Publications

We revisit the important issues of polymorphism, structure, and nucleation of cholesterol·H₂O using first-principles calculations based on dispersion-augmented density functional theory. For the lesser known monoclinic polymorph, we obtain a fully extended H-bonded network in a structure akin to that of hexagonal ice. We show that the energy of the monoclinic and triclinic polymorphs is similar, strongly suggesting that kinetic and environmental effects play a significant role in determining polymorph nucleation. Furthermore, we find evidence in support of various O-H···O bonding motifs in both polymorphs that may result in hydroxyl disorder. We have been able to explain, via computation, why a single cholesterol bilayer in hydrated membranes always crystallizes in the monoclinic polymorph. We rationalize what we believe is a single-crystal to single-crystal transformation of the monoclinic form on increased interlayer growth beyond that of a single cholesterol bilayer, interleaved by a water bilayer. We show that the ice-like structure is also relevant to the related cholestanol·2H₂O and stigmasterol·H₂O crystals. The structure of stigmasterol hydrate both as a trilayer film at the air-water interface and as a macroscopic crystal further assists us in understanding the polymorphic and thermal behavior of cholesterol·H₂O. Finally, we posit a possible role for one of the sterol esters in the crystallization of cholesterol·H₂O in pathological environments, based on a composite of a crystalline bilayer of cholesteryl palmitate bound epitaxially as a nucleating agent to the monoclinic cholesterol·H₂O form.

The most widely used antimalarial drugs belong to the quinoline family. Their mode of action has not been characterized at the molecular level in vivo. We report the in vivo mode of action of a bromo analog of the drug chloroquine in rapidly frozen Plasmodium falciparum-infected red blood cells. The Plasmodium parasite digests hemoglobin, liberating the heme as a byproduct, toxic to the parasite. It is detoxified by crystallization into inert hemozoin within the parasitic digestive vacuole. By mapping such infected red blood cells with nondestructive X-ray microscopy, we observe that bromoquine caps hemozoin crystals. The measured crystal surface coverage is sufficient to inhibit further hemozoin crystal growth, thereby sabotaging heme detoxification. Moreover, we find that bromoquine accumulates in the digestive vacuole, reaching submillimolar concentration, 1,000-fold more than that of the drug in the culture medium. Such a dramatic increase in bromoquine concentration enhances the drug's efficiency in depriving heme from docking onto the hemozoin crystal surface. Based on direct observation of bromoquine distribution in the digestive vacuole and at its membrane surface, we deduce that the excess bromoquine forms a complex with the remaining heme deprived from crystallization. This complex is driven toward the digestive vacuole membrane, increasing the chances of membrane puncture and spillage of heme into the interior of the parasite.

Invited for this month's cover are the group of Prof. Lia Addadi at the Weizmann Institute of Science, Israel and collaborators at the Università Degli Studi di Milano, Italy, and the ALBA Synchrotron Light Source, Spain. The front cover shows how cholesterol crystals form in macrophage cells and in lipid bilayers of different compositions. Cholesterol monohydrate stable triclinic crystals form in vitro as rhomb-shaped plates, whereas the monoclinic crystals fold into tubular or helical shapes. Read the full text of the article at 10.1002/cplu.201800632.

The eyes of some aquatic animals form images through reflective optics. Shrimp, lobsters, crayfish, and prawns possess reflecting superposition compound eyes, composed of thousands of square-faceted eye units (ommatidia). Mirrors in the upper part of the eye (the distal mirror) reflect light collected from many ommatidia onto the photosensitive elements of the retina, the rhabdoms. A second reflector, the tapetum, underlying the retina, back-scatters dispersed light onto the rhabdoms. Using microCT and cryo-SEM imaging accompanied by in situ micro-X-ray diffraction and micro-Raman spectroscopy, we investigated the hierarchical organization and materials properties of the reflective systems at high resolution and under close-to-physiological conditions. We show that the distal mirror consists of three or four layers of plate-like nanocrystals. The tapetum is a diffuse reflector composed of hollow nanoparticles constructed from concentric lamellae of crystals. Isoxanthopterin, a pteridine analog of guanine, forms both the reflectors in the distal mirror and in the tapetum. The crystal structure of isoxanthopterin was determined from crystal-structure prediction calculations and verified by comparison with experimental X-ray diffraction. The extended hydrogen-bonded layers of the molecules result in an extremely high calculated refractive index in the H-bonded plane, n = 1.96, which makes isoxanthopterin crystals an ideal reflecting material. The crystal structure of isoxanthopterin, together with a detailed knowledge of the reflector superstructures, provide a rationalization of the reflective optics of the crustacean eye.

A key drug target for malaria has been the detoxification pathway of the iron-containing molecule heme, which is the toxic byproduct of hemoglobin digestion. The cornerstone of heme detoxification is its sequestration into hemozoin crystals, but how this occurs remains uncertain. We report new results of in vivo rate of heme crystallization in the malaria parasite, based on a new technique to measure element-specific concentrations at defined locations in cell ultrastructure. Specifically, a high resolution correlative combination of cryo soft X-ray tomography has been developed to obtain 3D parasite ultrastructure with cryo X-ray fluorescence microscopy to measure heme concentrations. Our results are consistent with a model for crystallization via the heme detoxification protein. Our measurements also demonstrate the presence of considerable amounts of non-crystalline heme in the digestive vacuole, which we show is most likely contained in hemoglobin. These results suggest a tight coupling between hemoglobin digestion and heme crystallization, highlighting a new link in the crystallization pathway for drug development.

This cooperative endeavour first describes early studies in chemical crystallography, encompassing molecular packing modes, characterization of weak hydrogen bonds, the engineering of functional crystals and monitoring of reaction pathways in molecular crystals by x-ray and neutron diffraction. With the design of 'tailor-made' auxiliary molecules, it became possible to correlate molecular enantiomerism and crystal enantiomorphism, to control the early stages of crystal nucleation, to resolve enantiomers by crystallization, induce the precipitation of metastable polymorphs, and shed light on the role played by solvent on crystal growth. With such auxiliaries, the structure of mixed crystals was revised and the ability to perform 'absolute' asymmetric synthesis in host centrosymmetric crystals demonstrated. With the introduction of grazing incidence synchrotron x-ray diffraction from liquid surfaces it also became possible to design and characterize crystalline thin film architectures at the air-water interface providing a general insight on the mechanism of crystal nucleation at the molecular level, in particular that of ice and cholesterol. Finally the collective knowhow from these studies were crucial for obtaining homochiral peptides prepared from the polymerization of racemates of amphiphilic amino acids dissolved in aqueous solution, and for experiments towards elucidating the pathological crystallization of cholesterol and the malaria pigment in Plasmodium-infected red blood cells.

Heme detoxification is a critical step in the life cycle of malariaca-using parasites, achieved by crystallization into physiologically insoluble hemozoin. The mode of nucleation has profound implications for understanding the mechanism of action of antimalarial drugs that inhibit hemozoin growth. Several lines of evidence point to involvement of acylglycerol lipids in the nucleation process. Hemozoin crystals have been reported to form within lipid nanospheres; alternatively, it has been found in vitro that they are nucleated at an acylglycerol lipid-water interface.We have applied cryogenic soft X-ray tomography and three-dimensional electron microscopy to address the location and orientation of hemozoin crystals within the digestive vacuole (DV), as a signature of their nucleation and growth processes. Cryogenic soft X-ray tomography in the "water window" is particularly advantageous because contrast generation is based inherently on atomic absorption. We find that hemozoin nucleation occurs at the DV inner membrane, with crystallization occurring in the aqueous rather than lipid phase. The crystal morphology indicates a common {100} orientation facing the membrane as expected of templated nucleation. This is consistent with conclusions reached by X-ray fluorescence and diffraction in a companion work. Uniform dark spheres observed in the parasite were identified as hemoglobin transport vesicles. Their analysis supports a model of hemozoin nucleation primarily in the DV. Modeling of the contrast at the DV membrane indicates a 4-nm thickness with patches about three times thicker, possibly implicated in the nucleation.

Hemozoin is a crystalline byproduct formed upon host hemoglobin digestion in malaria-infected blood cells, crucial for parasitic survival. On the basis of published spectroscopic and X-ray powder diffraction (XRPD) data, hemozoin is believed to be very similar to the synthetic compound β-hematin, which consists of cyclic centrosymmetric dimers of ferriprotoporphyrin IX [Fe(3+) PPIX] molecules coordinated via Fe-O bonds. The enantio-facial symmetry of Fe(3+) PPIX implies, however, that four different Fe-O cyclic stereoisomers, two centrosymmetric and two chiral, of opposite handedness, should be formed in the crystallizing solution of β-hematin. A low-temperature XRPD study of β-hematin, i.e. synthetic hemozoin, revealed the presence, not only of the published phase (Pagola, S.; Stephens, P. W.; Bohle, D. S.; Kosar, A. D.; Madsen, S. K.Nature 2000, 404, 307) but also of a minor phase. We propose, based on Rietveld refinement and DFT+vdW computations (companion manuscript, DOI: 10.1021/cg200409d), that the minor phase consists mainly of the second centrosymmetric isomeric type in a crystal structure similar to that of the major phase. The enantiomeric chiral isomers may, on symmetry grounds, be enantioselectively occluded into the growing crystals, introducing disorder. The chiral dimers, on being first adsorbed on the crystal faces, would act as tailor-made additives, retarding crystal growth, which also explains the crystalline micrometer size. The existence of two phases in β-hematin may be crucial for a fuller understanding and more complete determination of the crystal structure of hemozoin, of which only one phase has crystallized according to published data.

Biological membranes comprise thousands of different lipids, differing in their alkyl chains, headgroups, and degree of saturation. It is estimated that 5%of the genes in the human genome are responsible for regulating the lipid composition of cell membranes. Conceivably, the functional explanation for this diversity is found, at least in part, in the propensity of lipids to segregate into distinct domains, which are important for cell function. X-ray diffraction has been used increasingly to characterize the packing and phase behavior of lipids in membranes. Crystalline domains have been studied in synthetic membranes using wide- and small-angle X-ray scattering, and grazing incidence X-ray diffraction. Herein we summarize recent results obtained using the various X-ray methods, discuss the correlation between crystalline domains and liquid ordered domains studied with other techniques, and the relevance of crystalline domains to functional lipid domains in biological membranes.

A pulsed IR laser beam was used to align a peptide at the air-water interface. This peptide was designed to form a cyclic ß-strand dimer through Glu-Lys interactions in solution, which, when spread onto water, yielded a self-assembled ß-sheet bilayer (see picture) following solvent evaporation. During this process illumination with linearly polarized laser light induced formation of an aligned crystalline film, whereas circular polarization did not. (Figure Presented).

