Steric effects conformation

Lipophilicity in particular, as reflected in partition coefficients between aqueous and non-aqueous media most commonly water (or aqueous buffer) and Z-octanol,has received much attention [105,141,152,153,176,199,232,233]. Logic )W for the octanol-water system has been shown to be approximately additive and constitutive, and hence, schemes for its a priori calculation from molecular structure have been devised using either substituent tt values or substructural fragment constants [289, 299]. The approximate nature of any partition coefficient has been frequently emphasized and, indeed, some of the structural features that cause unreliability have been identified and accommodated. Other complications such as steric effects, conformational effects, and substitution at the active positions of hetero-aromatic rings have been observed but cannot as yet be accounted for completely and systematically. Theoretical statistical and topological methods to approach some of these problems have been reported [116-119,175,289,300]. The observations of linear relationships among partition coefficients between water and various organic solvents have been extended and qualified to include other dose-response relationships [120-122,160,161,299-302]. 

Cyclic radicals are very often involved in the key step of a reaction sequence. They are particularly useful since the stereochemical outcome of their reactions can be easily predicted and in some cases directed. Selected examples from the recent literature have been chosen in order to illustrate the different factors governing the stereochemical outcome. The importance of steric effects, conformational effects, neighboring prochiral centers, pyramidalization, stereoelectronic effects and position of the transition states will be discussed based on examples of synthetic importance. 

The equilibrium between 2)6,3i5-disubstituted 5a- and 5)5-6-ketones (12) shows a surprising and unexplained dependence upon the nature of the C-17 substituent. The presence of an axial 2) -substituent destabilizes the 5a-isomer, shifting the equilibrium towards the 5jS-isomer where the 2)5,10/5 diaxial interaction is relieved. The influence of the C-17 substituent on the equilibrium varied, over a series of eight different compounds, between the extremes represented by 5 5a ratios of 0.13 (17/5-OH) and 7.06 (17/5-COMe). Steric effects, conformational transmission, and inductive and electrostatic field effects are each discussed and dismissed as being incapable of providing an adequate explanation of the data. 

In summary, for the last decade, selective alkene RCM has become a powerful tool for the synthesis of complex natural products. This method has been broadly applied to the construction of different ring systems including both medium-size (five- to ten-membered) and large rings. For the polyene substrate, terminal and less substituted alkenes are generally more reactive. In addition, steric effects, conformational effects as well as choice of catalysts are also key factors to achieve the selectivity. 

D-A rxns are sensitive to steric effects of the dienephiles, particularly at the I- and 2-postions. Steric bulk at the I-position may prevent approach of the dienophile while steric bulk at the 2-position may prevent the diene from adopting the s-cis conformation. 

Tetrakisligand nickel(0) complexes have tetrahedral stmctures. Electronic stmctures have been studied and conformational analysis performed. Quantitative equiUbria measurements of the ligands in these complexes imply a dominant role for ligand steric effects when the complexes are employed as catalysts (94). 

The effect of the conformation of amic acid on the imidi2ation rate is also consistent with the observation that the thermal cycli2ation of model compounds, N-substituted phthalamic acids, is strongly influenced by the steric effect imposed by N-substituents (18). 

The selectivity observed in most intramolecular functionalizations depends on the preference for a six-membered transition state in the hydrogen-atom abstraction step. Appropriate molecules can be constmcted in which steric or conformational effects dictate a preference for selective abstraction of a hydrogen that is more remote from the reactive radical. 

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

A very interesting steric effect is shown by the data in Table 7-12 on the rate of acid-catalyzed esterification of aliphatic carboxylic acids. The dissociation constants of these acids are all of the order 1(T, the small variations presumably being caused by minor differences in polar effects. The variations in esterification rates for these acids are quite large, however, so that polar effects are not responsible. Steric effects are, therefore, implicated indeed, this argument and these data were used to obtain the Es steric constants. Newman has drawn attention to the conformational role of the acyl group in limiting access to the carboxyl carbon. He represents maximum steric hindrance to attack as arising from a coiled conformation, shown for M-butyric acid in 5. 

Compare energies for both diaxial and diequatorial chair conformers of trans-2-fluorocyclohexanol (X = OH). Which conformer is preferred Does the preferred conformer minimize steric repulsion Is it reasonable to attribute the conformational preference solely to steric effects Explain. Examine dipole moments for the two conformers. Does the preferred conformer minimize electrostatic repulsion (or maximize electrostatic attraction) Is it reasonable to attribute the conformational preference solely to electrostatic effects Explain. 

Examine space-filling models for the two conformers and identify any likely unfavorable nonbonded interactions. Based on steric effects, which conformer would you anticipate would be the more stable Compare energies of anti-1,2-ethanediol and gauche-1,2-ethanediol to see if you are correct. Is this the same ordering of conformer energies as seen for n-butane (see Chapter 5, Problem 3)7... 

Monosubstituted cyclohexanes are more stable with their substituent in an equatorial position, but the situation in disubstituted cyclohexanes is more complex because the steric effects of both substituents must be taken into account. All steric interactions in both possible chair conformations must be analyzed before deciding which conformation is favored. 

