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

Article abstract of DOI:10.1002/poc.1332

Trityl trifluoroethyl (TFE) ether and its 4-methoxy, 4,4′-dimethoxy-, and 4,4′,4″-trimethoxy-substituted analogues have been prepared; the dimethoxy and trimethoxy compounds undergo ready acid-catalysed hydrolysis at constant ionic strength = 1 mol dm^-3 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⁺ where YH = H₂O, CF₃CH₂OH, ArNH₂ and RNH₂. There is a good correlation between logarithms of these rate constants and the pK_a values of the conjugate acids (YH ₂⁺) of the nucleofuges YH. Enthalpies and corresponding free energies at 25°C for the dissociation of the specifically solvated ions CH₃ - YH(H₂O)_n⁺ (YH = MeOH and CF₃CH₂OH, n = 1; H₂O, n = 2; and NH ₃, n = 3) have been calculated at the B3LYP/6-31+G* level. Corresponding gas phase calculations have also been carried out for Ph ₃C YH(H₂O)_n⁺ (YH = H₂O, n = 2; MeOH, n = 1; CF₃CH₂OH, n = 1 and NH₃, n = 3) and, in addition, structures for these solvated ions with (YH = H ₂O, MeOH and NH₃) have been calculated. The specifically solvated ion Ph₃C - O(H)CH₂CF₃(H ₂O)⁺ does not correspond to a stable bonded species in the gas phase, which suggests that acid-catalysed fragmentation of methoxy-substituted analogues of Ph₃C - OCH₂CF₃ in aqueous solution are concerted with proton transfer in which case the hydrolytic cleavage will be general acid catalysed. Copyright

Full text of DOI:10.1002/poc.1332

Special Issue
Received: 20 September 2007,
Revised: 21 December 2007,
Accepted: 23 December 2007,
Published online in Wiley InterScience: 12 May 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1332
Acid-catalysed hydrolysis of
methoxy-substituted trityl trifluoroethyl
ethers: a kinetic and computational
investigation of leaving group effects
a
by
b
*
´
´
Moises Canle Lopez , Ibrahim Demirtas , Howard Maskill
and Masaaki Mishimac
Trityl trifluoroethyl (TFE) ether and its 4-methoxy, 4,4(-dimethoxy-, and 4,4(,400-trimethoxy-substituted analogues
have been prepared; the dimethoxy and trimethoxy compounds undergo ready acid-catalysed hydrolysis at constant
ionic strength ¼ 1 mol dmS3 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 pKa values of protonated
substrates, first-order rate constants covering 12 orders of magnitude have been determined for heterolysis/
dissociation of 11 protonated dimethoxytrityl derivatives DMTrYHR where YH ¼ H2O, CF3CH2OH, ArNH2 and
RNH2. There is a good correlation between logarithms of these rate constants and the pKa values of the conjugate
acids (YHþ2 ) of the nucleofuges YH. Enthalpies and corresponding free energies at 25-C for the dissociation of the
specifically solvated ions CH3ꢀꢀYH(H2O)nþ (YH ¼ MeOH and CF3CH2OH, n ¼ 1; H2O, n ¼ 2; and NH3, n ¼ 3) have been
*
calculated at the B3LYP/6-31RG level. Corresponding gas phase calculations have also been carried out
for Ph3CꢀꢀYH(H2O)þn (YH ¼ H2O, n ¼ 2; MeOH, n ¼ 1; CF3CH2OH, n ¼ 1 and NH3, n ¼ 3) and, in addition, structures
for these solvated ions with (YH ¼ H2O, MeOH and NH3) have been calculated. The specifically solvated
ion Ph3CꢀꢀO(H)CH2CF3(H2O)R does not correspond to a stable bonded species in the gas phase, which suggests
that acid-catalysed fragmentation of methoxy-substituted analogues of Ph3CꢀꢀOCH2CF3 in aqueous solution are
concerted with proton transfer in which case the hydrolytic cleavage will be general acid catalysed. Copyright ß 2008
John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley InterScience at http://www.mrw.interscience.wiley.com/
suppmat/0894-3230/suppmat/
Keywords: trityl cation; trifluoroethyl ether; acid catalysis; hydrolysis; computational chemistry
