A kinetically favoured crystal, with many molecules in the asymmetric unit, may be a fossil relic of the crystal nucleus of a more stable polymorph.

Rate constants are reported for reaction of 4‐substituted 1‐chloro‐2,6‐dinitrobenzenes 1, 6‐substituted 1‐chloro‐2,4‐dinitrobenzenes 2, and some of the corresponding 1‐phenoxy derivatives, 3 and 4, with n‐butylamine, pyrrolidine and piperidine in acetonitrile as solvent. Values of k1, the rate constant for nucleophilic attack at the 1‐position, increase with increasing ring‐activation but may be reduced by steric repulsion at the reaction centre which increases in the order Cl < OPh, and n‐butylamine < pyrrolidine ≈ piperidine. ortho‐Substituents may also have adverse steric effects, and those of the trifluoromethyl group are particularly serious. X‐ray crystal structures of phenyl 2,4‐dinitro‐6‐trifluoromethylphenyl ether and phenyl 2,6‐dinitro‐4‐trifluoromethylphenyl ether are reported. Base catalysis in the 1‐phenoxy derivatives is attributed to rate‐limiting proton transfer from the zwitterionic intermediates 6 to base. Values of rate constants for this process decrease with increasing steric congestion at the reaction centre and in the order n‐butylamine > pyrrolidine > piperidine. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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.

The crystal structures and packing features of a family of 13 aminophenols, or supraminols, are analyzed and correlated. These compounds are divided into three groups: (a) compounds 1-5 with methylene spacers of the general type HO-C6H4-(CH2)n-C6H4-NH2 (n = 1 to 5) and both OH and NH2 in a para position; (b) compounds 1a, 2a, 2b, 2c, and 3a in which one or more of the methylene linkers in 1 to 3 are exchanged with an S-atom; and (c) compounds 2d, 1b, and 6a prepared with considerations of crystal engineering and where the crystal structures may be anticipated on the basis of structures 1-5,1a, 2a, 2b, 2c, and 3a. These 13 aminols can be described in terms of three major supramolecular synthons based on hydrogen bonding between OH and NH2 groups: the tetrameric loop or square motif, the infinite N(H)O chain, and the beta-As sheet. These three synthons are not completely independent of each other but interrelate, with the structures tending toward the more stable beta-As sheet in some cases. Compounds 1-5 show an alternation in melting points, and compounds with n = even exhibit systematically higher melting points compared to those with n = odd. The alternating melting points are reflected in, and explained by, the alternation in the crystal structures. The n = odd structures tend toward the beta-As sheet as n increases and can be considered as a variable series whereas for n = even, the beta-As sheet is invariably formed constituting a fixed series. Substitution of a methylene group by an isosteric S-atom may causes a change in the crystal structure. These observations are rationalized in terms of geometrical and chemical effects of the functional groups. This study shows that even for compounds with complex crystal structures the packing may be reasonably anticipated provided a sufficient number of examples are available.

Kinetic studies are reported for the reactions with aniline in acetonitrile of a series of X‐phenyl 2,4,6‐trinitrophenyl ethers [X=H, 2‐, 3‐, 4‐CH3, 2,4‐, 2,6‐(CH3)2, 2‐, 3‐, 4‐NO2, 2,4‐, 2,6‐(NO2)2]. X‐ray crystal structures for X=H, 2,6‐(CH3)2 and 2,6‐(NO2)2 are reported and provide evidence for steric crowding around the 1‐position of these molecules. Nevertheless, the kinetic data show that increasing substitution does not sterically inhibit nucleophilic attack by aniline and an ‘early’ transition state is likely. In general, the reactions are base catalysed; interpreted as rate‐limiting deprotonation of the zwitterionic intermediates. Only with the dinitro derivatives is an uncatalysed reaction involving intramolecular proton transfer observed and when X=2,6‐(NO2)2 this pathway takes all the reaction flux. Copyright © 2003 John Wiley & Sons, Ltd.Additional material for this paper is available in Wiley Intersciene