Benzene, trifluoromethyl-substituted

The use of trifluoromethyl-substituted a-pyrones in Diels-Alder reactions with all types of dienophiles provides an interesting route to trifluoromethyl-benzenes [I/Sj (equation 98)... 

Cycloaddition of furans followed by a subsequent transformation is still adopted as a useful strategy to prepare fluorine-containing benzene derivatives and isoquinoline compounds <00SL550>. The cycloaddition adduct can also be converted to a trifluoromethyl substituted cyclohexanone compound via hydrogenation and hydrolysis. Examples of these transformations are illustrated below. 

When reacted with trialkyl phosphite in benzene for 1 hr, dialkyl magnates (364, X = F) gave a mixture of amino(trifluoromethyl)methylene-malonates (365) (20% yields), dialkyl trifluoromethyl(substituted amino)-methylenemalonates (366) (40-45% yields), and dialkyl chlorophosphate (-20%) (86ZOB805). The reactions of dialkyl malonates (364, X = F, Cl) and triphenylphosphine in the presence of triethylamine in diethyl ether for 1 hr gave trihalomethyl(substituted amino)methylenemalonates (367) in 87-95% yields. The treatment of a solution of dialkyl trifluoromethyl-(substituted amino)methylenemalonates (366, R1 = Et) in benzene with aqueous hydrochloric acid gave amino(trifluoromethyl)methylene-malonates (368) in 82-84% yields (86ZOB805) (Scheme 32). 

As can be seen from the data for the benzene rings substituted with three, four, five, and six CF3 groups (Scheme 5.52), the deshielding effect becomes increasingly pronounced as more trifluoromethyl groups are added vicinal to each other on the benzene ring. 

In all cases, 4-acetyl-5-Z-8-methyl-ll-oxatricyclo[6.3.0.01,4]undeca-2,5-di-enes (Z = OMe, F, CH3, CF3), resulting from syn addition, were the predominant photoproducts, as determined by direct NMR analysis. Following thermal treatment, the cyclooctatriene and/or cyclohexadiene derivatives were then isolated in 60-70% yield in the ratios shown in Scheme 21. With 2-methyl, 2-methoxy, and 2-trifluoromethyl substitution, the reaction is 100% regioselective syn, addition of the remote double bond occurring only at the 3,4-positions of the benzene ring, not the 4,5. The 2-fluoro derivative alone provides both anti and syn regioisomers in a 15 85 ratio. The 2-cyano derivative did not react. The authors surmised that the... 

Irradiation with Corex filtered ultraviolet light of 65a in the presence of 20 equiv. of 1,1-dimethoxyethene in glyme or benzene solvent results in the formation of a cycloadduct, 6,6-dimethoxy-5-phenyl-4-oxa-l-azabicyclo[3.1.0]heptan-2-one (68a), in 65% yield and no oxiryl isocyanate 67a. Like the photocycloaddition of 3-etho-xyisoindolenone (50) to 1,1-dimethoxyethene, the cycloaddition occurs regiospeci-fically. The methoxy and trifluoromethyl substituted phenyloxazolinones 65 b, c, and d similarly photocycloadd regiospecifically to 1,1-dimethoxyethene. 

The primary standard betaine dye (44) is only sparingly soluble in water and less polar solvents it is insoluble in nonpolar solvents such as aliphatic hydrocarbons. In order to overcome the solubility problems in nonpolar solvents, the more lipophilic penta-t-butyl-substituted betaine dye (45) has additionally been used as a secondary reference probe [174]. The excellent Hnear correlation between the Ej values of the two dyes allows the calculation of t(30) values for solvents in which the solvatochromic indicator dye (44) is not soluble. Introduction of electron-withdrawing substituents e.g. Cl [323], F, CF3, C6F13 [324]) in the betaine molecule reduces the basicity of its phenolate moiety, which allows the direct determination of x(30) values for somewhat more acidic solvents. Moreover, the Hpophilic and fluorophilic penta(trifluoromethyl)-substituted betaine dye (46) is more soluble in nonpolar solvents e.g. hexafluoro-benzene) than the standard dye (44) [324]. Conversely, the solubility in aqueous media can be improved through replacement of some of the peripheral hydrophobic phenyl groups in (44) by more hydrophilic pyridyl groups, to yield the more water-soluble betaine dye (47) [325]. The Ej values of these new secondary standard betaine dyes correlate linearly with the x(30) values of (44), which allows the calculation of x(30) values for solvents in which only betaine dyes (45)-(47) are sufficiently stable and soluble for the UV/Vis spectroscopic measurements [324, 325]. 

