Structural problems reactive conformations

In essence, there are only two really important themes in chemistry structure and reactivity. In structural problems, we usually compare the relative stabilities of two isomers (1 and 2) or conformers (3 and 4). Their energy differences are of the order of a few percent. Thus, benzene (1) is more stable than Dewar benzene (2) by 60 kcal mol-1, about 5% of its molecular energy (-1230 kcal mol-1) 3 Similarly, frans-butadiene (3) is more stable than ds-butadiene (4) by 2.7 kcal mol-1, or 3% of its energy of formation. 

Reactivity. Hemoglobin can exist in either of two structural conformations, corresponding to the oxy (R, relaxed) or deoxy (T, tense) states. The key differences between these two structures are that the constrained T state has a much lower oxygen affinity than the R state and the T state has a lower tendency to dissociate into subunits that can be filtered in the kidneys. Therefore, stabilization of the T conformation would be expected to solve both the oxygen affinity and renal excretion problems. 

Whereas many scientists shared Mulliken s initial skepticism regarding the practical role of theory in solving problems in chemistry and physics, the work of London (6) on dispersion forces in 1930 and Hbckel s 7t-electron theory in 1931 (7) continued to attract the interest of many, including a young scientist named Frank Westheimer who, drawing on the physics of internal motions as detailed by Pitzer (8), first applied the basic concepts of what is now called molecular mechanics to compute the rates of the racemization of ortho-dibromobiphenyls. The 1946 publication (9) of these results would lay the foundation for Westheimer s own systematic conformational analysis studies (10) as well as for many others, eg, Hendrickson s (11) and Allinger s (12). These scientists would utilize basic Newtonian mechanics coupled with concepts from spectroscopy (13,14) to develop nonquantum mechanical models of structures, energies, and reactivity. 

Metalloenzymes pose a particular problem to both experimentalists and modelers. Crystal structures of metalloenzymes typically reveal only one state of the active site and the state obtained frequently depends on the crystallization conditions. In some cases, states probably not relevant to any aspect of the mechanism have been obtained, and in many cases it may not be possible to obtain states of interest, simply because they are too reactive. This is where molecular modeling can make a unique contribution and a recent study of urease provides a good example of what can be achieved119 1. A molecular mechanics study of urease as crystallized revealed that a water molecule was probably missing from the refined crystal structure. A conformational search of the active site geometry with the natural substrate, urea, bound led to the determination of a consensus binding model[I91]. Clearly, the urea complex cannot be crystallized because of the rate at which the urea is broken down to ammonia and, therefore, modeling approaches such as this represent a real contribution to the study of metalloenzymes. 

On the other hand, we may desire a compound which has the activity of a particular lead, but is of apparently different structure. That is a new lead. In this case we would try to design compounds which possess different chemical structures but maintain identical steric, transport, and reactivity properties. It was for this purpose that we have developed a computerized tool, called MOLY, which can assist in the molecular design problem. In this paper we will briefly review what this system is and detail our efforts to parameterize the conformational analysis section of MOLY. 

The photochemical fragmentation of 7-methyl-2,2,5-triphenyl-l-oxa-5,6-diaza-spiro-[2,4]-hept-6-en-4-one has been studied." Interest in solid state photochemistry continues to burgeon. The present paper" discusses the problems associated with the proximity of the components of radical pairs or biradicals within the constrictions of the crystalline environment. This problem has been addressed by examining the photochemical reactivity of a series of cyclohexanone derivatives (119) whose solution-phase photochemistry is well known. The irradiations, using X = 350 nm, were carried out on microcrystals dispersed in potassium bromide. The influence of the conformations within the crystals and substitution were studied. The relative yields of the product, the corresponding cyclopentane, are shown beside the appropriate structure." ... 

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