Trifluoromethyl substituent effects

To illustrate substituent effects on rate consider the nitration of benzene toluene and (trifluoromethyl)benzene... 

Our analysis of substituent effects has so far centered on two groups methyl and triflu oromethyl We have seen that a methyl substituent is activating and ortho para directing A trifluoromethyl group is strongly deactivating and meta directing What about other substituents ... 

In contrast, 13C nmr spectra of ring-substituted /J-bromocumyl cations [2] can be unambiguously interpreted in terms of open /1-bromocarbocations, since the ring substituent effects on the chemical shifts are similar to those on the corresponding non-brominated cations [1], even for the electron-attracting p-trifluoromethyl group (Olah et al, 1972). 

The use of aryltrimethylsilanes as intermediates has been found to be a useful complement to direct thallation in the preparation of arylthallium intermediates. The advantages are (a) position specificity, because the thallium always replaces the silane substituent, and (b) improved ability to effect thallation of certain deactivated rings, such as those having trifluoromethyl substituents. What role does the silyl substituent play in these reactions ... 

Thioxanthenes lack the ring nitrogen of phenothiazine, and the side chain is attached by a double bond. In all cases, the cis isomer (relative to the substituted phenyl ring) is more active. Electron-attracting substituents seem to have a cumulative effect. For instance, pifluthixol (4.89), with a fluorine and a trifluoromethyl substituent, is 5-10 times more potent than its parent flupenthixol (4.90), and has an inhibitory effect (IC50 = 9.7 X 10 ° M) on the DA-sensitive adenylate cyclase of the striatum. 

The presence of the electron-withdrawing trifluoromethyl substituent in the a-position has a dramatic effect on the reactivity of both the carboxy and the amino groups. The latter, in particular, shows a very marked decrease ( 4 units) in the pK.t value with respect to the corresponding natural amino acids, whereas the carboxy group experiences a more limited deviation (0.3-1.1 units) 111 As a consequence, activation of the carboxy group of... 

However, note that the values of pAR in Scheme 29 were measured in 50-50 v v TFE-water mixtures rather than water. In general, for anionic nucleophiles pAR is expected to be highly sensitive to solvent. Results of Pham and McClelland222 indicate that pAR pA 1 increases by 8 log units between water and 2% aqueous acetonitrile. The effect of a change from water to TFE-water will be much less than this, but a comparison for the /)-mcthoxybcn/yi cation shows that pAR decreases by 1 log unit.223 Thus neglecting any difference between pAR values in the two solvents the estimate of pAR for the a-trifluoromethyl-substituted /7-methoxybenzyl cation is increased to —22.5. This value has been considered at some length because equilibrium measurements for the ions summarized as 58 are relevant to the effects of a-trifluoromethyl substituents on reactivity discussed later in the chapter (p. 80). 

If steric hindrance is important we should see evidence for this in the effect substitutents in the olefin have on the orientation ratio (see Table 14). The first feature to notice about Table 14 is that the methyl and trifluoromethyl substituent groups have similar directive effects towards the three electrophilic radicals. This is in sharp contrast to electrophilic ionic addition where, for... 

Trifluoromethyl is a wonderful group with numerous substituent effect surprises84. Within the context of discussions of positive halogen , it is well-established85 that solution-phase nucleophilic reactions of trifluoromethyl iodide are consistent with the presence of formally positive iodine, e.g. equation 53. ]... 

The cross-coupling reaction of alkenyl(fluoro)silanes with aryl halides sometimes produces, in addition to the desired ipso-cowpled products, small amounts of cmc-coupled products [14]. The czne-coupling is often striking in the reaction with organotin compounds. The isomer ratio of products produced by the reaction of l-fluoro(dimethyl)silyl-l-phenylethene with aryl iodides is found to depend on the electronic nature of a substituent on aryl iodides (Eq. 11) an electron-withdrawing group like trifluoromethyl and acetyl favors the formation of the ipso-coupled product. To explain the substituent effect, the mechanism depicted in Scheme 3 is proposed for the transmetalation of alkenylsilanes with palladium(ll) complexes. It is considered that an electron-donating substituent on Ar enhances... 

The stabilizing effect of the secondary orbital interactions of the trifluoromethyl substituent with dienes is exemplified in the cydoaddition reaction of a-(trifluorornethyI)styrene (7) with Danishefsky s diene 4. A phenyl substituent is known to stabilize the c t/o-phenyl transition state. Furthermore, the steric hindrance of a trifluoromethyl group should favor its exo approach. However, cycloadducts 8 are obtained in a 1 1 mixture of tran.sicis stereoisomers which are converted into the cyclohexenone 9. Under the same thermal conditions, st-mcthyl-styrene is unreactive. ... 

The Yukawa-Tsuno equation continues to find considerable application. 1-Arylethyl bromides react with pyridine in acetonitrile by unimolecular and bimolecular processes.These processes are distinct there is no intermediate mechanism. The SnI rate constants, k, for meta or j ara-substituted 1-arylethyl bromides conform well to the Yukawa-Tsuno equation, with p = — 5.0 and r = 1.15, but the correlation analysis of the 5 n2 rate constants k2 is more complicated. This is attributed to a change in the balance between bond formation and cleavage in the 5 n2 transition state as the substituent is varied. The rate constants of solvolysis in 1 1 (v/v) aqueous ethanol of a-t-butyl-a-neopentylbenzyl and a-t-butyl-a-isopropylbenzyl p-nitrobenzoates at 75 °C follow the Yukawa-Tsuno equation well, with p = —3.37, r = 0.78 and p = —3.09, r — 0.68, respectively. The considerable reduction in r from the value of 1.00 in the defining system for the scale is ascribed to steric inhibition of coplanarity in the transition state. Rates of solvolysis (80% aqueous ethanol, 25 °C) have been measured for 1-(substituted phenyl)-l-phenyl-2,2,2-trifluoroethyl and l,l-bis(substi-tuted phenyl)-2,2,2-trifluoroethyl tosylates. The former substrate shows a bilinear Yukawa-Tsuno plot the latter shows excellent conformity to the Yukawa-Tsuno equation over the whole range of substituents, with p =—8.3/2 and r— 1.19. Substituent effects on solvolysis of 2-aryl-2-(trifluoromethyl)ethyl m-nitrobenzene-sulfonates in acetic acid or in 80% aqueous TFE have been analyzed by the Yukawa-Tsuno equation to give p =—3.12, r = 0.77 (130 °C) and p = —4.22, r — 0.63 (100 °C), respectively. The r values are considered to indicate an enhanced resonance effect, compared with the standard aryl-assisted solvolysis, and this is attributed to the destabilization of the transition state by the electron-withdrawing CF3 group. 

Substantial effects on both stability and metabolism might be expected from the presence of a trifluoromethyl substituent at C-10 in DHA and its ethers. The following effects were anticipated ... 

Fungicidal activity of these compounds was striking several hydrazine- and diazenecarboxamides were effective in one or more plant pathogenic fungi below 1 ppm. Although only eight analogs were evaluated, it appears that fluorine or trifluoromethyl substituents... 

Halogens (particularly chlorine) can be replaced by other electron-attracting functions snch as trifluoromethyl or cyano groups. In the antibiotic chloramphenicol, both the chlorine atoms of the dichloroacetic moiety and of the para-nitro-phenyl group yielded productive isosteric replacements (Table 15.6). Many other examples of univalent atoms or groups replacements are found in the chapter dealing with substituent effects (Chapter 20) and with quantitative structure-activity relationships (Chapter 23). 

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