X-ray scattering experiments on mixed films of cholesterol and phospholipids at air-water and Si solid-water interfaces were undertaken to glean information on pathological crystallization of cholesterol bilayers. Grazing-incidence X-ray diffraction patterns at the air-water interface of various cholesterol:dipalmitoyl-phosphatidylcholine (Ch:DPPC) monolayer mixtures compressed beyond monolayer collapse yielded the established 10×7.5 Å2 Ch bilayer motif, for Ch:DPPC molar ratios higher than 2.5:1. Attempts to obtain a diffraction signal from various Ch:phospholipid film mixtures at the Si solid-water interface, indicative of the presence of the Ch bilayer motif, were unsuccessful. Only after removal of sufficient water from the cell was a weak diffraction signal obtained suggestive of a cholesterol film two bilayers thick. Off-specular X-ray reflectivity measurements made on a 1.75:1 mixture of Ch and bovine cardiac phosphatidylcholine (BCPC) deposited as a bilayer on a Si wafer and placed in a cell filled with water yielded positive results. The derived electron density profile showed the presence of a bilayer mixture consistent with a phase separation of cholesterol and BCPC, and possible formation of a crystalline cholesterol bilayer within the hydrated mixed bilayer, but not a proof thereof.

The key to functionalize of engineered molecularly nanometer thick films lies in the ability to reproducibly control their structure. A number of factors influence the film morphology of self-assembled films on solid or liquid surfaces, such as the structure of the molecules/particles, wetting, solvent hydrodynamics, and evaporation. An important example is the deposition of amphiphilic molecules from a volatile solution, self-assembled onto a water surface at monolayer coverage. Upon evaporation, a myriad of microscopic two-dimensional (2D) crystallites forms a ruptured film lying in random orientation on the surface, resulting in "2D powders." Here we present a general technique, employing linearly polarized laser pulses and varying solvent composition to influence the assembly of molecules such as poly-benzyl-L-glutamate and alamethicin on water surfaces, resulting in ultrathin molecular films with aligned regions that point in the same direction, though macroscopically separated. The experimental results are tentatively explained by a mechanism that is based on excluded volume forces and "kick model" for the effect of laser pulses to induce molecular rotation that eventually results in an aligned pattern when the system is at a collective state.

We investigated the fine structure of a self-assembled monolayer of dodecanethiol functionalized by α-quaterthiophene on gold (α-4TC₁₂H₂₄SH). The molecular orientation, quantified using polarization modulation infrared reflection-absorption spectroscopy, was studied as a function of the adsorption time. The α-4T moieties arrange in the upright position on the surface as the adsorption time increases, while the alkyl chain organization remains poor. Here we quantify the orientation of the self-assembled monolayer and, more significantly, reveal through surface X-ray diffraction that after a long incubation period (12 h) the α-4T on the gold surface adopts a 2D crystal structure.

Symmetry violation: Recent results by Tremel and co-workers on the phase selection of calcium carbonate through the chirality of adsorbed amino acids appear to provide a deterministic route to "mirror-symmetry breaking", which may have ramifications for the emergence of homochirality on Earth. In our view, however, the crystallization experiments violate basic rules of symmetry and we suspect the presence of chemical, biological, or other homochiral or achiral contaminants in the system.

Recent experimental and theoretical studies on functional self-assemblies formed at interfaces are presented and placed in perspective to earlier studies. The focus is on chiral and achiral systems that are at the boundary between two-dimensional and three-dimensional architectures and investigated at almost molecular level. More specifically, we present studies on: (i) self-organization of achiral molecules and separation of racemates into two-dimensional enantiomorphous domains at the air-water interface; (ii) molecular recognition between solute molecules and Langmuir films; (iii) the structural correlation between chiral morphology of mesoscopic architectures and the absolute configuration of the component molecules; (iv) polymerization of amphiphilic molecules at various interfaces and (v) the use of two-dimensional films as templates in three-dimensional crystallization, with relevance to biomineralization.

The morphology of micrometer-sized β-hematin crystals (synthetic malaria pigment) was determined by TEM images and diffraction, and by grazing incidence synchrotron X-ray diffraction at the air-water interface. The needle-like crystals are bounded by sharp {100} and {010} side faces, and capped by {011} and, to a lesser extent, by {001} end faces, in agreement with hemozoin (malaria pigment) crystals. The β-hematin crystals grown in the presence of 10% chloroquine or quinine took appreciably longer to precipitate and tended to be symmetrically tapered toward both ends of the needle, due to stereoselective additive binding to {001} or {011} ledges. Evidence, but marginal, is presented that additives reduce crystal mosaic domain size along the needle axis, based on X-ray powder diffraction data. Coherent grazing exit X-ray diffraction suggests that the mosaic domains are smaller and less structurally stable than in pure crystals. IR-ATR and Raman spectra indicate molecular based differences due to a modification of surface and bulk propionic acid groups, following additive binding and a molecular rearrangement in the environment of the bulk sites poisoned by occluded quinoline. These results provided incentive to examine computationally whether hemozoin may be a target of antimalarial drugs diethylamino-alkoxyxanthones and artemisinin. A variation in activity of the former as a function of the alkoxy chain length is correlated with computed binding energy to {001} and {011} faces of β-hematin. A model is proposed for artemisinin activity involving hemozoin nucleation inhibition via artemisinin-β-hematin adducts bound to the principal crystal faces. Regarding nucleation of hemozoin inside the digestive vacuole of the malaria parasite, nucleation via the vacuole's membranous surface is proposed, based on a reported hemozoin alignment. As a test, a dibehenoyl- phosphatidylcholine monolayer transferred onto OTS-Si wafer nucleated far more β-hematin crystals, albeit randomly oriented, than a reference OTS-Si.

In a recent paper, Srinivasan and Sherwood reported that α-resorcinol crystals grow unidirectionally at the {011} faces in the vapor phase and suggested that this phenomenon of unidirectional growth is intrinsic to polar crystals. Here, we present a molecular modeling study suggesting a plausible "self-poisoning" mechanism that may explain the unidirectional growth of α-resorcinol in the vapor phase, a process that does not exclude the inhibition of crystal growth by solvent.

Theories of prebiotic life suggest that homochirality emerged in Nature in abiotic times via deterministic or chance scenarios. This chapter deals with experiments demonstrating the feasibility of stochastic mirror symmetry breaking that occurs via autocatalytic processes involving the self-assembly of molecular clusters, 2-D and 3-D crystals, supramolecular organo-metallic catalysts, and polymeric helices and sheets. Once generated spontaneously by chance, chirality can be preserved and propagated to the environment provided that the symmetry breaking step is coupled with a sequential step of efficient amplification via self-replication reactions. Common features for the systems of relevance are that they take into consideration small fluctuations from the racemic state, and they display non-linear kinetic effects induced by diastereoisomeric supramolecular self-assemblies that exhibit different physical or chemical properties.

(Graph Presented) Crystallization of the thermodynamically metastable β glycine is explained on the basis of its growth at the opposite poles of the crystal (see graph) and by considering the structure of the relevant surfaces of the three polymorphs and their interactions with solvent molecules.

Cholesteryl-L-glutamate (CLG) thin films were investigated when deposited on pure water and on saturated solutions of water soluble amino acids, to test the capacity of the CLG monolayer to recognize and incorporate amino acids from the subphase. Analysis of grazing incidence X-ray diffraction measurements indicates that the hydrophobic amino acids, leucine, isoleucine, and valine, are adsorbed between the glutamate moieties, within the CLG crystalline monolayer, but also around their domains, forming, for L-Leu and D-Val, crystalline bilayers. The presence of Cu²⁺ ions in the aqueous subphase enhances the crystallinity of the CLG monolayer without overly affecting the lateral packing, by bridging glutamate moieties on neighbor molecules. When amino acids are injected in a Cu²⁺ containing solution, the domain size of the mixed monolayers formed with the CLG molecules and hydrophobic amino acids is drastically increased.

In this review, the delicate interplay between stereochemical control, monitoring at the subnanometer level, and an understanding of crystal nucleation is probed. Control of crystal nucleation may be achieved employing tailor-made auxiliaries, which are either nucleation inhibitors or promoters. The process may be monitored at an interface via grazing incidence X-ray diffraction (GIXD). By these means, we can glean experimental knowledge of crystal nucleation in various molecular systems. A hypothesis was invoked that supersaturated solutions containing molecular clusters adopt various arrangements and shapes, some of which resemble the crystals into which they develop. This hypothesis was taken advantage of for the design of tailored inhibitors in achieving kinetic resolution of enantiomers and induced precipitation of particular crystal polymorphs. The control and behavior of polymorphic crystallization may be understood at the molecular level through the interplay between inhibitor, solvent, solute, crystal and layer lattice energies, as well as surface layer structures. With respect to promotion of crystal nucleation, it may be achieved by Langmuir monolayers at the air-aqueous solution interface, acting as a templating agent. Determination of the monolayer crystal structure by GIXD yields the extent and nature of the complementary fit between nucleator and nucleant. Finally, GIXD was applied to monitor by a snapshot technique the layer-by-layer crystalline assembly of cholesterol molecules at the air-water interface, which involved changes in molecular packing as the film grew in thickness.

A grazing-incidence X-ray-diffraction (GIXD) study of the self-assembly, on water, of nonracemic γ-stearyl glutamic acid (pure or as a mixture with racemic or (S)-1,2 -dipalmitoyl-glycero-3-phosphoethanolamine (DPPE)) demonstrated a phase separation of the α-amino acid amphiphile into racemic and enantiomorphous two-dimensional crystallites within the phospholipid domains. The packing arrangements of the two α-amino acid crystalline phases were identical to those found in the absence of DPPE and have been determined, at almost atomic resolution, by X-ray structure-factor calculations. By contrast, racemic and nonracemic N^ε -stearoyllysine spontaneously segregated into two-dimensional enantiomorphous domains within the DPPE environment that induced a change in the tilt direction of the hydrocarbon chains of the α-amino acid molecules. Phase separation of nonracemic amphiphiles, originating from preferred lateral homochiral or heterochiral intermolecular interactions, is in agreement with the formation of enantiomerically pure or enriched homochiral oligopeptides in overrepresented amounts in the polycondensation of activated nonracemic amphiphilic α-amino acids on plain water or within phospholipid monolayers.

