Stereoelectronic factor

The interaction between the diene HOMO and the dienophile LUMO takes place when die ends of the two ir systems overlap to permit the transfer of electrons from die HOMO into the LUMO. This requirement of overlap imposes stereoelectronic constraints on die two reaction partners. First, the diene must be able to adopt an s-cis conformation so the ends of the diene can contact and overlap with the ends of the dienophile n system. For acyclic dienes, even though the s-trans conformer is favored, rotation about the central carbon-carbon bond is rapid and there will be a steady-state population of the required s-cis form present so that the cycloaddition can occur. 

However, when the diene system is constrained to the s-cis conformation by a cyclic framework, the effective concentration of the s-cis diene is much higher than for acyclic dienes, which have the s-cis conformer as a minor component of the rotomeric equilibrium. Such conformationally constrained dienes react much more easily and are excellent Diels-Alder dienes. Examples are cyclopentadi-enes, 1,3-cyclohexadienes, and furans. 

Second, substituents on the dienophile (olefinic or azo) can adopt a position in the transition state either exo or endo to the diene system. It has been found that the endo transition state is favored significantly over the exo transition state. This preference has been attributed to secondary orbital interactions (attraction) between the diene and polar substituents on the dienophile. 

This distinction is important because exo and endo transition states lead to different diastereomers. Control of diastereoselection is extremely important to 

For example, reaction of ( , )-2,4-hexadiene with methyl crotonate gives a single product in which the relative stereochemistry of four contiguous stereogenic centers is explicitly defined by die geometry of the starting materials and the endo transition. 

It was proposed that the transition state requires approach of the radical directly above the site of attack and perpendicular to the plane containing the carbon-carbon double bond. An examination of molecular models shows that for the 3-butenyl and 4-pentenyl radicals (16, =1,2) such a transition state can only be reasonably achieved in Xf -cyclization (i.e. 16— 15). With the 5-hexcnyl and 6-heptenyl radicals (16, w=3,4), the transition state for exo-cyclization (16- 15) is more easily achieved than that for enc/o-cyclization (i.e. 16 — 17). 

The mode and rate of cyelization can be modified substantially by the presence of substituents at the radical center, on the double bond, and at positions on the 

Stereoelectronie factors may also become important in polymerization when bulky substituents may hinder adoption of the required transition state. They may help explain why rate constants for addition of monomeric radicals may be very different from those for addition of dimeric or higher radicals.4 

for radicals 19, there is a strong preference for 1,5-hydrogeii atom transfer (Table 1.5). Although 1,6-transfer is also observed, the preference for 

5-hydrogen atom transfer over 1,6-transfer is substantial even where the latter pathway would afford a resonance stabilized bcnzylic radical. No s ign of 

7-transfer is seen in these cases. Similar requirements for a co-lincar transition state for homolytic substitution on sulfur and oxygen have been postulated.  

The most direct evidence that stereoelectronic effects are also important in these reactions follows from the specificity observed in hydrogen atom abstraction from confoiTnatioually constrained compounds. C-H bonds adjacent to oxygen or nitrogen and which subtend a small dihedral angle with a lone pair orbital ( 30°) are considerably activated in relation to those where the dihedral angle is or approaches 90 . fhus, the equatorial H in 20 is reported to be 12 times more reactive towards /-butoxy radicals than the axial 11 in 21. 

A further example of the importance of this type of stcrcoclcctronic effect is seen in the reactions of /-butoxy radicals with spiro[2,n]alkanes (22) where it is found that hydrogens from the position a- to the cyclopropyl ring arc specifically abstracted. 1 his can be attributed to the favorable overlap of the breaking C-H bond with the cyclopropyl a bonds.No such specificity is seen with bicyclo[n, 1,0]alkanes (23) where geometric constraints prevent overlap. 

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The case of a, -unsaturated caAonyl compounds is analogous to that of 1,3-dienes, in that stereoelectronic factors favor coplanaiity of the C=C—C=0 system. The rotamers that are important are the s-trans and s-cis conformations. Microwave data indicate that the s-trans form is the only conformation present in detectable amounts in acrolein (2-propenal). The equilibrium distribution of s-trans and s-cis conformations of a,fi-unsatuiated ketones depends on the extent of van der Waals interaction between substituents. Methyl vinyl ketone has minimal unfavorable van der Waals repulsions between substituents and exists predominantly as the s-trans conformer ... 