Trifluoromethyl-substituted compounds can also be lithiated with butyllithium. Thus, all three isomers of tris[(trifluoromethyl)phenyl]phosphanc 8 have been prepared via lithiation of the corresponding bromo(trifluoromethyl)benzene. ... 

Niu YM, Zhu XL, Liu LZ, Zhao Y, Wang GB, Jiang ZH, et al. Synthesis and properties of poly(aryl ether ketone) copolymers with trifluoromethyl-substituted benzene in the side chain. J Macromol Sci Pure Appl Chem 2006 43(9) 1459-67. 

Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 474 Substituent Effects in Electrophilic Aromatic Substitution Activating Substituents 476 Substituent Effects in Electrophilic Aromatic Substitution Strongly Deactivating Substituents 480 Substituent Effects in Electrophilic Aromatic Substitution Halogens 482 Multiple Substituent Effects 484 Retrosynthetic Analysis and the Synthesis of Substituted Benzenes 486 Substitution in Naphthalene 488 Substitution in Heterocyclic Aromatic Compounds 489... 

Trifluoromethyl-substituted alkynes were found to give good yields of the hydroary-lation products in superacid (Scheme 21). ° i For example, the propyne derivative (91) gives a nearly quantitative yield of the addition product (92) by reaction in triflic acid. Protonation initially leads to the resonance-stabilized vinyl cation (93), which reacts with benzene. The diarylalkyl cation (94) is generated by a second protonation - its presence confirmed through direct observation by NMR - and this yields the olefin (92) upon workup of the reaction. 

Synthesis and characterization of poly(aryl ether ketone) with trifluoromethyl-substituted benzene in the side chain... 

Figure 10.18 DSC traces of PAEK copolymers containing trifluoromethyl-substituted benzene (A) 0.00, (B) 0.20, (C) 0.40, (D) 0.60, (E) 0.80, (F) 1.00 [41]. Reproduced with permission from Taylor and Francis.

Nitration of (trifluoromethyl)benzene on the other hand yields almost exclusively m nitro(trifluoromethyl)benzene (91%) The ortho and para substituted isomers are minor components of the reaction mixture... 

Because substitution m (trifluoromethyl)benzene occurs primarily at positions meta to the substituent we say that a trifluoromethyl group is a meta director... 

Turning now to electrophilic aromatic substitution in (trifluoromethyl)benzene we con sider the electronic properties of a trifluoromethyl group Because of their high elec tronegativity the three fluorine atoms polarize the electron distribution m their ct bonds to carbon so that carbon bears a partial positive charge... 

Because the carbon atom attached to the ring is positively polarized a carbonyl group behaves m much the same way as a trifluoromethyl group and destabilizes all the cyclo hexadienyl cation intermediates m electrophilic aromatic substitution reactions Attack at any nng position m benzaldehyde is slower than attack m benzene The intermediates for ortho and para substitution are particularly unstable because each has a resonance structure m which there is a positive charge on the carbon that bears the electron withdrawing substituent The intermediate for meta substitution avoids this unfavorable juxtaposition of positive charges is not as unstable and gives rise to most of the product... 

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

When we exanine the cyclohexadienyl cation intermediates involved in the nitration of (trifluoromethyl)benzene, we find that those leading to ortho and para substitution ar e strongly destabilized. 

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