The advent of intense X-rays from synchrotron sources made possible to probe, at the molecular level, the structural aspects of self-assemblies generated at interfaces. Here we present the two-dimensional (2-D) packing arrangements of two-, three- and multi-component organo-metallic self-assemblies formed via interfacial reaction at the air-aqueous solution interface, as determined by grazing incidence X-ray diffraction (GIXD) and X-ray specular reflectivity techniques. GIXD yields structural information on the crystalline part of the Langmuir film, including the ions and counterions lateral order. Specular reflectivity yields the electron density profile of the film in the direction normal to the air-solution interface and, by modeling, gives independent information on the structure of both crystalline and amorphous parts of the film. In particular, we focus on the following systems: ordering of metal ions bound to the polar head groups of amphipilic molecules; use of bolaamphiphiles to generate oriented thin films with metal ions arranged in periodic layers; delineation of differences in the lateral organization of metal ions at interfaces as induced by racemates and enantiomerically pure amphiphiles; organization of ionophores in the presence of metal ions in membrane-like environment; self-assembly of 2×2 and 3×3 silver(I) grid-type complexes generated at the air-solution interface.

A 30-residue peptide, BS30, which incorporates two proline residues to induce reverse turns, was designed to form a triple-stranded β-sheet monolayer at the air-water interface. To discern the structural role of proline, a second peptide, BS30G, identical to BS30 but with glycine residues replacing proline, was prepared and examined in parallel fashion. Surface pressure-molecular area isotherms indicated a limiting area per molecule (ca. 460 Ų) for BS30 that corresponds well to that estimated from the known dimensions of crystalline β-sheet monolayers (492 Ų). Comparable measurements on BS30G yielded a smaller molecular area (380 Ų). Grazing incidence X-ray diffraction measurements performed on the BS30 monolayer at nominal area per molecule of 500 Ų, exhibited two Bragg peaks corresponding to 4.79 and 34.9 Å spacings, consistent with formation of triple-stranded β-sheet structures that assemble into two-dimensional crystallites at the air-water interface. Visualized by Brewster angle microscopy, BS30 monolayers displayed uniform, solidlike domains, whereas BS30G appeared to be disordered.

Five bifunctional alpha -amino acid-epsilon -carboxy bolaamphiphiles [(2-RS, or RS)-(HOOC)-(CH2)(m)-CONH-(CH2)(n)-CH(COOH)(NH2) m=20,22, n=3,4 labeled (l), (d,l)-C(22)Orn (l), (d), (d,l)-C(22)Lys, (d,l)-C(24)Lys respectively] were synthesized. These molecules were deposited on different aqueous subphases, and studied by means of grazing incidence X-ray diffraction (GIXD). On deionized water, the bolaamphiphiles (dl)-C(22)Lys yield a mixture of crystallites: both a monolayer, in which the chains are tilted from the normal, and a multilayer in which the molecules lie parallel to the water. On the other hand, when deposited on mono- or bi-metal ionic subphases, they self-assemble into crystalline multilayer films in which the molecules lie parallel to the aqueous solution surface, linked head-to-head and tail-to-tail in the form of extended chains. The latter are juxtaposed such that the metal ions form sheets separated by the organic molecules, aligned perpendicular to the plane of the aqueous solution. Deposition of either the enantiomerically pure or racemic bifunctional bolaamphiphiles on an aqueous solution of mixed Cu(Acetate)(2) and Pb(Acetate)(2), yields self-assembled crystalline films composed of the two different metal cations, arranged in alternating sheets, separated by the organic spacer. Both GIXD and X-ray-photoelectric-spectroscopy (XPS) studies (after deposition on solid support) demonstrate that the structures of these films differ form the ones formed on either pure Pb(Ac)(2) or on Cu(AC)(2) solutions, thus excluding the simultaneous formation of the two monometallic crystalline phases.

Cholesterol and some cholesterol-like derivatives such as stigma-sterol and cholesterol acetate self-assemble into semicrystalline monolayers, bilayers, or trilayers on the surface of water, as has been reported previously. Here we have extended our thin film studies toward cholesteryl esters that, in their bulk crystals, pack as interdigitated bilayers due to the mismatch between the cross-sectional area of the rigid cholesterol moiety (40 Ų) and the attached hydrocarbon chain (20 Ų). As shown by grazing incidence X-ray diffraction (GIXD), cholesteryl esters spontaneously self-assemble on the surface of water in order to form interdigitated bilayer films. The unit cell parameters of such bilayers at the water surface almost match those of their three-dimensional counterparts. Other experiments such as surface pressure vs area per molecule isotherms and ellipsometry measurements corroborate this result. To control the growth of the interdigitated films, we have used "tailor-made" additives (long-chain alcohols or acids) that fill the voids in the chain region of the cholesteryl ester layer caused by the structural mismatch, thereby inhibiting interdigitation. Using this strategy, we were able to form a mixed monolayer composed of the ester and the additive molecules in a 1:1 ratio, where the hydrocarbon chain of additive molecule intercalates between the ester chains and effectively inhibits the growth of the interdigitated bilayer.

Keywords: MOLECULAR-DYNAMICS SIMULATIONS; OCTYL-D-GLUCONAMIDE; ALPHA-RESORCINOL; SUPERSATURATED SOLUTIONS; SOLUTION INTERFACE; ORGANIC-CRYSTALS; SURFACE; WATER; RECOGNITION; WETTABILITY

Electrostatic interactions between amidinium and carboxylates were used for the construction of interdigitated architectures at the air-solution interface. Spreading the water-insoluble amphiphile p-pentadecylbenzoic acid (A) on an aqueous solution of p-methylbenzamidinium (B) ions results in an intercalation of the water-soluble base between the acidic headgroups of the water-insoluble amphiphile to form an amorphous A-B-A-B monolayer according to grazing incidence X-ray diffraction (GIXD) and X-ray reflectivity measurements. Upon compression the monolayer transforms into a crystalline film composed of three bilayers with interdigitated hydrocarbon chains, and a top layer whose chains are disordered. Water-insoluble p-heptadecylbenzamidinium spread on an aqueous solution of benzoic acid displays a surface pressure-area isotherm similar to that obtained from the above system. A mechanism that accounts for the formation of these films is presented. Deposition of p-heptadecylbenzamidinium and p-pentadecylbenzoic acid amphiphiles in a 1:1 ratio on pure water led to the formation of a crystalline monolayer phase but which is partially disordered. Over an aqueous solution containing a 1:1 mixture of benzamidinium and benzoic acid no measurable binding of these solute molecules to the polar headgroups of the 1:1 mixed monolayer could be detected by X-ray reflectivity or GIXD.

The growth of a cholesterol crystalline phase, three molecular layers thick at the air-water interface, was monitored by grazing incidence x-ray diffraction and x-ray reflectivity. Upon compression, a cholesterol film transforms from a monolayer of trigonal symmetry and low crystallinity to a trilayer, composed of a highly crystalline bilayer in a rectangular lattice and a disordered top cholesterol layer. This system undergoes a phase transition into a crystalline trilayer incorporating ordered water between the hydroxyl groups of the top and middle sterol layers in an arrangement akin to the triclinic 3-D crystal structure of cholesterol · H₂O. By comparison, the cholesterol derivative stigmasterol transforms, upon compression, directly into a crystalline trilayer in the rectangular lattice. These results may contribute to an understanding of the onset of cholesterol crystallization in pathological lipid deposits.

The absolute orientations of the amphiphilic molecules α-hydroxy ω-bromo alcohols BrC_nH_2n OH, n= 21, 22, and the alkyl hydroxy esters C_mH_2m+1COO(CH₂)_nOH, m = 14, 15, n = 10, in crystalline monolayer forms on water have been determined, the former by grazing incidence X-ray diffraction (GIXD) and the latter by sum frequency generation (SFG). The assignment was made for the alkyl hydroxy esters by establishing the polar angle between the terminal CH₃-C bond and the normal to the plane of the monolayer; for the bromo alcohols the assignment was made by a determination of the two-dimensional crystal structure via X-ray structure factor calculations. The SFG results are in agreement with reported GIXD and lattice energy analyses of the alkyl hydroxy esters m = 19, n = 9, 10. These studies have further revealed the absolute orientation of the alcohol C-OH bonds at the water surface, which in turn can be correlated with the ice-nucleating behavior of the monolayers on supercooled water drops in terms of the odd and even values of n.

Insertion of the 1,3-bis(ethynylene)benzene unit as a rigid spacer into a linear alkyl chain, thus separating the two resulting stems by 9 Å, induces chain folding at the air-water interface. These folded molecules self-assemble into crystalline monolayers at this interface, with the plane of the folding unit almost perpendicular to the water surface, as determined by synchrotron grazing-incidence X-ray diffraction. Three distinct molecular shapes, of the types U, inverted U, and M, were obtained in the two-dimensional crystal-line state, depending upon the number of spacer units, and the number and position of the hydrophilic groups in the molecule. The molecules form ribbons with a higher crystal coherence in the direction of stacking between the molecular ribbons, and a lower coherence along the ribbon direction. A similar molecule, but with a spacer unit that imposes a 5 Å separation between alkyl chains, yields the conventional herring-bone arrangement.

To provide more direct information on the role played by "tailor-made" auxiliary molecules in the early stages of crystal nucleation, the interplay between clusters of polar headgroups of monolayers of the copper complexes 5-Cu-S and S-Cu-R and water-soluble copper complexes S-Cu-S and R-Cu-R were investigated [where S represents enantiomerically pure (S)-palmitoyl-N^ε-lysine, and S and R represent chiral resolved (S) and (R) forms of alanine, serine, or valine]. The different monolayers were formed by spreading the amphiphilic (R) or (S) α-amino acid on an aqueous solution of copper acetate followed by injection of the water-soluble (S) or (R) α-amino acid into the subphase. The surface pressure-molecular area isotherms of the Langmuir monolayers of the two type of complexes (S-Cu-S and S-Cu-R) are different, the former being substantially more expanded. The polar headgroups of the S-Cu-S and of the S-Cu-R monolayers transferred onto a solid support assume a trans and cis configuration, respectively, according to comparative X-ray photoelectron spectroscopy (XPS) studies with appropriate cis and trans three-dimensional (3-D) α-amino acid Cu complexes. A grazing incidence X-ray diffraction (GIXD) analysis demonstrated that the S-Cu-S and S-Cu-R monolayers have different 2-D crystal structures, in keeping with the XPS results. A model is presented suggesting that the water-soluble S-Cu-S copper complexes are enantioselectively bound to the periphery of the domains of the cis S-Cu-S monolayers, but not to the domains of the trans S-Cu-R monolayers. By symmetry, the same principal holds for the monolayers and water soluble copper complexes of α-amino acids of the opposite handedness.

