Ortho methyl group

The very slow onset of action and side effects which follow from the anticholinergic side effects characteristic of the tricyclic antidepressants has led to a continuing effort to find replacements from other structural classes which might thus be devoid of this defect. A series of alkoxy phenylpropylamines has been investigated extensively in this search for non-tricyclic antidepressants. The most recent analogue, tomoxetine (69), is accessible by the same route [15] used to prepare the earlier analogue, nisoxetine, in which methoxyl replaces the ortho methyl group. 

The influence of steric constraints on the nucleophilic substitution of Cl- by a nucleophile is not very important and does not much influence the yield even in the presence of two ortho-methyl groups. Steric inhibition was only found when... 

Brook et al. 5X1 observed such reactions during the formation of siienes by photolysis. Using radiation with A > 360 nm, they photolyzed acylsi-lanes such as 127, which bears a mesityl group attached to the carbonyl carbon. On prolonged photolysis of the initially formed silene 128, the C—H bond of the ortho methyl group of the mesityl group added to the silicon-carbon double bond to form the benzocyclobutane 129. Alternatively a 1,5-H shift would lead to the species 130, which would also yield the benzocyclobutane on electrocyclic rearrangement. 

By contrast, the addition of a pair of ortho-methyl groups to the aromatic ring of X-[8+] to give X-[10+] has the following dramatic effects on partitioning of the carbocations between nucleophilic addition of solvent and proton transfer 27-41... 

The addition of two ortho-methyl groups to Me-[8+] to give Me-[10+] results in a 70-fold decrease in the rate constant ks for nucleophilic addition of 50/50 (v/v) trifluoroethanol/water.27... 

The addition of a pair of ortho-methyl groups to the alkene Me-[9] to give Me-[11] results in a greater than 5000-fold decrease in the equilibrium constant ATadd for hydration of the alkene to give the corresponding cumyl alcohol (Amyes, T.L., unpublished results). 

Fig. 6 Hypothetical free energy reaction coordinate profiles for the interconversion of X-[8]-OH and X-[9] (R = H) and X-[10]-OH and X-[ll] (R = CH3) through the corresponding carbocations. The arrows indicate the proposed eifects of the addition of a pair of ortAo-methyl groups to X-[8]-OH, X-[8+] and X-[9] to give X-[10]-OH, X-[10+] and X-[ll]. A Effect of a pair of or/Ao-methyl groups on the stability of cumyl alcohols. B Effect of a pair of or/Ao-methyl groups on the stability of cumyl carbocations. C Effect of a pair of ortho-methyl groups on the stability of the transition state for nucleophilic addition of water to cumyl carbocations. D Effect of a pair of orf/io-methyl groups on the stability of the transition state for deprotonation of cumyl carbocations.

The addition of two ortho-methyl groups to cumyl derivatives also results in a decrease in the Hammett reaction constant from p+ = —4.3 for cleavage of X-[8]-(4-nitrobenzoate) to p+ = —3.0 for cleavage of X-[10]-(4-methoxy-benzoate).27 This provides additional support for the conclusion that rotation about the CAr—Ca bond, which will minimize destabilizing steric interactions between methyl groups in the transition state, also reduces stabilizing resonance electron donation from the ring substituent to the benzylic carbon (Scheme 9). 

Substituent effect on the stability of the transition state for deprotonation (D, Figure 6). The addition of two ortho-methyl groups to Me-[8+] to give Me-[10+] results in an increase in kp for proton transfer to solvent from 1.4 x 106 s 1 to 8.3 x 107 s 1 (Table 1). There should be relatively little steric hindrance to the reaction of solvent with the /1-hydrogens of Me-[10+] because these are relatively distant from the ortho-methyl groups. However, the twisting about the CAr-Ca bond that minimizes steric interactions between the methyl... 

A combination of steric and electrostatic factors is presumably decisive with regard to the form of the acid most stable in sulfuric acid solution. The simple protonated form XX of benzoic acid is stabilized by resonance structures sterically prohibited in mesitoic acids. The ortho methyl groups of mesitoic acid would interfere with a coplanar dihydroxymethylene group. On the other hand, the inductive and resonance effects of the methyl groups help stabilize the acylium ion form of mesitoic acid as in the formulae XXI. In the case of 2,4,6-tribromobenzoic acid the steric effect and its abetting electronic effects are not sufficient, and this acid behaves like benzoic acid.17 >177... 

A photolytic study with a 5-azidotetrazole derivative also led to the formation of a tetrazolo[l,5-/z]quinazoline compound, although the yield was fairly low. Araki et al. published findings that irradiation of 110 in aqueous medium resulted in formation of the mesoionic enolate 112 in 8% yield <2000JHC1129> (Scheme 20). The authors concluded that the formation of the tricyclic structure can be rationalized by an intramolecular insertion of the triplet nitrene formed from 110 to a C-H bond of an ortho-methyl group to give at first intermediate 111, which was converted under the applied reaction conditions to produce 112. 

In the case of 2,6-dimethylanilines (Table 7), although the chemical shifts for corresponding para substituents are at somewhat higher shielding than those of para substituents of aniline, owing to the shielding effect of the ortho methyl groups, the... 

In contrast, in the radical 44 there is steric congestion (particularly by the ortho methyl groups) around the carbonyl carbon, C. The t-Bu radical cannot be bound to the carbonyl carbon C anymore, and normal Grignard adduct formation is prohibited. The steric hindrance in 44 is consistent with the experimental evidence (no normal adduct). 

Curiously, when liquid sulfur dioxide is used as a solvent and Mel as the quatemizing agent, one ortho methyl group retards the rate by 1% and the second by 44%.73 Although nonadditivity is observed, these kinetic effects are surprisingly small. 

One example does exist where the effects of ortho methyl groups are essentially additive. With ethyl methanesulfonate in water as the quatemizing agent, one methyl substituent suppresses reactivity by a factor of 2, the second by only 4.3. Moreover, the reaction is unusual in... 

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