equivalent).[9–12] This reversible reaction shown in Scheme 2 is
INTRODUCTION
the basis of the well-known HR acidity function scale where HR
relates to KRþ,[13–17] and the experimentally observed pseudo-
first-order rate constant for the overall equilibration, kobs, is for
the sum of forward and reverse processes (kobs ¼ kr þ kf [H3Oþ])
regardless of the initial extent of reaction.[9,10]
The substituted trityl (triphenylmethyl) group is a common
protecting group for hydroxyl and amino functions in the
synthesis of a wide range of compounds.[1,2] p-Methoxy-
substituted trityl derivatives are much easier to deprotect than
the parent trityl compounds although this depends, to some
degree, upon the rest of the molecule.[3–8] The deprotection of a
(substituted) tritylated alcohol, that is the aqueous acid-induced
cleavage of a (substituted) trityl alkyl ether (Tr0ꢀꢀOR where Tr0
represents the parent or 4-methoxy-substituted analogues) is
shown in Scheme 1. This reaction is closely similar to the
protonation/dissociation of the corresponding alcohols Tr0ꢀꢀOH,
Scheme 2.[9,10] In the ether cleavage, the final equilibrium
proportions of the trityl alcohol and trityl carbenium ion are the
same as from the trityl alcohol itself under the same conditions.
Indeed, the reverse of the mechanism of Scheme 2 (or its
concerted equivalent) is an expansion of the final equilibration
shown in Scheme 1.
*
School of Natural Sciences, University of Newcastle, Newcastle upon Tyne, NE1
7RU, UK.
E-mail: h.maskill@newcastle.ac.uk
´
M. C. Lopez
Chemical Reactivity and Photoreactivity Group, Department of Physical
a
˜
Chemistry and Chemical Engineering I, University of A Coruna, E-15071 A
˜
Coruna, Galicia, Spain
b
c
I. Demirtas, H. Maskill
Department of Chemistry, University of Gaziosmanpasa, 60250 Tokat, Turkey
The mechanism of the protonation/dissociation of substituted
trityl alcohols has been studied in considerable detail and
involves a pre-equilibrium protonation followed by ionisation
and dissociation via ion–molecule pairs (or the concerted
M. Mishima
Institute for Materials Chemistry and Engineering, Kyushu University, Hakozaki,
Higashi-ku, Fukuoka, Japan
y
Department of Chemistry, University of Gaziosmanpasa, 60250 Tokat, Turkey.
J. Phys. Org. Chem. 2008, 21 614–621
Copyright ß 2008 John Wiley & Sons, Ltd.

HYDROLYSIS OF SUBSTITUTED TRITYL TFE ETHERS
Scheme 1. Heterolytic cleavage of a substituted trityl alkyl ether in dilute
aqueous acidic solution and subsequent hydrolysis of the substituted
trityl cation
Scheme 3. Ion–molecule pair mechanism for deprotection of substi-
tuted N-trityl alkylamines in dilute aqueous acid
Scheme 1, and the protonation/dissociation of trityl alcohols
themselves (Scheme 2).
We investigated the effect of alkyl groups, R, upon reactivity in
the acid-induced deprotection of (substituted) trityl amines,
Tr0ꢀꢀNHR, and observed huge but very similar rate enhancing
effects compared with the deamination of Tr0ꢀꢀNH2.[7,8] If the
effect of converting the nucleofuge in Scheme 2 from ꢀꢀOHþ2 to
ꢀꢀO(H)Rþ in Scheme 1 is similar to that of converting ꢀꢀNHþ3 to
ꢀꢀNH2Rþ in Scheme 3, rate constants for the hydrolysis of
Tr0ꢀꢀOR in dilute aqueous acidic solution would be extremely
high and possibly beyond the range of quantification by
conventional or even stopped flow UV spectrophotometric
investigation. To avoid this possible difficulty, we initiated our
present investigation by using 2,2,2-trifluoroethyl ethers
(Tr0ꢀꢀOTFE) in the expectation that the CF3 group would reduce
the base strength of the ethers thereby leading to lower
concentrations of the putative protonated reactive intermediate.