On studies of large scale optical resolution by crystallization, it was found that α-amino acid salts crystalline in the form of conglomerates. The conglomerates were composed of lamellar twins, hence are not amenable to large scale resolution. By conducting further studies, it was found that the occurrence of the lamellar twins can be prevented with the assistance of 'tailor-made' enantioselective crystal nucleation inhibitors that allow the resolution of hydrophobic racemic α-amino acids by kinetic crystallization.

Single crystals of benzamide which form hydrogen-bonded (001) bilayers are obtained from ethanol or 1-propanol solutions. The added presence of amide cosolvent such as X-CONH₂, X = CH₃ or CF₃, yields very thin (001) plates which are twinned. Grazing incidence X-ray diffraction (GIXD) measurements from the (001) surface of pure benzamide indicates that the surface almost exclusively exposes the phenyl substituents. The observed GIXD data from the (001) surface of the affected crystals revealed lamellar twinning. Structural modeling of the data showed that the top surface layer contains about 15% adsorbed amide cosolvent, all oriented with their -X moieties exposed to air. A simple structural model has been invoked to account for the solvent-induced twinning.

Model molecules, designed to simulate a chain fold, self-assemble into crystalline monolayers at the air - water interface, the structure of which has been determined, in situ, by synchrotron grazing-incidence X-ray diffraction. The two-dimensional packing arrangement in such monolayers is consistent with a structure composed of ribbons containing translationally related molecules adopting an inverted U-shape. The distance between these molecules along the ribbon is optimum for creating an additional chain fold, leading to the possibility that a polymeric molecule will undulate on the water surface.

The structure of mixed Langmuir films of the normal alkane C₃₂H₆₆ with different quantities of the normal alcohol C₃₁H₆₃OH or the diol HO(CH₂)₃₀OH on pure water were determined in situ by applying surface-sensitive methods that include grazing incidence X-ray diffraction (GIXD) and infrared reflection - absorption spectroscopy (IRRAS) and by induced freezing of water drops. Random solid solutions were formed between the alkane and C₃₁H₆₃OH. On the other hand, segregation of the two components was observed in the mixed systems of the alkane and HO(CH₂)₃₀OH. These findings suggest new ways for the design of hydrophobic surfaces bearing hydrophilic sites, which may be appropriate for epitaxial ice nucleation and cloud seeding purposes.

We present a study of two-dimensional (2D) crystallites of cholesterol formed at the air-water interface. Grazing-incidence X-ray diffraction (GIXD) measurements performed along the surface pressure-area isotherm revealed a transition from a monolayer to a highly crystalline rectangular phase, about two layers thick. This variation in the film thickness was confirmed by ellipsometry measurements. Films transferred onto solid support by the Langmuir-Blodgett technique were seen by atomic force microscopy (AFM) to display elongated and faceted crystallites about 10 layers thick. The effect of the phospholipid dipalmitoylphosphatidylcholine (DPPC) on the 2D crystallization of cholesterol was studied by GIXD and AFM with three cholesterol:DPPC mixtures in molar ratios 1:1, 2:1, and 5:1. The phospholipid additive reduced the crystallinity of the cholesterol in the 5:1 and 2:1 mixtures, totally suppressing it in the 1:1 mixture.

Oriented crystalline thin films of alpha,omega-tetracosanedioic acid metal salts form in situ at the air-liquid interface, following the simple procedure described here. It is shown that the Cd2+ and Pb2+ metal ions have a dramatic influence on the packing of the diacid molecules, which self-assemble as multilayer domains approximately 50 Angstrom thick, with the molecules and bound ions perfectly ordered laterally over distances up to 1000 Angstrom. These oriented crystallites preserve their integrity upon transfer to a mica support and can be used to prepare quantum dots (see following communication).

Monolayers of the long-chain alcohols on water promote nucleation of ice. In order to determine the minimum size of crystalline alcohol monolayer domains that induce ice nucleation, we reduced their size in two distinct ways. One approach encompassed embedding the pure hydrocarbon alcohol, C_nH_2n+1OH(n = 20, 31), into a matrix of an immiscible monolayer of perfluoro alcohol C₁₀F₂₁C₂H₄OH, which is inert as an ice nucleator. The second set of experiments involved the introduction of random defects into the monolayer crystalline domains of C₂₉H₅₉OH through the use of the fully miscible guest alcohol molecule, C₃₁H₆₃OH, as additive. By these methods we estimated that ∼450 water molecules are necessary to form a stable ice cluster at the onset of induced ice nucleation at a temperature just below 0°C.

The formation of Langmuir monolayers at the air water interface has long been believed to be limited to amphiphilic molecules containing a hydrophobic chain and a hydrophilic headgroup. Here we report the formation of crystalline mono- and multilayer self-assemblies of oligothiophenes, a class of aromatic nonamphiphilic molecules, self-aggregated at the air water interface. As model systems we have examined the de position of quaterthiophene (S₄), quinquethiophene (S₅), and sexithiophene (S₆) from chloroform solutions on tile water surface. The structures of the films were determined by surface pressure area isotherms, by scanning force microscopy (SFM after transfer of the films onto atomically smooth mica, by cryo-transmission electron microscopy (Cryo-TEM) on vitreous ice, and by grazing incidence synchrotron X-ray diffraction (GII) directly on the water surface. S₄ forms two polymorphic crystalline multilayers. In polymorph χ, of structure very similar to that of the three-dimensional solid, the molecules are aligned with their long molecular axis tilted by about 23 from the normal to the water surface. In polymorph β the long molecular axis is perpendicular to the water surface. S⁵ self-aggregates at tile water surface to form mixtures of monolayers and bilayers of the β polymorph: S₆, forms primarily crystalline monolayers of both χ and β forms. The crystalline assemblies preserve their integrity during transfer from the water surface onto solid supports. The relevance of the present results for the understanding of the early stages of crystal nucleation is presented.

A correlation is presented between the crystalline structure of monolayers and multilayers of α,ω-alkanediols HO-(CH₂)_n-OH (n = 16, 18, 19, 21, 22, 23, 24, 30) at the air-water interface and their function as ice nucleators. Structural elucidation was carried out by the following methods: grazing incidence X-ray diffraction, scanning force microscopy, cryo-transmission electron microscopy and external reflection Fourier transform-infrared spectroscopy.

Grazing incidence synchrotron X-ray diffraction measurements were made on an uncompressed monolayer of 1:1 triacontanoic acid (C₂₉H₅₉COOH) and nonacosylamine (C₂₉H₅₉NH₂), spread on pure water and on aqueous ZnCl₂ solution. The measured diffraction data of the mixed monolayer on water provides clear evidence of a complete mixing of the acid and amine molecules into a two-dimensional crystal where the hydrocarbon chains pack in a herringbone motif. A model has been proposed in which the ionized acid and amine moieties are ordered and form a continuous hydrogen-bonded array.

Structure, morphology, and mechanical properties of mono- and several-layer structures of amphiphiles or pure n-alkane crystallites generated by spontaneous self-assembly on aqueous subphase have been analyzed by scanning force microscopy (SFM). Pure-component and heterogeneous mixtures of molecules were allowed to spread and self-assemble without compression on an aqueous subphase. The self-assembled films were transferred to an atomically smooth mica substrate by drainage for measurement using SFM. Results were compared with a variety of techniques including cryo-transmission electron microscopy, grazing incidence X-ray diffraction. X-ray reflectivity, and reflectance/absorption infrared spectroscopy. Whereas the collaborative techniques provide spatially-averaged information, we find that the SFM accesses both individual crystallites and amorphous material, thus providing unique information on the morphology, number of layers, and complementary structural features.

Organisms can exert a remarkable degree of control over crystal growth. One way of achieving this is by the adsorption of specialized macromolecules on specific planes of the growing crystals. With continued growth of the crystal, the macromolecules are incorporated inside the crystal bulk. Their presence does not change the crystal structure, but creates discontinuities in the perfect lattice. Here we study in detail three unusual cases of reduction in symmetry at the level of crystal domain shapes, induced by this controlled intercalation. We examined sponge spicules, which are single crystals of Mgbearing calcite. They were specifically chosen for this study, because their morphologies do not reflect the hexagonal symmetry of calcite. Their crystal textures (coherence lengths and angular spreads) were characterized by highresolution Xray diffraction with wellcollimated synchrotron radiation. The results are compared to analogous studies of synthetic calcite and Mgbearing calcite. In all the selected spicules reduction in symmetry is observed in the coherence lengths among symmetryrelated crystallographic directions. The reconstructed shapes of the domains of perfect structure closely match the specific spicule morphologies. The synthetic crystals show no such reduction in symmetry. Although the manner by which such exquisite control is achieved is not known, we envisage it involving a combination of oriented nucleation with either physical or stereochemically driven adsorption.

Tailor-made auxiliaries for the control of nucleation and growth of molecular crystals may be classified into two broad categories: inhibitors and promoters. Tailor-made inhibitors of crystal growth can be used for a variety of purposes, which include morphological engineering and etching, reduction of crystal symmetry, assignment of absolute structure of chiral molecules and polar crystals, elucidation of the effect of solvent on crystal growth, and crystallization of a desired polymorph. As for crystal growth promoters, monolayers of amphiphilic molecules on water have been used to induce the growth of a variety of three-dimensional crystals at the monolayer-solution interface by means of structural match, molecular complementarity or electrostatic interaction. A particular focus is made on the induced nucleation of ice by monolayers of water-insoluble aliphatic alcohols. The two-dimensional crystalline structures of such monolayers have been studied by grazing incidence X-ray diffraction. It has become possible to monitor, by this method, the growth, dissolution and structure of self-aggregated crystalline nonolayers, and indeed multilayers, affected by the interaction of solvent molecules in the aqueous. suphase with the amphiphilic headgroups, and by the use of tailor-made amphiphilic additives.

We enjoyed reading the article by Ron Dagani (C&EN, Aug. 29, 1994, page 28) on the current field of catenanes. We were dismayed by his reference to "a chemist" who synthesized the first catenane in 1960. That pioneering study was performed by Ed Wasserman, who is considered as the originator of this field of science. Wasserman not only synthesized the first catenane, but also elaborated on the topological aspects of this class of materials. Wasserman, who is well known for his original contributions in pure and applied chemistry, is currently at DuPont Experimental Station, Wilmington, Del. [1st paragraph]

The spontaneous aggregation of the bolaamphiphile α,ωdocosanediol into embryonic threedimensional crystallites at the airwater interface can be inhibited by additives. A study with the aim of determining the necessary properties of such supplements is reported, which uses additives with molecular recognition properties and methods such as Xray reflectivity, cryotransmission electron microscopy, and atomic force microscopy in order to detect structural changes at the nanometer level.

