The Configurations and Conformations of Molecules

The other systems, esters 2.71, enamines 2.72, and enol ethers 2.73, similarly have restricted rotation about the bond drawn as a single bond, but the barrier is 

Whereas the allyl anion, with a plane of symmetry through the central atom, has a node at that atom in j/ j, amides, esters, enamines, enol ethers and enolate ions do not have a node precisely on the central atom. Taking planar A V-dimethylviny-lamine and the enolate of acetaldehyde as examples, simple Hiickel calculations give the n orbitals in Fig. 2.15, which includes the allyl anion for comparison. 

One remaining detail to be explained is the relative energy of the two planar conformations available to amides and esters. Secondary amides adopt the Z conformation 2.74a rather than the E 2.74b, and esters adopt the s-trans conformation 2.75a rather than the s-cis 2.75b. In both the esters and the amides, the conformations 2.74a and 2.75a benefit from the anti orientation of the carbon chains R1 and R2. In other words, the alkyl chain R1 is effectively a larger substituent than the carbonyl oxygen, and the amide and ester alkyl groups R2 prefer to be anti to R1. However, this is not the whole story, because formate esters, with R1 only a hydrogen atom, ought to be the other way round, and they are not. There is a 

This effect is supplemented by terminal electronegative substituents, which increase the overall electron population at the extremities of the conjugated 

At the same time, rotation about the formally single bond between N-l and C-2 in these compounds is more restricted than the drawing of a single bond implies, just as it was with amides. The two A-methyl groups in both enamines 2.63 and 2.82 have different chemical shifts and coalescence measurements show that the free energy of activation for rotation is 56 kJ mol 1 (13 kcal mol-1) for the former and 69 kJ mol-1 (16.5 kcal mol-1) for the latter. Decreasing the stabilisation of the anionic centre in the transition structure with a less powerful acceptor than a nitro group, as in the ester 2.83 reduces the barrier to rotation about the N—C bond to 58 kJ mol-1 (14 kcal mol-1). 

1 One 11 Bond. It hardly needs saying that a n bond is not usually free to rotate. The n energy 2En that we saw in Fig 1.26 (280 kJ mol ) would be lost at the transition structure for rotation about the C—C bond, which would have the two p orbitals orthogonal. This value is higher than the energy normally available for a chemical reaction. For rotation about a n bond to become easy in the ground state, either the transition structures like diradical 2.101 or the zwitterion 2.102 must be stabilised or the planar structure 2.100 must be destabilised. 

An experimental value for the activation barrier for the isomerisation of cw-2-butene 2.104 is 259 kJ mol-1 (62 kcal mol-1). Phenyl groups stabilise radical centres, and the barrier to rotation in stilbenes 2.105 is correspondingly reduced from that in 2-butene to 179 kJ mol-1 (43 kcal mol-1). Steric interaction between the cA-vicinal substituents raises the energy of the planar structure, and contributes to lowering the barrier to rotation. In a fairly extreme example, the bifluorenylidene 2.106 benefits from both effects, and the barrier falls to 95 kJ mol-1 (23 kcal mol-1).136 

Alternatively, the substituents A and B may stabilise a cationic centre on one side and the substituents C and D an anionic centre on the other 2.102. Alkenes having donor substituents at one end and acceptors at the other are called push-pull alkenes, and the barriers to rotation are indeed lowered,137 with the enamine system of the alkene 2.107 having a barrier of 66 kJ mol-1 (16 kcal mol-1).138 More subtly, the substituents in the allene 2.108 enable the phenyl and the methyl groups to exchange places rapidly, with coalescence of 

Alternatively, interconversion between the stereoisomeric allyl cations can take place by capture of a nucleophile at either end, followed by rotation about the more or less normal single bond, and then regeneration of the cation by ionisation. Interconversion between the corresponding anions can take place similarly by cr coordination (771) to a metal at one end or the other. Because of the availability of these pathways, experimental measurements of the barrier to rotation have confirmed that it is less than the very approximate theoretical value of 116 kJ mol-1 (28 kcal mol ). Furthermore, measurements have generally been made on significantly more substituted systems. Such substitution can stabilise the filled, half-filled or empty p orbital, or the double bond, even when these components are no longer conjugated, and so appropriate substituents lower the barrier to rotation. 

In one of the most simple cases, with a methyl group at C-l and C-3, the U-shaped cation 2.112 generated in a superacid medium was converted into the sickle-shaped cation 2.111 with a half-life of about 10 min at 

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NMR methods have also been used extensively to determine the configuration and conformation of both moderate-size molecules and synthetic polymers, whose primary molecular structure is already known. During the past decade high resolution NMR, particularly employing 2D and 3D methods, has become one of only two methods (x-ray crystallography is the other) that can be used to determine precise three-dimensional structures of biopolymers—proteins, nucleic acids, and their cocomplexes—and NMR alone provides the structure in solution, rather than in the solid state. 