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

Numerous literature references104 attest to the fact that the naturally occurring spiroketals and many synthetic products adopt conformations in which the anomeric effects are maximized and the steric effects are minimized. However, in some such compounds, the steric effects of bulky substituents and diaxial interactions can result in a conformation in which the anomeric effect cannot operate. 

In order for an experimental test of the kinetic behaviour to be as informative as possible, the system investigated should fulfil various specific requirements. From the experimental point of view, the reaction should cause a minimum of change in the reaction medium and be without side-reactions as far as possible, in order for accurate and well-defined rate measurements to be feasible. For the same reason an accOTate physical method which can be applied without distiubing the reacting system is to be preferred. From the theoretical point of view, it is desirable that the steric effects play as important a role in the reaction as possible, because only then is a sizeable effect to be expected. Finally, a transition state of well-known conformation is a necessary prerequisite for the quantitative application of the theory. 

The work of Melander and Carter (1964) on 2,2 -dibromo-4,4 -di-carboxybiphenyl-6,6 -d2 (1) has been referred to above in the introductory and theoretical sections, where it was pointed out that the availability of two detailed theoretical computations of the inversion barrier (Westheimer and Mayer, 1946, Westheimer, 1947 Hewlett, 1960) made this system especially attractive for the study of steric isotope efifects. Furthermore, in the preferred initial-state conformation the two bromines are probably in van der Waals contact (cf. Hampsoii and Weissberger, 1936 Bastiansen, 1950), and thus initial-state steric effects are unaffected by deuterium substitution in the 6 and 6 positions. The barrier calculations provided two different theoretical values for the non-bonded H Br distance in the transition state which, together with the corresponding H Br potential function, could be inserted in equation (10) to yield values for A AH. For... 

Syn elimination and the syn-anti dichotomy have also been found in open-chain systems, though to a lesser extent than in medium-ring compounds. For example, in the conversion of 3-hexyl-4-d-trimethylammonium ion to 3-hexene with potassium ec-butoxide, 67% of the reaction followed the syn-anti dichotomy. In general syn elimination in open-chain systems is only important in cases where certain types of steric effect are present. One such type is compounds in which substituents are found on both the P and the y carbons (the unprimed letter refers to the branch in which the elimination takes place). The factors that cause these results are not completely understood, but the following conformational effects have been proposed as a partial explanation. The two anti- and two syn-periplanar conformations are, for a quaternary ammonium salt ... 

The enamines derived from cyclohexanones are of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17.106 A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the tt orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.107 A serious nonbonded repulsion (A1,3 strain) in 18 destabilizes this isomer. 

These results are consistent with a directive effect by the silyloxy substituent through the sterically favored conformation of the reactant. 

Another type of steric effect results from interactions between diene substituents. Adoption of the s-cis conformation of the diene in the TS brings the d.v-oricnlcd 1- and 4-substituents on a diene close together. /(-1,3-Pcnladicnc is 103 times more reactive than 4-methyl-l,3-pentadiene toward the very reactive dienophile tetracyanoethylene. This is because the unfavorable interaction between the additional methyl substituent and the C(l) hydrogen in the s-cis conformation raises the energy of the TS.20... 

Similarly, the 2,8,10-triene 3a gives a mixture of four isomers, but introduction of a TMS group as in 3b gives a single stereoisomer in 89% yield. The reason for the improved stereoselectivity is that the steric effect introduced by the TMS substituent favors a single conformer. 

Synclinal and antiperiplanar conformations of the TS are possible. The two TSs are believed to be close in energy and either may be involved in individual systems. An electronic tt interaction between the stannane HOMO and the carbonyl LUMO, as well as polar effects appear to favor the synclinal TS and can overcome the unfavorable steric effects.161bi 162 Generally the synclinal TS seems to be preferred for intramolecular reactions. The steric effects that favor the antiperiplanar TS are not present in intramolecular reactions, since the aldehyde and the stannane substituents are then part of the intramolecular linkage. 

The success of such reactions depends on the intramolecular hydrogen transfer being faster than hydrogen atom abstraction from the stannane reagent. In the example shown, hydrogen transfer is favored by the thermodynamic driving force of radical stabilization, by the intramolecular nature of the hydrogen transfer, and by the steric effects of the central quaternary carbon. This substitution pattern often favors intramolecular reactions as a result of conformational effects. 

Steric and conformational factors are also important, especially in cyclic systems.233 There is a preference for the migration of the group that is antiperiplanar with respect to the peroxide bond. In relatively rigid systems, this effect can outweigh the normal preference for the migration of the more branched group.234... 

As shown in Table VII, [2 + 4] cycloaddition is the most common reaction pathway followed by Me2Si=C(SiMe3)2, but it is usually accompanied by significant quantities of the product of an ene reaction. As the diene becomes more sterically hindered in its s-cis conformation, as in cis/trans-2,4-hexadiene, the product of an ene reaction predominates. With butadiene, where minimal steric effects are to be expected, the exclusive product of the reaction was found to be the [2 + 4] cycloaddition... 

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