The advent of well collimated, high intensity synchroton X-ray sources and the consequent development of surface-specific X-ray diffraction and fluorescence techniques have recently revolutionized the study of Langmuir monolayers at the air-liquid interface. These methods allowed for the first time the determination of the in-plane and vertical structure of such monolayers with a resolution approaching the atomic level. We briefly describe these methods, including grazing incidence X-ray diffraction, specular reflectivity, Bragg rods, standing waves and surface fluorescence techniques, and review recent results obtained for Langmuir films from their use. The methods have been successfully applied for the elucidation of the structure of crystalline aggregates of amphiphilic molecules at the water surface such as alcohols, carboxylic acids and their salts, α-amino acids and phospholipids. In addition, it became possible to monitor by diffraction the growth and dissolution of the crystalline self-aggregates as well as structural changes occuring by phase transitions. Furthermore, via the surface X-ray methods, new light is shed on the structure of the underlying attached solvent or solute ionic layer. Examples are given where singly or doubly charged ions bound to the two-dimensional (2D) crystal form either an ordered or diffuse counter-ionic layer. Finally, the surface diffraction methods provide data on transfer of structural information from 2D clusters to 3D single crystals which had been succesfully accomplished by epitaxial-like crystallization both in organic and inorganic crystals.

Composite materials in which the organic host is stiffened by guest particles, are widely used in nature and are produced synthetically by man. Organisms also produce a different type of composite in which the host is a crystal and the guests are macromolecules occluded in an orderly fashion within the crystal. The best studied examples, to date, are biogenic calcite crystals, and in particular those formed by the echinoderms. In vitro experiments with calcite crystals grown in the presence of echinoderm intracrystalline proteins, show that these macromolecules are occluded inside the crystal on specific planes, and their presence alters the mechanical properties of the crystal host. Furthermore, the proteins also influence the crystal textural properties. Model studies using crystals of dicarboxylic acid salts grown in the presence of intracrystalline proteins show that the coherence length is reduced in directions perpendicular to the planes on which the proteins adsorb. We found anisotropic effects in almost all the biogenic calcite crystals we examined. Furthermore, we noted an interesting relationship between the variations in coherence length in the different crystallographic directions and the gross morphology of the single crystal elements, suggesting that these proteins may also function in determining the morphology of the crystal during growth. These novel single crystal-protein composites may be just one example of strategies used in nature for producing materials with special properties.

Crystals of β-alanine and the α-form of glycine, when grown in the presence of 3% molar CdCl₂, display morphologies which are different from those obtained from pure water solution. This effect was interpreted in terms of binding of Cd²⁺and Cl^-ions to the exposed CO₂- and NH₃+ moieties at the various faces, so changing their relative rates of growth and leading to the development of new faces. The structure of the crystal face of β-alanine most affected by the presence of CdCl₂was mimicked by a monolayer containing an equimolar mixture of two different amphiphiles octadecylamine (C₁₈H₃₇NH₂) and stearic acid (C₁₇H₃₅COOH) spread on aqueous solution. Binding of the Cd²⁺and Cl^-ions to such a monolayer has been investigated. X-ray specular reflectivity measurements reveal that the mixed monolayer is fully bound by Cd²⁺and Cl^-ions when their concentration reaches 0.1 M. Grazing incidence X-ray diffraction measurements, using synchrotron radiation, of the mixed monolayer on pure water and on a 0.1 M CdCl₂solution provide strong evidence that the monolayer CO₂^-and NH₃⁺head groups are arranged in ordered array and the Cd²⁺and Cl^-ions are bound to the monolayer head groups at ordered sites.

Grazing incidence X-ray diffraction (GID) studies were performed on self-assembled monolayers of carboxylic acids C_nH_2n+1CO₂H (n = 13,19,29) spread over CdCl₂ or CaCl₂ solutions at pH values 8.85 and 10, respectively, adjusted with ammonia, and subphase temperatures in the range 5 to 9 °C. The GID results show the tendency for spontaneous two-dimensional (2-D) crystalline aggregation of the molecules which pack in a rectangular cell with the hydrocarbon chains tending to be vertically aligned with respect to the solution surface. The molecular chains form a herring bone arrangement with the two molecules in the unit cell related essentially by glide symmetry. Detailed Bragg rod fitting analysis shows however, that the two molecules are crystallographically independent so that the plane group symmetry is chiral p1. For n= 29, it was possible to determine the extent of molecular thermal motion parallel to the water surface and which proved to be in the same range as in layered 3-D crystal structures containing aliphatic chains. The GID data did not provide definite evidence for ordered ion binding although the extent of crystallinity is enhanced by the presence of the bound counterion. For example, myristic acid (n = 13) yielded the GID pattern only when spread over CdCl₂ but not on pure water. A simple packing model is provided for ordered binding of counterions with high degree of coordination to the oxygen atoms of the carboxylate head groups. The proposed model is also in keeping with the observed lower area per amphiphilic molecule than over pure water.

The two-dimensional (2D) crystal structures of self-aggregated clusters of amphipbilic alcohols (C_nH_2n+1OH, n = 23, 30, 31, and C₁₉H₃₉CO₂(CH₂)_nOH, n = 9, 10) on pure water at a temperature of 5 °C have been determined to near-atomic resolution in order to understand the relative abilities of these monolayers to induce ice nucleation. The structures were solved making use of grazing incidence synchrotron X-ray diffraction (GID) data, complemented by lattice energy calculations. The GID data of the different monolayers within each of the two series (C_nH_2n+1OH, C₁₉H₃₉CO₂C_nH_2nOH) are very similar. The molecules pack in a rectangular unit cell of average dimensions a = 5.0 Å, b = 7.5 Å for the normal alcohols C_nH_2n+1OH and a = 5.7 Å, b = 7.5 Å for C₁₉H₃₉CO₂C_nH_2nOH. The plane group symmetry is essentially p1g1 for the normal alcohols C_nH_2n+1OH and essentially p1g1 for the other group. The molecular chains are tilted from the vertical by an average angle of 9°, in the direction of the b axis, for C_nH_2n+1OH and by 29°, in the direction of the a axis, for the other molecular type. The molecular chains related by glide (g) symmetry are arranged in a herringbone pattern. The fit to the Bragg rod intensity data of C_nH_2n+1OH permitted a reliable estimate of 0.07 Ų for the molecular mean-squared motion parallel to the water surface. The a bsolute orientations of the molecules C₁₉H₃₉CO₂C_nH_2nOH were determined by lattice energy calculations. The anisotropic coherence lengths of the crystallites of C₁₉H₃₉CO₂C_nH_2nOH derived from the widths of the two observed Bragg peaks have been correlated with the binding energies of molecules in different directions.

Two approaches are used to study suggested mechanisms for heterogeneous ice nucleation. In one, an epitaxial-like mechanism is studied by using Langmuir monolayers of aliphatic alcohols C n H 2n +1OH (n=16 to 31) spread on supercooled water drops. The packing arrangement of several of these uncompressed.monolayers on water, have been determined by grazing incidence x-ray diffraction (GID) and correlated with the structure of water molecules at the (001) face of hexagonal ice. The roles played by lattice match between the monolayers and ice, the coherence length of the amphiphile crystallites and the orientation of the hydroxyl groups at the interface in determining the nucleation efficiencies are specifically addressed. In another induced nucleation of ice by an electric field is studied using hydrophobic surfaces of chiral resolved and racemic α-amino acid crystals onto which water vapor has been condensed and nucleated into ice.

Tailor-made molecular auxiliaries for the control of nucleatiw and growth of molecular crystals may be classified into two broad categories: Inhibitors and promoters, Tailor-made inhibitors of crystal growth can be used for a variety of purposes which include morphological engineering, reduction of crystal symmetry, assignment of absolute structure of polar crystals, elucidation of the effect of solvent on crystal growth and crystallization of a desired polymorph. As for crystal growth promoters, Langmuir monolayers on water have been used to induce growth of 3D crystals at the monolayer-solution interface by means of structural match, molecular complementarity or an electrostatic interaction. The 2D crystalline structures of these monolayers have been studied by grazing-incidence x-ray diffraction (gixd). It has become possible to monitor, by gixd, the growth and dissolution of self-aggregated crystalline monolayers affected by the interaction of solvent molecules in the aqueous subphase with the monolayer headgroups.

The method of cryo-transmission electron microscopy has been applied to study twinning behavior of mixed monolayers of 3-(eicosanoylamino) propionic acid and eicosanoamide spread on water and CdCl2 aqueous solution. The monolayers were deposited with a thin layer of aqueous subphase on grids which were vitrified by plunging into liquid ethane. Various electron diffraction patterns were observed and interpreted in terms of formation of two-dimensional (2-D) crystallites which display single and multiple twinning. Morphological features of the monolayer films were also obtained from bright and dark field images.

A unique set of proteins extracted from a variety of invertebrate calcitic mineralized tissues is able to selectively interact in vitro with certain crystal faces and not others. This was previously demonstrated by observing changes in morphology of crystals grown in the presence of proteins as compared to those grown in the absence of proteins. Following interaction, the proteins are overgrown by the crystal and are subsequently occluded within the crystal itself. Here we address the fundamental question of whether or not the proteins also alter the crystal texture in an anisotropic manner. For this purpose we used high-resolution synchrotron X-ray diffraction to monitor changes in coherence length and angular spread. We studied the interactions of proteins extracted from the mineralized skeletal hard parts of sea urchins and mollusks, with crystals of two calcium dicarboxylic acids, calcium fumarate and calcium malonate, as well as the polymorph of CaCO₃ calcite. For the calcium dicarboxylate crystals, we did demonstrate that the coherence lengths are reduced in the directions perpendicular to the planes onto which the proteins preferentially adsorb. In contrast the calcite crystals grown in the presence of the proteins exhibited an increase in angular spread compared to the controls, but no anisotropic effect in coherence length was detected. A biologically produced calcite crystal, on the other hand, showed a preferential reduction in coherence length in the direction of the c axis. Clearly in the case of calcite, the processes controlling crystal texture in the biological environment are more sophisticated than those in vitro. The detection of a reduction in coherence length in the directions perpendicular to the planes onto which the proteins preferentially adsorbed represents one of very few direct demonstrations that an additive that is able to selectively alter crystal morphology also affects crystal texture in an anisotropically specific manner. An understanding of this phenomenon may, in the future, improve our ability to control crystal texture in synthetic materials.

