Structure and Physicochemical Properties

As pointed out in the introduction, if one of the substituents on the nitrogen atom is a hydrogen atom, tautomeric equilibrium between enamino and imino forms strongly favors the latter form 18,140,141). According to physiochemical measurements, the occurrence of simply substituted /1 -pyrrolines and zl -piperideines is very improbable. The formulation of this type of compound with a double bond in the position (used mainly by early authors) was of formal meaning only, having no experimental evidence (142-144). 

The piperideine derivatives have not been studied as extensively as the analogous pyrrolines (151,152). The imino structure has been established, for example, for the alkaloid y-coniceine (146) (46). The great influence of conjugation on the structure is seen with l-(a-picolyl)-6,7-methylenedioxy-3,4-dihydroisoquinoline (47), possessing an enamine structure, whereas the analogous 1-methyl derivative (48) possesses an imine structure according to infrared spectra (152,153). 

In contrast to the five-membered ring, conformational factors would be expected to influence the equilibrium between the imine and enamine forms in the case of the six-membered-ring piperideine derivatives (154). 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

The ultraviolet spectra were also used for determination of the pyrroline structure (1,158-160). They exhibit a bathochromic shift to 225-235 m, caused by the auxochromic action of the nitrogen-free electron pair which is in conjugation with n electrons of the enamine double bond (161,162). 

The existence of an enamine grouping in a molecule makes possible several interconvertible isomeric structures. This fact is responsible for the high reactivity of these compounds. Their use in organic syntheses and their relatively frequent appearance in nature have stimulated a continuing intensive study of their structure. 

Unsaturated amines in which the double bond is separated from the nitrogen atom by at least one saturated carbon atom show behavior typical of saturated amines and non-con jugated olefins. A double bond in the position a,)3 to the nitrogen atom leads, by contrast, to the formation of a new reactive grouping in which the free electron pair of nitrogen is conjugated with the v-electrons of the double bond. The character of both the original structural elements is considerably 

An N-unsubstituted pyrroline derivative in which an exocyclic double bond has been established is compound 2. 

The double bond is kept in the exocyclic position by conjugation with the carbonyl group (the free base absorbs at 3270 cm-1). The free base of l-(a-picolyl)-6,7-methylenedioxy-3,4-dihydroisoquinoline also possesses the stabilized enamine structure, whereas the imino structure is exhibited by the 1-methyl analog, as shown by comparison of the 

Schneider, and H. J. Bernstein, High-Resolution Nuclear Magnetic Resonance, p. 281. McGraw-Hill, New York, 1959. 

---

Fig. 2.1 Dependency of DMPK and safety/toxicity properties on structural and physicochemical properties.

After the introductory section, work from the 19th century is briefly considered. The subsequent sections discuss in turn the structure and physicochemical properties of aminomethylenemalonates (1 and 2), syntheses, the cyclization of the title compounds, and other reactions of aminomethylenemalonates. 

Demange P, Wendenbaum S, Linget C, Bateman A, MacLeod J, Dell A, Albrecht AM, Abdallah MA (1989) Pseudomonas Siderophores Structure and Physicochemical Properties of Pyoverdins and Related Peptides. Second Forum on Peptides 174 95... 

The past 20 to 25 years have witnessed remarkable growth in our understanding of the basic structures and physicochemical properties of the proanthocyanidins. When taken in conjunction with a growing realization of their biological significance (described in, e.g.. Chapters 4 to 6), such a comprehension of their chemical characteristics has highlighted the importance of this area of natural products chemistry. 

Hoover, R. (2001). Composition, molecular structure, and physicochemical properties of tuber and root starches a review. Carbohydr. Polym., 45, 253-267. 

Table 4.1 Names, Structures, and Physicochemical Properties of Selected Ionic Liquids Evaluated as Gas-Liquid Chromatographic...

Discusses structure and physicochemical properties, activity coefficients, phase equilibrium with other liquids, and modeling... 

ChemSpider www.chemspider.com Large database of chemical structures and physicochemical properties... 

MPTP is also metabolized by other routes involving cytochromes P-450, FAD-dependent monooxygenases, and aldehyde oxidase. However, these seem to be detoxication pathways, as they divert MPTP away from uptake and metabolism in the brain. However, MPTP may inhibit its own metabolism by cytochromes P-450 and thereby reduce one means of detoxication. This example illustrates the importance of structure and physicochemical properties in toxicology. MPTP is sufficiently lipophilic to cross the blood-brain barrier and gain access to the astrocytes. The structure of the metabolite is important for uptake via the dopamine system, hence localizing the compound to a particular type of neuron. Again, uptake into mitochondria is presumably a function of structure, as a specific energy-dependent carrier is involved. 

Numerous theoretical studies have dealt with the structural and physicochemical properties of the unsaturated series of compounds and calculations have been performed at various levels of sophistication. A particular problem inherent in dealing with the sulfur-containing rings is whether, or in what manner, allowance should be made for -orbital participation (70SST(1)1, 75SST(3)728). The point is of some consequence in this series of compounds, particularly in connection with the question of aromaticity. Simple addition of potential cyclic 7r-electrons gives a total of eight, but resonance canonical forms of type (8b) and (8c), which invoke participation of 3d-orbitals, imply aromatic stabilization. However, whilst... 

Hoover, R. and Vasanthan, T. 1994a. Effect of heat-moisture treatment on the structure and physicochemical properties of cereal, legume and tuber starches. Carbohydr. Res. 252 33-53. 

Chemical reactivity and biological activity can be related to molecular structure and physicochemical properties. QSAR models can be established among hydrophobic-lipophilic, electronic, and steric properties, between quantum-mechanics-related parameters and toxicity and between environmental fate parameters such as sorption and tendency for bioaccumulation. The main objective of a QSAR study is to develop quantitative relationships between given properties of a set of chemicals and their molecular descriptors. To develop a valid QSAR model, the following steps are essential ... 

Written by international experts knowledgeable about many aspects of nucleic acid-based therapeutics, this book will be an essential guide to aspiring scientists interested in the various aspects of nucleic acid-based therapeutics as well as established scientists in the gene therapy field and related disciplines. This book presents a comprehensive account of the structures and physicochemical properties of gene delivery and expression systems, with emphasis on their in vivo applications for the production of therapeutic... 

Syunyaeva, R. 1981. Relationship Between Molecular Structure and Physicochemical Properties of n-Alkanes. Chem. Technol. Fuels Oils. 17, 161. 

The specific process(es) by which a substance crosses a membrane depends largely upon the substance s structural and physicochemical properties (Benet et al., 1996 Hrudey et al., 1996 Medinsky and Klaassen, 1996 Rozman and Klaassen, 1996 Wright, 1995). Note that the individual molecules of a substance cross cell membranes, not the aggregated forms (e.g., crystals or powder) or formulations of the substance to which exposure may occur. Hence, for a substance to cross cell membranes and be absorbed, it must first leave its aggregated form and reach a state of molecular disaggregation, i.e, individual molecules. The relative ease with which a substance can disaggregate into individual molecules depends largely on its structural and physicochemical properties. 

Owing to the extraordinary diversity of the chemical structure and physicochemical properties of metabolites, there is no a single analytical platform or methodology capable to detect, quantify, and identify all metabolites in the same analysis. Two major analytical platforms are currently used for... 

L. I. Trakhtenberg, G. N. Gerasimov, Metal-Containing Polymers Cryochemical Synthesis, Structure and Physicochemical Properties, in G. Carotenuto, L. Nicolais (Eds.), Metal/Polymer Nanocomposites, Wiley, New York, 2005, p. 37. 

---