Of course, the CF3 group should also enhance the nucleofugality
of the protonated leaving group, so there will be a balance of two
opposing effects.
Scheme 2. Reversible protonation/dissociation of substituted trityl alco-
hols in dilute aqueous acidic solution (the involvement of ion–molecule
pairs in the k1/kꢀ1 step[9,10,12] has been omitted in the interests of brevity)
The anticipated corresponding mechanism for (substituted)
trityl alkyl ethers is included in Scheme 1; there should be no
appreciable extent of return from the trityl cation and the alcohol
ROH in dilute aqueous solution so the reaction is essentially
unidirectional. This mechanism leads to a first-order rate
dependence on the ether concentration and to specific acid
catalysis due to the involvement of the reversibly formed
protonated ether as a reactive intermediate.[18] Thus, for
(substituted) trityl alkyl ethers (Tr0ꢀꢀOR), which are only weak
bases in aqueous solution, there should be no detectable
reaction at [H3Oþ] ¼ 0 and, for dilute aqueous solutions, the
pseudo-first-order rate constants should increase linearly with
[H3Oþ].
The mechanism for the deprotection of substituted trityl-
amines, Tr0ꢀꢀNHR, in aqueous solution has also been studied in
detail,[7,8,19,20] and is characteristically different from the
mechanism for the corresponding reaction of substituted trityl
alcohols because the amines are strong bases. The initial
tritylamine is virtually wholly protonated when [H3Oþ] ꢁ
[tritylamine]0 under the normal reaction conditions (dilute
aqueous strong acid containing a low concentration of cosolvent)
so the reaction was initially not expected to show acid catalysis.
Unexpectedly, the deamination of substituted tritylamines
Tr0ꢀꢀNH3þ was found to be specific acid catalysed (rate ¼ kobs
[Tr0NHþ3 ] where kobs ¼ ko þ kH [H3Oþ]) with appreciable
reactivity under the hypothetical extrapolated conditions of
[H3Oþ] ¼ 0.[7,8,19,20] These wholly unprecedented results were
accommodated by a mechanism involving ion–molecule pairs,
Scheme 3, that is by invoking the distinction between ionisation
and dissociation of Tr0ꢀꢀNH2Rþ.[9,10,12] The final equilibrium here
in which the (substituted) trityl carbenium ion undergoes
reversible nucleophilic capture by water is, of course, exactly
the same as in the acid-induced deprotection of trityl ethers,
We report here our experimental kinetics results for the
hydrolysis of methoxy-substituted trityl 2,2,2-TFE ethers in
dilute acidic aqueous solution at 258C (the reactivity of the
parent Ph3CꢀꢀOTFE was too low to quantify by our method under
these conditions). In addition, we report a computational
comparison of the enthalpy and free energy at 258C of the
heterolytic dissociation of the central bond in CH3ꢀꢀYHþ
and Ph3CꢀꢀYHþ (and their specifically solvated analogues)
where YH is H2O, MeOH, CF3CH2OH and NH3, and computed
structures for specifically solvated ions Ph3CꢀꢀYHðH2OÞþ where
n
YH is H2O (n ¼ 2), MeOH (n ¼ 1) and NH3 (n ¼ 3).
METHODS
Experimental
Trityl TFE ethers were made by conventional methods which are
described in the experimental section; in all cases, spectral and
analytical characterisations were satisfactory although only the
parent trityl TFE ether was crystalline. Detritylation of the
methoxy-substituted trityl TFE ethers under acidic conditions led
to trifluoroethanol and equilibrium mixtures of the substituted
trityl carbenium ions and the corresponding alcohols. The
kinetics of the detritylations were investigated by our usual
J. Phys. Org. Chem. 2008, 21 614–621
Copyright ß 2008 John Wiley & Sons, Ltd.