Backscattered dual circular polarization results on ephedrine and its stereoisomers are reported by Yu et al. (1993). All four stereoisomers examined show very similar Raman spectra, but their ROA spectra nicely show the sensitivity of ROA to the configurations and conformations of the molecules. As the features observed seem to be connected to the local stereochemistry, it seems to be possible that in the near future, with some more experimental data at hand, to deduce the absolute configuration of molecules of unknown stereochemistry directly from the ROA spectra. 

The above mechanisms provide a basis for rationalizing the nitrous acid deamination of amino sugars, a reaction which yields a variety of products and often proceeds with the formation of a new ring-structure. Many of these reactions are profoundly affected by the nature of the neighboring group and by the configuration and conformation of the molecule. 

The configuration and conformation of a molecule are partial aspects of its static stereochemistry, that is, the spatial arrangement of the atoms of the molecule. Stereochemical considerations presume knowledge of symmetry properties. 

IR and Raman spectra are particularly sensitive to the configurations and conformations of the polymer molecules. The variations in the conformational and configurational structures are reflected in specific observable frequencies. Consequently, it is possible to detect and quantify the amounts of the conformational isomers whether they be crystalline, liquid crystalline, or disordered (amorphous). The vibrational spectroscopic approach to structural elucidation in polymers relies on the comparison of vibrational spectra of polymers containing specific conformational structures (incorporated into the polymer during polymerisation or by thermal or chemical modification), with spectra of models (polymers and small molecules) containing similar structures presumed to be present in the polymers. 

Because the cross peaks in NOESY spectra arise from spatial interactions, this type of spectroscopy is particnlarly well suited to the study of configurations and conformations of molecules. The example of acetanilide demonstrates the capabilities of the NOESY experiment. The structural formula is shown, with the proton NMR chemical shifts of the relevant protons indicated. 

The carbon chemical shifts for steroids are the most readily available data from a routine 13C NMR determination. Since they reflect the electronic and steric environments of the various carbon nuclei, they provide sensitive insights to the configurational and conformational features of such molecules. While much interesting work on ab initio molecular orbital calculations of carbon chemical shifts is now appearing, it is probably true that the difficulties of carrying out such calculations on large molecules will prevent their applications to steroids for some time. We are limited, therefore, to a more empirical approach to steroid carbon chemical shifts. (3, 38)... 

Residual Dipolar Couplings for the Configurational and Conformational Analysis of Organic Molecules... 

The chiroptical properties of molecules are of substantial interest in chemistry and biochemistry and become important tools for the determination of the absolute configuration and conformation of molecular systems. In particular, the circular dichroism [1] is a quantitative measure of the difference in absorption coefficient for left and right circular polarized light ... 

Figure 26 shows the formula, conformation, and absolute configuration of veratridine (52). The structure and conformation of the C27-steroidal base is very similar to that determined for zygacine (C32H49N08) another Veratrum alkaloid (53). Variations in the pharmacological effects of Veratrum alkaloids appear to be dependent on the substituents attached to the essentially rigid molecular framework. The numerous intramolecular hydrogen bonds that enhance the molecular rigidity are indicated in Fig. 26. The positions of all the hydrogen atoms have been located for the veratridine molecule and the intramolecular donors and acceptors are identified as...

For fundamental research, the relevance of optically active Mannich bases lies in the stereochemical aspects of their synthesis and the study of structural parameters such as absolute configuration and conformation of the molecules. In particular, besides interesting asymmetric syntheses of amino aci[Pg.36]

The 9(10-> l9)-abeo analogue (6) of oestrone methyl ether has been shown by X-ray crystallography to have the normal 9a -configuration, but because of the chair conformation of the enlarged ring b the molecule differs considerably in shape from oestrone methyl ether. X-Ray, n.m.r., and o.r.d. data establish the structures and absolute configurations of a series of insect-repellent steroids isolated from Nicandra physaloides. The structure and conformation of the 6-sila-steroid (7) have been determined. ... 

Molecules in LCPs may develop correlated rotations about their chain axes, or correlated side chain rotations may develop, over optically resolvable distances. The optical properties of a correlated domain depend both on the configurational and conformational symmetry of the individual molecules and on the extent to which this symmetry is preserved on a larger scale by the correlations. 

In combination, the class of biflavonoids represents a library of over 20,000 different molecules, each of which is capable of multiple H-bondings and hydrophobic interactions. Not all these have been found to exist in nature so far. However, biflavonoid theoretical library covers a wide range of the configurational and conformational space, thus suggesting that the scope of interesting biological activities may be extraordinary. [2]... 

Structure The constitution, configuration, and conformation of a molecule. Formerly, the term was used as a synonym for constitution alone. 

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