The spontaneous formation of highly crystalline two-dimensional films of uncompressed long chain amide and carboxylic acid amphiphiles spread on formamide has been demonstrated by grazing incidence X-ray diffraction. These results were compared to those found for the same amphiphiles on water. The observed diffraction data Of C29H59CONH2 over both water and formamide and those Of C29H59CO2H over formamide are strikingly similar, while those Of C29H59CO2H over water are different. Arachidamide (CH19H39CONH2) over water subphase forms a unimolecular layer with the molecules tilted by 18-degrees. Over formamide, the crystallites are made up, at least in part, of three molecular layers, with the molecules standing vertically. This was confirmed by X-ray specular reflectivity. These results are analogous to the well known, but as yet unexplained, influence which solvent may have on the growth of polymorphic modifications of three-dimensional crystals.

Principles are outlined for symmetry lowering of a mixed crystal composed of host and tailor-made additive molecules, based on selective occlusion of the latter through a subset of surface sites of the growing crystal, the symmetry of the surface generally being lower than that of the bulk. A survey is given of the various methods and approaches used to detect the reduction in symmetry. These include changes in crystal morphology, detection of enantiomeric segregation of chiral additives in 'centrosymmetric' crystals, generation of second-harmonic optical signals, optical birefringence, asymmetric photoreactions in the crystalline state and X-ray and neutron diffraction. The last two methods are applied to mixed crystals of cinnamamide (host) and thienylacrylamide (additive). The diffraction analysis demonstrated that the mixed crystals are composed of six sectors of reduced symmetry, from monoclinic centrosymmetric P2₁/c to triclinic P1 in four sectors and possibly Pc in the remaining two. The X-ray diffraction data were not sufficiently accurate to permit assignment of the absolute structures of the P1 sectors with the use of anomalous X-ray scattering. Thus, by this method one could not ascertain the absolute orientation of the guest molecules on the surface sites through which they were selectively occluded. This ambiguity was resolved by assignment of the absolute configuration of the chiral heterophotodimers, between host and guest, in enantiomeric excess in the P1 sectors, after irradiation with UV light. These results led to the definite conclusion that the selective occlusion of thienylacrylamide arises from a replacement of attractive C-H⋯π (electron) interactions between host molecules by repulsive sulfur (lone-pair electron)⋯π (electron) interactions between guest and host at the crystal surfaces.

The advent of wellcollimated, highintensity synchrotron Xray sources and the consequent development of surfacespecific Xray diffraction and fluorescence techniques have recently revolutionized the study of Langmuir monolayers at the airliquid interface. These methods allowed for the first time the determination of the inplane and vertical structure of such monolayers with a resolution approaching the atomic level. We briefly describe these methods, including grazing incidence Xray diffraction, specular reflectivity, Bragg rods, standing waves, and surface fluorescence techniques, and review recent results obtained from them for Langmuir films. The methods have been successfully applied in the elucidation of the structure of crystalline aggregates of amphiphilic molecules such as alcohols, carboxylic acids and their salts, αamino acids, and phospholipids at the water surface. In addition, it became possible to monitor by diffraction the growth and dissolution of the crystalline selfaggregates as well as structural changes occurring by phase transitions. Furthermore, the surface Xray methods shed new light on the structure of the underlying ionic layer of attached solvent or solute species. Examples are given where singly or doubly charged ions bound to the twodimensional (2D) crystal form either an ordered or diffuse counterionic layer. Finally, the surface diffraction methods provide data on transfer of structural information from 2D clusters to 3D single crystals, which had been successfully accomplished by epitaxiallike crystallization both in organic and inorganic crystals.

The hydrophobic faces of single crystals of a series of pairs of racemic and chiral-resolved hydrophobic α-amino acids were used as a substrate, onto which water vapor has been cooled to freezing. The morphologies and molecular packing arrangements within each crystal pair are similar but only one of each pair exhibits a polar axis, parallel to the hydrophobic face exposed to water. Those crystals that have a polar axis induce a freezing point higher by 4° to 5°C than the corresponding crystals that do not have a polar axis. The results are interpreted in terms of an electric field mechanism that helps align the water molecules into ice-like clusters en route to crystallization.

A general approach is presented toward the determination at near atomic resolution of two-dimensional (2-D) crystalline structures of amphiphilic molecules at the air-water interface. It involves fitting of grazing incidence X-ray diffraction (GID) data from the 2-D crystal using molecular models, complemented by lattice energy calculations. In this way, one may eliminate ambiguities associated with assignment of the 2-D crystal symmetry, the molecular conformation, and the packing arrangement. The method was applied to the elucidation of the low temperature (5°C) structure of an uncompressed monolayer of triacontanoic acid C₂₉H₅₉CO₂H. We deduced a packing of the molecules in a rectangular unit cell in plane group pg. The molecular chain axes are tilted from the vertical by 27° along the short 5.53-Å axis of the unit cell and oriented so as to form the orthogonal O_⊥ packing type. The CO₂H groups are not directly interlinked by O-H⋯O hydrogen bonds. A distinct improvement of the agreement between observed and calculated GID data was achieved by partial relaxation of the glide plane symmetry. The observed Bragg peaks suggested very anisotropic shapes for the crystallites. This anisotropy was correlated with the energy of attachment of a molecule to a specific crystallite facet.

Xray diffraction methods for Langmuir films on the surface of water are briefly presented, together with recent results for docosanoic acid monolayers on pure water and for eicosanoic acid monolayers on an ionic subphase.

The contact angle of a crystal face affords information about the absolute configuration of the molecules forming the crystal. This could be demonstrated with the alkylgluconamides 1, which crystallize with the molecules arranged in layers. The angle of contact at the face consisting of the chainend alkyls is 7587°, while at the oppositely disposed face consisting of the CH₂OH groups it is 4456°C. (Figure Presented.)

Nucleation, growth, and dissolution of crystals have been studied by stereochemical approach involving molecular recognition at interfaces. A methodology is described for using "tailor-made" additives designed to interact stereospecifically with crystal surfaces during growth and dissolution. This procedure was instrumental in controlling crystal morphology and in revising the concept of the structure and symmetry of solid solutions. Consequently, it was applied to the transformation of centrosymmetric single crystals into solid solutions with polar arrangement displaying second-harmonic generation and to the performance of asymmetric synthesis of guest molecules inside centrosymmetric host crystals. The method has led to a discovery of a new "relay" mechanism explaining the effect of solvent on crystal growth. Finally, it allowed for the design of auxiliary molecules that act as promoters or inhibitors of crystal nucleation that can be used to resolve enantiomers and crystallize desired polymorphs.

Sea urchin skeletal elements are composed of single crystals of calcite. Unlike their synthetic counterparts, these crystals do not have well-developed cleavage and are consequently much more resistant to fracture. This phenomenon is due in part to the presence of acidic glycoproteins occluded within the crystals. By means of x-ray diffraction with synchrotron radiation, it is shown that the presence of the protein in synthetic calcite only slightly decreases the coherence length but significantly increases the angular spread of perfect domains of the crystals. In biogenic calcite, the coherence length is 1/3 to 1/4 as much as that in synthetic calcite and the angular spread is 20 to 50 times as wide. It is proposed that the presence of macromolecules concentrated at mosaic boundaries that are oblique to cleavage planes is responsible for the change in fracture properties. These results may be important in the material sciences, because of the unusual nature of this material, namely, a composite based on the controlled intercalation of macromolecules inside single-crystal lattices.

A new series of amphiphilic molecules bearing two amide groups along the hydrocarbon chain form head-to-tail Z-type (polar) multilayers by the Langmuir-Blodgett (LB) technique, in contrast with the common amphiphiles that tend to deposit in the head-to-head, tail-to-tail Y-type fashion. Molecules with one amide group along the chain form Y-type or Z-type structures, depending on the location of the amide along the chain. p-Nitroaniline or merocyanine groups could be aligned in a polar sense, by attaching them covalently to such amphiphiles, to yield multilayers displaying second-harmonic generation (SHG). These films were characterized by ellipsometric, X-ray diffraction, IR, UV, and SHG measurements. The Z-type deposition correlates with the observed low water contact angles of the films, indicating formation of porous structures in which water may penetrate. This behavior is rationalized in terms of the hydrophilic nature of the amide groups that retain water by hydrogen bonding. In keeping with this mechanism, it was anticipated that amphiphiles bearing other polar groups, such as hydroxyls along the hydrocarbon chain, also form Z-type LB films.

In order to provide, on the molecular level, information on crystal nucleation of monolayers at air-water interfaces, the self-aggregation of lH,lH,2H,2H-perfiuorododecyl aspartate CF3(CF2)9(CH2)20COCH2CH(NH3+)C02~ (PFA) over water subphases at various pH values was studied using synchrotron X-ray grazing incidence diffraction (GID), including Bragg rods (BR) and reflectivity (XR) measurements. Two-dimensional crystalline domains with coherence lengths exceeding 1 500 A were detected for low surfactant surface densities and zero surface pressure. GID measurements reveal structural changes with subphase pH and composition. Structural models are proposed at high, neutral, and low pH. For water subphases containing KOH at pH > 11.2, the diffraction is consistent with molecules arranged in a hexagonal net and vertically aligned. Over pure water and acidic subphases containing HC1 at pH = 1.5, the molecules pack in a distorted hexagonal net with the fluorocarbon chains tilted from the vertical. The growth in time of the uncompressed crystallites over aqueous glycine solutions was directly monitored by GID. Compression and subsequent decompression of the monolayers over pure water and HC1 (pH = 1.5) subphases, for which the fluorocarbon chains are originally tilted, were found to reduce the crystallinity of the system considerably. By contrast, over KOH at pH > 11.2, the hexagonal net with vertically aligned molecules is preserved at all surface pressures and the crystalline order of the system is reduced upon compression but increases again upon release of pressure. Estimates of the degree of crystallinity of the monolayer were made over water for various states of compression and over KOH at pH >11.2 in the uncompressed state. The packing characteristics and the dynamics involved in the formation and partial destruction of the crystallites can be understood in terms of interaction between the hydrophilic ionic head groups of the monolayer and, if present, the attached molecules or ions (water, K+ or Cl"). Additional support for the packing arrangements proposed at high, neutral, and low pH was obtained from studies of the oriented growth of sodium chloride under PFA monolayers.