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´
M. C. LOPEZ ET AL.
method of monitoring the rate of increase in UV absorption due
to the formation of the substituted trityl cation at a suitable
wavelength in the thermostatted cell block of a spectropho-
tometer connected to a PC for data collection.[7,8,21,22] Rate
constants were calculated by nonlinear optimisation from
absorbance-time data measured under pseudo-first-order con-
ditions using perchloric acid ([H3Oþ] ꢁ [substrate]0) and low
concentrations of acetonitrile to maintain complete solubility
at ionic strengths kept constant with sodium perchlorate.
Solutions for kinetics were prepared by adding a concentrated
solution of the substrate in acetonitrile to the aqueous solution of
electrolytes. The clarity of all solutions and the excellent fitting of
the data to the first-order rate law of individual runs indicate that
the nonlinear correlations of kobs against [H3Oþ] for mono-
methoxytrityl (MMTr) and dimethoxytrityl (DMTr) TFE-ethers are
not due to solubility problems. Kinetic runs were carried out at
least twice and the expressed uncertainty in tabulated rate
constants (kobs in Supplementary Tables S1–S3) indicates
reproducibility.
Figure 1. Graph of kobs versus [H3Oþ] for 4,40,4000-trimethoxytrityl
trifluoroethyl ether in aqueous solution, [Substrate]0 ¼ 2.11 ꢂ
10ꢀ5 mol dmꢀ3; ionic strength (NaClO4) ¼ 1.00 mol dmꢀ3; T ¼ 298.0 K;
l ¼ 483 nm; 0.7% CH3CN. ko ¼ 8.7 ꢂ 10ꢀ4 sꢀ1 and kH ¼ 2.10 ꢂ
10ꢀ2 dm3 molꢀ1 sꢀ1 (R ¼ 0.995)
Reactions of the trimethoxytrityl (TMTr) and DMTr TFE-ethers
were carried out at perchloric acid concentrations up to
1 mol dmꢀ3, and 1 mol dmꢀ3 constant ionic strength. The MMTr
analogue was insufficiently reactive under these conditions so
this compound was investigated at acid concentrations up to
absorbance of the carbenium ion which is in equilibrium with
the trityl alcohol according to the final equation of Scheme 1. The
equilibrium concentration of carbenium ion, therefore, depends
upon the acid concentration and the equilibrium constant for the
particular system under the particular physical conditions. At low
acidities in water at 258C, the product mixture from the parent
trityl TFE ether contains too low a proportion of the carbenium
ion in equilibrium with the alcohol for the kinetics of cleavage to
be reliably quantified.
2.66 mol dmꢀ3 and ionic strength constant at 3.0 mol dmꢀ3
.
However, the kinetic effect of sodium perchlorate is quite
appreciable for the ionisation of trityl alcohols[9,10,23–25] and the
deamination of tritylamines.[20] Consequently, results for
MMTrOTFE at ionic strength (I) ¼ 3 mol dmꢀ3 are not directly
comparable with those for DMTrOTFE and TMTrOTFE at
I ¼ 1 mol dmꢀ3
.