Stereoelectronic factors are also important in determining the stmcture and reactivity of complexes. Complexes of catbonyl groups with trivalent boron and aluminum compounds tend to adopt a geometry consistent with directional interaction with one of the oxygen lone pairs. Thus the C—O—M bond angle tends to be in the trigonal (120-140°) range, and the boron or aluminum is usually close to die carbonyl plane. ... 

Most dienones that have been reduced have structures such that they cannot give epimeric products. However, reduction of 17 -hydroxy-7,17a-dimethyl-androsta-4,6-dien-3-one (63) affords 17 -hydroxy-7j9,17a-dimethylandrost-4-en-3-one (64), the thermodynamically most stable product, albeit in only 16% yield. The remainder of the reduction product was not identified. Presumably the same stereoelectronic factors that control protonation of the / -carbon of the allyl carbanion formed from an enone control the stereochemistry of the protonation of the (5-carbon of the dienyl carbanion formed from a linear dienone. The formation of the 7 -methyl compound from compound (63) would be expected on this basis. 

Enolization is the rate-determining step in the halogenation of normal ketones. Where alternate directions for enolization exist, the preferred direction (and hence the position of kinetic bromination) depends on the substituents and stereochemistry. Furthermore, the orientation of the bromine introduced depends on stereochemical and stereoelectronic factors. 

When, in the phosphorous oxychloride-pyridine dehydration of an alcohol these rules conflict, the stereoelectronic factor determines the direction of elimination ... 

The stereochemistry of the 1,4-addition to A -octal-l-one and 1,1-di-methyl-A -octal-2-one has been investigated by House and Marshall, respectively. In summary, steric and stereoelectronic factors play a part in the mechanism of conjugate addition of Grignard compounds. With methylmagnesium iodide, the introduction of an axial methyl group into steroidal 5a-A -3-ketones (3) and 5 -A -3-ketones (6) is favored by stereo-electronic factors in the transition state. 

The bulk of enamine studies since Stork s original publication have focused on establishing the breadth and limitations of individual substitution reactions and on extending the list of useful electrophiles. In addition, auxiliary studies have enriched our knowledge about the ambident nature of the vinyl nitrogen system, stereoelectronic factors governing its reactivity, its stability and spectroscopic properties. An increasing number of synthetic applications of these fundamental studies can be expected in future years. 

Addition of trimethylaluminum to norcamphor (3), regardless of the stoichiometry of the reactants, leads to a mixture of the diastereomeric alcohols in a ratio of 95 5 also in favor of the erafo-alcohol6. Examination of the norcamphor model indicates that endo attack is sterical-ly more hindered than exo attack. However, steric interaction may not fully account for the exceptionally high exo selectivity. On the other hand, no severe torsional strain is involved if the nucleophile approaches the carbonyl group from the exo side, however, a nucleophile approaching from the endo side encounters torsional strain between the incipient bond and the C-l to C-6 carbon-carbon bond. Thus, in the case of norcamphor, steric and stereoelectronic factors reinforce each other, resulting in a strong directional influence for exo attack. 

These side reactions may occur if the /V-acyliminium ion is not trapped quickly enough by a nucleophile. So problems may arise with relatively poor nucleophiles or if there is too much steric hindrance, while in the case of intramolecular reactions, unfavorable stereoelectronic factors or intended formation of medium- or large-sized rings may play a role. The reaction conditions, such as the nature of the (acidic) catalyst and the solvent, may also be of importance. 

The coordinated cyclohexenones react from half-chair conformations A and B in order to show a maximum of tr-overlap. The 4-methyl-2-cyclohexenone prefers, for stereoelectronic factors, the half-chair A, which leads to the ci.s-product on (2-propenyl)silane addition (path a), even if this is not the sterically least hindered approach. 