The formation of two-dimensional ordered aggregates of water-soluble hydrophobic α-amino acids at the air-solution interface has been demonstrated through the induced epitaxial nucleation of α-glycine crystals at these interfaces. This crystallization method, albeit indirect, has been found to be very sensitive to small changes in the structure of the presumed aggregates. The hydrophobic-amino acids used were divided into two classes: The first, including valine, leucine, phenylalanine, norleucine, isoleucine, and n-aminooctanoic acid, induced fast oriented crystallization of α-glycine, at the solution surface, whereas the second class, tert-butylglycine, neopentylglycine, and hexafluorovaline, did not. The comparison between the packing arrangement of the α-glycine crystalline face attached at the interface and that of various hydrophobic α-amino acid crystals, complemented by surface tension measurements, brought evidence in favor of the formation of structured domains which must carry precise enantioselective information to generate the oriented crystallization process. These results may be relevant to any process involving structural self-aggregation.

Monolayers of PFA, a fluorinated surfactant, on water were studied using synchrotron X-ray grazing incidence diffraction (GID) and reflectivity measurements (XR). The uncompressed monolayer is found to self-assemble into crystalline domains giving a strong GID peak. Upon compression and decompression a surface pressure driven solid-solid phase transition takes place. A hexagonal lattice with vertical molecules at high pressure undergoes a distortion due to a rigid molecular tilt as the pressure is decreased. Bragg rod scans provide conclusive evidence for a tilt of about 20 " at 10 mN/m and show the tilt to be towards nearest neighbours. The uncompressed monolayer has a molecular tilt of about 25 '.

A network of hydrogen bonds determines the structure of the complex A of nylon66 and perfluoroglutaric acid, HO₂C(CF₂)₃CO₂H. This explains why shorter or longer dicarboxylic acids do not form complexes with nylon66. The nylon partial structure differs from the structure of pure nylon not in the CC bond lengths but rather in the CCC angles, which result in a longer b axis. Complexes of type A are unusual, because they consist of a molecular mixture of otherwise immiscible hydrocarbons and fluorinated hydrocarbons. (Figure Presented.)

We have demonstrated, for the first time by diffraction methods, that a solid solution composed of host and guest molecules can exhibit a crystal symmetry lower than that of the host. The study proves that the symmetry of a solid solution is dependent not only upon the host crystal structure and the guest molecular structure but also upon the surface structure and symmetry of the host crystal. The crystal structures of (S)-asparagine monohydrate [D₂NCOCH₂CH(ND₃)CO₂.D₂O] and of the solid solution (0.848:0.152) (S)-asparagine/(S)-aspartic acid [DO₂CCD₂CD(ND₃)CO2] monohydrate were refined by using neutron diffraction data obtained at 15 K. The space group of the pure host crystal is P2₁2₁2₁(Z = 4), whereas that of the host/guest crystal is monoclinic P12₁1 with two molecular sites per asymmetric unit. The ratios of guest/host occupancies of the two independent sites are 0.173:0.827 and 0.132:0.868. The reduction in symmetry is in accordance with the preferred adsorption of guest aspartic acid on the (010) crystal face at half of the orthorhombic, symmetry-related surface sites. Aspartic acid mimics, at the preferred (010) surface sites, molecular asparagine, participating in all hydrogen bonds. At the less-favored (010) surface sites a \u201cnormal\u201d N-H.O(host) hydrogen bond is replaced by O(hydroxyl).O(host) repulsion between lone-pair electrons.

We have determined the packing arrangement of a floating monolayer of palmitoyl-(R)-lysine at the air-water interface by grazing incidence X-ray diffraction and reflection measurements. These techniques utilize the unique properties of synchrotron radiation: high intensity within a small natural collimation. In the grazing angle diffraction experiment two peaks were detected in the "twodimensional powder" pattern from a monolayer of palmitoyl-(R)-lysine. Their widths indicated coherence lengths of 500 J~. The positions and intensities of these peaks allowed us to choose between various models and to determine the monolayer structure. The packing arrangement of the Qt-amino acid headgroups in the model proved to be very similar to that found in the crystal structures of the 0t form of glycine and several hydrophobic at-amino acids, thus providing a simple explanation for the oriented crystallization of 0t-glycine at monolayer-solution interfaces. The tilt of the molecule calculated from the model is consistent with the results from reflectivity measurements and X-ray powder diffraction data of the crystalline powder material. Reflectivity measurements indicate that at surface pressures as high as 30 mN m- 1 the monolayer covers only about 90% of the surface. Reflectivity measurements of the monolayer over water and over solutions of 29/o (S)-glutamine showed significant differences, indicating binding of the solute molecules to the monolayer.

A new class of monomeric and polymeric crystal dissolution inhibitors has been prepared taking into consideration the packing arrangements and the morphologies of organic crystals. The efficiency of these inhibitors has been demonstrated by comparative morphological studies of α-glycine and by the kinetic resolution of the racemic conglomerates of his·HCl·H
2O, threonine, glu·HCl, and 2,4-sec-phenethyl-3,5-dinitrobenzoate

The structures of the partially reacted crystals of the two complexes (5:2) deoxycholic acid (DCA)-acetophenone and (8:3) DCA-p-fluoroacetophenone were determined by low-temperature (-170 °C) X-ray diffraction. the structure analyses indicated that both independent guest acetophenone molecules G and G in DCA-acetophenone react and that in DCA-p-fluoroacetophenone the guest molecule G reacts whereas the other guest molecule G remains unreacted because of packing of G and G molecules along the channel. the observed guest photoconversion in DCA-acetophenone is 40%; the maximum value according to packing considerations is 50%. In DCA-p-fluoroacetophenone the observed guest photoconversion is 35%, very close to the maximum theoretical yield of 33% based on packing considerations. the analysis demonstrated that during the course of photoconversion there is minimal motion of the (guest) phenyl ring, pronounced rotation of the acetyl group about the exocyclic C-C bond, and displacement of unreacted and reacted molecules. Atom-atom potential energy calculations showed that in DCA-acetophenone a guest ketyl radical with a pyramidal geometry may rotate by a full 180° without inducing prohibitively short intermolecular contacts.

The two inclusion complexes of guest acetophenone and m, chloro-acetophenone with host deoxycholic acid (DCA) each yielded on UV irradiation a single diastereomeric photoaddition product at steroid atom C5, of configuration S at the generated stereogenic centre (DCAOHCH₃C₆H₄). Comparison of the host-guest arrangement at the sites of reaction with the S configuration at the new chiral atom C of the photoproducts indicates a net rotation of 180° by the guest acetyl group prior to C-C bond formation since the guest molecules expose their Re faces to the C5-H5 steroid bonds¹. To elucidate this rotation, photochemical and crystallographic studies were performed on four DCA complexes with engineered guest ketone arrangements. The guests were p-fluoroacetophenone and (p-substituted) propiophenones (XC₆H₄CO₂C₂H₅, X=H, F, Cl). The crystal structures of two isolated photoproducts are also reported. The channels of DCA-fluoroacetophenone contain two independent guest molecules G' and G, respectively exposing their Re and Si faces to the steroid C5-H5 bond vectors at the potential sites of reaction. Only one diastereomeric photoproduct was obtained with addition at atom C5, with absolute configuration S at the generated stereogenic centre, akin to that of the DCA-acetophenone complexes. The reaction is interpreted in terms of a 180° rotation of the acetyl group of the G' molecule; the absence of the R diastereomer is explained by a preclusion of photoaddition of guest G to DCA because of guest packing along the channel. The guest arrangements in the two complexes DCA-propiophenone and DCA-p-fluoropropiophenone are almost isomorphous. There are two independent guest molecules G and Ḡ related by a pseudo centre of inversion. Each of the two guest molecules exposes its Re face to a steroid C5-H5 bond at a site of reaction. Thus photoaddition takes place with and without 180° rotation of the propionyl group since the two complexes each yield the two diastereomeric photoproducts at C5. DCA-p-chloropropiophenone yields only one diastereomeric photoproduct at C5, with absolute configuration R about the new stereogenic centre. The crystal structure analysis suggests three independent guest molecules G, G' ana Ḡ; G and G' are related by pseudo two fold screw symmetry along the channel axis; Ḡ is related to G and G' by pseudo centre of inversion; once again the guests G, G' and Ḡ appear to expose their Re faces to the C5-H5 bonds at the sites of reaction.

Photochemical reactions in crystals proceed under control of the structure, including absolute configuration, of the bulk, unless preceeded by energy transfer, in which case defects may be important. The reaction may be followed by phase separation. Two-phase systems allow wider scope for reactant selection. The presence during growth of additives, matched stereochemically to the crystal, modifies habit and growth-rate, with far-reaching consequences. Some partially ordered systems are considered.

This chapter contains sections titled: Introduction; Statement of the Problem; The Bijvoet Method; A Bridge Between Crystal Structure, Crystal Morphology, and Molecular Chirality; Absolute Configuration from Chemical Reactivity in Polar and Enantiopolar Crystals; The Solvent Effect; Pyroelectricity, Piezoelectricity, and Optical Activity in Crystals; Determination of Absolute Configuration by Electron Microscopy; Conclusions

When crystals of organic compounds are grown in the presence of growth inhibitors, there is a change in crystal morphology. A stereochemical correlation exists between the crystal structure, its modified morphology, and the molecular structure of the inhibitor. This correlation has been successfully exploited for the efficient resolution of conglomerates, the engineering of organic crystals with desired morphologies, the direct and relative assignment of the absolute configurations of chiral molecules and crystals, and for the design of a new model for the spontaneous generation of optical activity. In an analogous way dissolution of organic crystals in the presence of these growth inhibitors induces etch pits at preselected faces. The effect of solvent on crystal growth has been analyzed in some model systems. The experimental results are complemented by atomatom potential energy calculations.

