
Section, crystallographic table (Table SI1), Table SI2, Figure
SI3, Figure SI4, Figure SI5, Table SI6, Table SI7, and Summary
Table SI8 for aminols 2, 2a, 2b, 2c, 3, 3a, 3b, 3c, 3d, 4, 4a,
and 4b. For the predicted structures 5-13, see Table SI9,
Summary Table SI10, and Figure SI11 for 12 and 6, Scheme
SI12 (PDF). 213 coordinate files for predicted crystal structures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(43) (a) Blagden, N.; Davey, R. J. Cryst. Growth Des. 2003, 3, 873. (b)
Gavezzotti, A. CrystEngComm 2003, 439. (c) Kirchner, M. T.; Reddy, L.
S.; Desiraju, G. R.; Jetti, R. K. R.; Boese, R. Cryst. Growth Des. 2004, 4,
701.
JA042738C
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