Acid‐catalysed hydrolysis of methoxy‐substituted trityl trifluoroethyl ethers: a kinetic and computational investigation of leaving group effects

Abstract

Trityl trifluoroethyl (TFE) ether and its 4-methoxy, 4,4(-dimethoxy-, and 4,4(,4 00 -trimethoxy-substituted analogues have been prepared; the dimethoxy and trimethoxy compounds undergo ready acid-catalysed hydrolysis at constant ionic strength ¼ 1 mol dm S3 at 25-C. The monomethoxy compound is less reactive and the parent trityl analogue showed minimal reactivity. Using presently reported and literature kinetics results with pK a values of protonated substrates, first-order rate constants covering 12 orders of magnitude have been determined for heterolysis/ dissociation of 11 protonated dimethoxytrityl derivatives DMTrYH R where YH ¼ H 2 O, CF 3 CH 2 OH, ArNH 2 and RNH 2 . There is a good correlation between logarithms of these rate constants and the pK a values of the conjugate acids (YH þ 2 ) of the nucleofuges YH. Enthalpies and corresponding free energies at 25-C for the dissociation of the specifically solvated ions CH 3 À ÀYH(H 2 O) þ n (YH ¼ MeOH and CF 3 CH 2 OH, n ¼ 1; H 2 O, n ¼ 2; and NH 3 , n ¼ 3) have been calculated at the B3LYP/6-31RG * level. Corresponding gas phase calculations have also been carried out for Ph 3 CÀ ÀYH(H 2 O) þ n (YH ¼ H 2 O, n ¼ 2; MeOH, n ¼ 1; CF 3 CH 2 OH, n ¼ 1 and NH 3 , n ¼ 3) and, in addition, structures for these solvated ions with (YH ¼ H 2 O, MeOH and NH 3 ) have been calculated. The specifically solvated ion Ph 3 CÀ ÀO(H)CH 2 CF 3 (H 2 O) R does not correspond to a stable bonded species in the gas phase, which suggests that acid-catalysed fragmentation of methoxy-substituted analogues of Ph 3 CÀ ÀOCH 2 CF 3 in aqueous solution are concerted with proton transfer in which case the hydrolytic cleavage will be general acid catalysed. equivalent). [9][10][11][12] This reversible reaction shown in Scheme 2 is the basis of the well-known H R acidity function scale where H R relates to K R þ , [13][14][15][16][17] and the experimentally observed pseudofirst-order rate constant for the overall equilibration, k obs , is for the sum of forward and reverse processes (regardless of the initial extent of reaction. [9,10] (www.interscience.wiley.com) HYDROLYSIS OF SUBSTITUTED TRITYL TFE ETHERS 3 (pK a ¼ 5.07; [53] k o ¼ 37 s À1 ); 4-MeOC 6 H 4 NH þ 3 (pK a ¼ 5.29; [53] k o ¼ 45 s À1 ); 4-FC 6 H 4 NH þ 3 (pK a ¼ 4.52; [53] k o ¼ 43 s À1 ). k o values from references [7,8,50] Scheme 4. Comparison of rates of unimolecular heterolyses of DMTr-YH þ in aqueous solution for YH ¼ H 2 O, CF 3 CH 2 OH and NH 3 . k 1 in Eqn (i) % 1.7 Â 10 5 s À1 (see the text); k in Eqn (ii) % 7 Â 10 6 s À1 (see the text); k o in Eqn (iii) ¼ 3.67 Â 10 À5 s À1 for R ¼ H; [20]

Stabilities of Trityl‐Protected Substrates: The Wide Mechanistic Spectrum of Trityl Ester Hydrolyses

“…Because the cleavage of trityl ethers often requires conditions which also lead to the deprotection of other acid‐labile groups, like glycosides, Khorana introduced 4‐methoxy‐ and the 4,4′‐dimethoxytrityl derivatives, which are more acid‐labile 6. 4‐Methoxy‐substituted tritylium systems have been studied extensively by Maskill,7 who determined rate constants of acidic detritylations of amines7a and trifluoroethanol 7b. Destabilized trityl compounds, like the heptafluorotrityl system, were designed to serve as acid‐stable protecting groups, for example, for the γ‐carboxy group of glutamic acid 8…”

Reaction mechanisms : Part (iii) Polar reactions

“…The acid-catalyzed hydrolysis of methoxy-substituted trityl trifluoroethyl ethers 34 has been studied by UV-Vis spectrophotometry in dilute acidic aqueous solution at 25 1C (trityl = triphenylmethyl). 22 The reactivity of the parent trityl trifluoroethyl ether 34a was found to be too low to quantify under these conditions. A computational study of the enthalpy and free energy for dissociation of Ph 3 C-O(H)CH 2 CF 3 Á (H 2 O) + in the gas phase showed that it is not a stable bonded species.…”