A general method for the controlled modification of the morphology of organic crystals is described. The method comprises stereospecific inhibition of growth of preselected faces with the assistance of "tailor-made" growth inhibitors. The change in crystal habit is explained by a mechanism which takes into consideration a stereochemical correlation between the molecular structure of the additive, the crystal structure of the substrate, and the affected growth directions. The method has been successfully applied to primary amides ((E)-cinnamide, benzamide, p-toluamide, and p-clorobenzamide), carboxylic acids ((E)-cinnamic acid and benzoic acid), and steroids (androsterone and epiandrosterone). Dramatic changes in habit were induced by replacement, at the crystal surface, of a substrate N-H ..,0 bond by an Q...Q repulsion, by replacement of an attractive C-H ..,0 interaction by a C-H ..,H or C-Cl..,0 repulsion, or by insertion of a methyl or chlorine substituent instead of hydrogen, etc. The induced morphological modifications were used to obtain information on molecular interactions and conformations of the adsorbed inhibitor at the crystal surface. Thus, we could show that adsorbed additives benzamide and picolinamide assume twisted and planar conformations, respectively, on the affected faces of host benzoic acid, which is planar in the solid. In contradistinction, p-aminobenzoic acid tends to be planar when interacting with the growing faces of the nonplanar p-aminobenzamide. The additive (E)-cinnamide assumes a syn-planar C=C-C=O conformation on the affected surface of host (E)-cinnamic acid, which tends to assume an antiplanar C=C-C=O conformation. The effect of various additives on crystal habit is accounted for and quantitatively evaluated by atom-atom potential energy calculations.

A model for the separation of enantiomers of several classes of compounds by copper complexes of N,Ndialkylαamino acids, based on chromatographic results and supported by crystal growth and dissolution studies, is described.

The centrosymmetric monoclinic crystals of glycylglycine were grown in the presence of three dipeptides (racemic and resolved GlyAla, AlaGly and GlyLeu); the presence of each yielded a different morphology. It was found by a combined theoretical and experimental study that the conformation of the guest molecule is determined by the highly stereospecific intermolecular interactions between adsorbed additive and the molecules of particular surface layers of the growing crystals. Theoretical calculations predicted the preferred conformation of the leucine side chain of GlyLeu consistent with the change in morphology. Occluded racemic GlyLeu segregates along the b axis of the single crystals of GlyGly.

Doubly vs. singly hydrogen-bonded arrangements in crystalline N-acylated amino acids R-CONH-CHR-C02H are examined by energy calculations. The O(amide) is a significantly stronger proton acceptor than the O(carboxyl). Thus in one-third of the crystal structures the molecules form doubly hydrogen-bonded systems O-H-O(amide) and N-H-O(amide), despite the general preference for the maximum number of proton acceptor sites to participate in hydrogen bonds, dictated by molecular packing and conformation. The energy results are consistent with the tendency for the molecules to be interlinked via single hydrogen bonds O-H-O(amide) and N-H-O(carboxyl), rather than the reverse, and the total absence of the doubly hydrogen-bonded systems O-H-O(carboxyl) and N H-(carboxyl).

Information contained in electron density distributions, derived from X-ray diffraction data, was exploited to improve the electrostatic parameters of atom-atom potential functions of the carboxyl group and thus to obtain a better estimate of the Coulomb intermolecular energies. The proton affinities of the carbonyl oxygen atom of the amide and carboxyl groups were compared in terms of electrostatic potential energy around these atoms and correlated with hydrogen-bonding properties. Energy calculations were undertaken to account for various characteristic packing motifs of carboxylic acid molecules, including the geometry of the catemer motif, order-disorder of the carboxyl dimer, preferred stacking of carboxyl dimers, the role played by C-H⋯O(carbonyl) interactions in stabilizing overall packing, characteristic packing of substituted benzoic acids, and the stability of the observed crystal structures of oxalic acid and formic acid, via the generation and analysis of ensembles of alternative crystal structures.

A method for resolution of conglomerates, based on morphological differences between the enantiomorphic crystals induced by tailor-made resolved impurities is described. The relationship between the crystal structure of the affected enantiomorph and the stereochemistry of the added impurity is analysed in the systems glutamic acid. HCl, asparagine. H₂O and threonine in the presence of L- or D-amino acids, and it is found that the additive binds stereoselectively at the surface of the enantiomer of the same absolute configuration, occupying the same site of the amino acid groups of the host molecule. The modified side chains perturb in a second stage the regular growth of the crystal in the directions along which the side chains of the host are hydrogen bonded.

The ability of molecules, chiral by virtue of the presence of an s-butyl group, to display conformational polymorphism has been exploited for the performance of asymmetric syntheses of either sense on the same chiral molecule; this phenomenon is illustrated for the asymmetric solid-state polymerization of the monomer (R)-()-(1).

A molecular model which accounts for stereoselective interactions within the series of chiral secondary amides RCONHCH(CH₃)Ar is proposed. It assumes that a guest molecule intercalates between two host molecules in their 5-Å translation H-bonded array to form diastereomeric arrangements for the two enantiomers, differing in stability. The model explains various aspects of chiral recognition: (1) the gas chromatographic separation of enantiomers achieved with N-acyl-α-arylethylamines as chiral phases; (2) the difference in solubility of (R)- and (S)-N-trifluoroacetyl-α-(1-naphthyl)ethylamine in solid (R)-N-lauroyl-α-(1-naphthyl)ethylamine. The packing arrangement of certain diamide molecules was examined in order to reinforce the assumptions on which the explanation of the stereoselective effects was based. Energy computations support the stability relationships which follow from the model.

NA

Resolved 1-phenylpropyl and 1-phenylbutyl 9-anthroates, when crystallised from n-hexane, form 6:1 inclusion molecular complexes which are isostructural; X-ray analysis of the propyl derivative demonstrates the formation of a channel structure by the anthracenes, in which the n-hexane is included.

The title compound crystallises in space group Pca2₁ with two molecules in the asymmetric unit, the cell having dimensions a = 8.060, b = 4.195, c = 25.433 Å. The phases were determined from a diffractometer data by a multi-solution method and the structure refined by a least-squares procedure to R 0.067 for 968 independent reflections. The bond lengths are C≡C 1.175, 1.179; ≡C-C 1.455, 1.453; C-CO₂H 1.484, 1.506; C=O 1.221, 1.214; C-OH 1.307, 1.259 Å. The C(:O)·O·C⋮C system is syn-planar. The molecules are hydrogen-bonded (O-H ⋯ O 2.69 and 2.65 Å) in pseudo-centrosymmetric pairs. In the crystal there are no intermolecular ethynyl-H ⋯ O=C interactions: rather, the acetylenic C-H bond points at the C≡C triple bond, [H ⋯ C⋮C(midpoint) 3.0 Å]. The C(sp³)-H ⋯ bond is directed towards the carbonyl oxygen (C-H ⋯ O 3.45, and H ⋯ O 2.6 Å). But-3-ynoic acid also appears in a pseudo-orthorhombic form showing order-disorder. The relationship of the two forms is discussed.

The crystal structure of pentafluorobenzoic acid has been solved from 1598 three-dimensional counter data, and refined by least-squares to R 0.04. Crystals are triclinic, space group P1, with Z = 2 in a unit cell of dimensions: a = 7.925, b = 8.637, c = 6.262 Å, α = 97.55, β = 89.65, and γ = 121.86°. Values of σ for bond lengths are 0.002 Å. The angle between the planar pentafluorophenyl group and the carboxy-group is 29.8°. The molecules form cyclic hydrogen-bonded dimers (OH ⋯ O 2.668 Å) in which the C-OH and C=O bond lengths are 1.278 and 1.221 Å. The structure of mesitoic acid was refined similarly to R 0.05 for 2060 reflections. Crystals are monoclinic, space group C2/c, Z = 8, in a unit cell of dimensions: a = 15.142(1), b = 7.026(1), c = 17.439(1) Å, β = 89.35 (1)°. The mean σ values of the heavy-and hydrogen-atom co-ordinates are 0.001 and 0.03 Å. The angle between the mesityl and carboxy-groups is 48.4°. The molecules form cyclic hydrogen-bonded pairs (OH ⋯ O 2.640 Å) in which the C-O bond lengths are nearly equal (1.275 and 1.248 Å). The molecular dimensions and the packing arrangements of both structures are discussed.

The crystal structures of β-methyl-cis-, (III), β-chloro-cis-, (II), and β-chloro-trans-cinnamic, (I), acids have been determined from three-dimensional counter data by Patterson and Fourier methods. (I): a = 19.588, 6 = 5.374, c = 16.683 Å, β = 103.62°, Z= 8, space group A2/a, R 0.054 (1873 reflections): (II): a = 5.797, b = 24.247, c = 7.240 Å: β = 121.56° Z = 4, space group P2¹/c, R 0.046 (1917 reflections); (III): a = 7.504 b = 7.442, c = 17.056 Å, β = 107.00°, Z = 4, space group P2₁/c, R 0.066 (1987 reflections). The σ values of the experimental bond lengths are

Die Kristallstrukturen von Hexamphenylen (1) und Pentamphenylen (2) wurden anhand dreidimensionaler (sin Θ/λ ≤0.66) Zählerdaten gelöst, die nach der DifferenzFilterMethode bei Raumtemperatur mit Mo_KαStrahlung auf einem SiemensDiffraktometer gemessen worden waren. Die Strukturen wurden mit einem BlockMatrixKleinsteQuadrateVerfahren zu R 0.047 (1) und 0.050 (2) verfeinert; die Standardabweichungen der Bindungslängen und winkel betragen 0.002₄ Å bzw. 0.1₅°. Bei Annahme der Symmetrie m anstelle von 6 der Benzolkerne belaufen sich die Streuungen chemisch gleichwertiger Bindungen und Winkel auf 0.002 Å und 0.3°. Die Abweichungen der beobachteten Strukturen von den idealisierten Konformationen (1: ō m; 2 : 2) werden intermolekularen Packungseffekten zugeschrieben. Der \u201eovercrowding effect\u201d in beiden Molekeln (1 : C C 2.9582.968; HH 2.192.30 Å. 2: 2:8012.839; 1.842.19 Å) erzeugt eine Verdrillung von etwa 18° um die Achsen, die durch die Mittelpunkte der exocyclischen Bindungen gehen, und eine Deformation der Benzolkerne. Die Längen der exocyclischen Bindungen (1 : 1.487; 2 : 1.495 Å) werden diskutiert. Ein energetisch günstiger Inversionsmechanismus von 2 wird zur Erklärung der kernmagnetischen Äquivalenz der inneren Protonen vorgeschlagen.

The crystal structure of trans,trans-sorbamide has been solved from 1380 three-dimensional counter data (Cu K_α radiation), corrected for absorption, and refined by a least-squares method with anisotropic temperature factors of all but the hydrogen atoms. The "final" agreement factors were r = 0.009, R = 0.046 and 0.045, including and excluding |F_c| > kF_t, respectively. The e.s.d. of heavy-atom and hydrogen co-ordinates are estimated as 0.002 and 0.03 Å, respectively. A rigid-body analysis of the molecule has been carried out, and the bond lengths have been corrected accordingly. The molecular dimensions and the packing arrangement are discussed.