The 5-methyl-2-cyclohexenone prefers, for stereoclectronic reasons, the half-chair B. Now, both steric- and stereoelectronic factors work in the same direction, to yield in all cases the Irani-products (path d). 

Figure 1.8 Preferred site of attack in hydrogen abstraction by various radicals. 1.3.4 Stereoelectronic Factors...

This latter term is considered in more detail under stereoelectronic factors (Scetion 1.4.3.4). 

Another explanation follows from the above discussion on stereoelectronic factors.145 If overlap between the semi-occupied orbital and the breaking C-H bond favors disproportionation, then substituents which delocalize the free spin will serve to reduce this interaction and disfavor disproportionation. A proposal along these lines was made originally by Nelson and Bartlett148 who also noted that diminisbment of the spin density at Ca could retard combination. Flowever, it is not necessary that the two effects should cancel one another. 

Intramolecular eyclization is subject to the same factors as intermolecular addition (see 2.3). However, stereoelectronic factors achieve greater significance because the relative positions of the radical and double bond are constrained by being part of the one molecule (see 2.3.4) and can lead to head addition being the preferred pathway for the intramolecular step. 

The hydrosilylation of alkynes has also been studied using as catalysts Pt, Rh, Ir and Ni complexes. The improvement of the regioselectivity of the catalyst and the understanding of stereoelectronic factors that control it have been major incentives for the ongoing research. From numerous studies involving non-NHC catalysts, it has been established that there is a complex dependence of the product ratio on the type of metal, the aUcyne, the metal coordination sphere, the charge (cationic versus neutral) of the catalytic complex and the reaction conditions. In the Speier s and Karstedt s systems, mixtures of the thermodynamically more stable a- and -E-isomers are observed. Bulky phosphine ligands have been used on many occasions in order to obtain selectively P-f -isomers. 

Allylic alkylations of cinnamyl carbonate by sodium malonate have been studied with a series of ruthenium catalysts, obtained from the azohum salts 126-128 and the ruthenium complex 129 (Scheme 2.25) in MeCN or THF to give moderate yields of mixtures of alkylated products in the allylic and ipi o-carbons (90 10 to 65 35). The observed regioselectivity is inferior to similar ruthenium systems with non-NHC co-ligands. The stereoelectronic factors which govern the observed regioselectivity were not apparent [102]. 

The efficiency of cyclization can also be affected by stereoelectronic factors. For example, there is a significant difference in the efficiency of the cyclization of the Z- and F-isomers of 3. Only the Z-isomer presents an optimal alignment for electronic stabilization.14 These effects of the terminating substituent point to considerable concerted character for the cyclizations. 

Carbocations, as we learned in Chapter 4 of Part A, can readily rearrange to more stable isomers. To be useful in synthesis, such reactions must be controlled and predictable. This goal can be achieved on the basis of substituent effects and stereoelectronic factors. Among the most important rearrangements in synthesis are those directed by oxygen substituents, which can provide predictable outcomes on the basis of electronic and stereoelectronic factors. 

The selectivity in the Heck reaction of allylic alcohol 111 is interesting, and the factors that lead to the observed preference for (3-hydride elimination toward nitrogen in this system are unclear, although a combination of steric effects and stereoelectronic factors (i.e., alignment of C-H and C-Pd bonds, nN a c H interactions) is likely involved. Examination of related examples from the literature (Scheme 4.20) reveals no clear trend. Rawal and Michoud examined substrate 115, which lacks the influence of both the amine and hydroxyl substituents and also seems to favor (3-hydride elimination within the six-membered ring over formation of the exocyclic olefin under standard Heck conditions [18a]. However, under... 

Stereoelectronic factors are also important in the conformational dynamics of acyclic acetals [6] (Cosse-Barbi and Dubois, 1986). Here the usual preference for staggered conformations is supplemented by the anomeric effect (Kirby, 1983), which favours the gauche stereochemistry ( = 60°) about both central C-O bonds, mainly because this allows optimal n-rr overlap between an oxygen lone pair and the antibonding (cr ) orbital of the C-0 bond. Thus the pathway for conformational isomerization suggested by... 

Stereoelectronic Factors That Control the Fate of the Tetrahedral Intermediate in Serine Peptidases... 

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