Kinetics results for the three methoxy-substituted compounds
are illustrated in Figs 1–3 and experimental data are given in the
accompanying Supplementary Tables S1–S3. The increase in
pseudo-first-order rate constants with increasing acid concen-
tration was initially linear, which allowed the determination of
second-order rate constants for the hydronium-ion-catalysed
reaction (kH); these are shown in the footnotes to the figures and
Computational
*
The geometries were fully optimised at the B3LYP/6-31þG level
of theory with normal convergence using the Gaussian 03
programme.[26] Vibrational normal mode analyses were per-
formed at the same level to ensure that each optimised structure
was a true minimum on the potential energy surface and to
calculate the thermal correction needed to obtain the Gibbs free
energies. Bond dissociation enthalpies in water were also
estimated using the Onsager reaction field model at the same
level of theory.[27–29] The TrꢀꢀYHþ series did not give stable
structures in either type of calculation, that is TrꢀꢀY bond
cleavage occurs without a barrier. Solvated complexes in which
acidic hydrogens H-bond with specific water molecules were
then calculated. By this method, stable structures were obtained
for TrꢀꢀYHðH2OÞþ with YH ¼ NH3 (n ¼ 3), H2O (n ¼ 2) and MeOH
n
(n ¼ 1); bond dissociation enthalpies were then obtained from
the enthalpy of the gas phase reaction of Eqn 1 where n is the
number of water molecules in the specifically solvated proto-
nated complexes:
TrꢀYHðH2OÞþ ¼ Trþ þ YHðH2OÞ ; DHo
(1)
n
n
RESULTS
Figure 2. Graph of kobs versus [H3Oþ] for 4,40-dimethoxytrityl trifluoro-
ethyl ether in aqueous solution, [Substrate]0 ¼ 2.82 ꢂ 10ꢀ5 mol dmꢀ3
;
Experimental
ionic strength (NaClO4) ¼ 1.00 mol dmꢀ3
;
T ¼ 298.0 K; l ¼ 495 nm;
1% CH3CN. ko ¼ 2.3 ꢂ 10ꢀ4 sꢀ1 and kH ¼ 6.9 ꢂ 10ꢀ3 dm3 molꢀ1 sꢀ1
The effect of the acidity of the reaction medium is not simply
kinetic. The reaction was monitored by following the UV
(R ¼ 0.98) from results up to [HClO4] ¼ 0.614 mol dmꢀ3
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 614–621

HYDROLYSIS OF SUBSTITUTED TRITYL TFE ETHERS
Table 2. Enthalpies and free energies (258C) of heterolytic
bond dissociation of protonated species Tr–YHðH2OÞþ
n
*
calculated at the B3LYP/6-31þG level
Solvated modela
Tr–YHðH2OÞþ
DHo (kJ molꢀ1
)
DGo (kJ molꢀ1
)
25
n
Tr–OH2ðH2OÞþ
11
ꢀ54
2
Tr–O(H)CH3(H2O)þ
ꢀ33
ꢀ96
Tr–NH3ðH2OÞþ
69
20
3
a Standard state ¼ ideal gas at 1 atm.
Figure 3. Graph of kobs versus [H3Oþ] for 4-methoxytrityl trifluoroethyl
ether in aqueous solution, [Substrate]0 ¼ 4.43 ꢂ 10ꢀ5 mol dmꢀ3; ionic
strength (NaClO4) ¼ 3.00 mol dmꢀ3; T ¼ 298.0 K; l ¼ 471 nm; 1% CH3CN.
ko ¼ 1.4 ꢂ 10ꢀ3 sꢀ1 and kH ¼ 4.4 ꢂ 10ꢀ3 dm3 molꢀ1 sꢀ1 (R ¼ 0.997) from
results up to [HClO4] ¼ 1.66 mol dmꢀ3
Table 2 contains the gas phase results for dissociation
of Ph3CꢀꢀYHðH2OÞþ (YH ¼ H2O, MeOH and NH3) specifically
n
solvated as indicated above for the methyl analogues. Results for
YH ¼ CF3CH2OH are not included as TrꢀꢀO(H)TFE(H2O)þ does not
correspond to a stable bonded ion, that is protonation of
TrꢀꢀOTFE with one water molecule of solvation led to
spontaneous dissociation of the central bond. Thus, Fig. 5 shows
the optimised structures of the H-bonded solvated complexes
tables along with the extrapolated rate constants at [H3Oþ] ¼ 0
which correspond to the uncatalysed reactions.
TrꢀꢀYHðH2OÞþ at the B3LY/6-31þG level (n ¼ 1 for YH ¼ MeOH,
*
n
n ¼ 2 for YH ¼ H2O and n ¼ 3 for YH ¼ NH3) whereas the
optimised structure for YH ¼ CF3CH2OH (n ¼ 1) shows the
propeller-shaped trityl carbenium ion to be essentially planar
at the central carbon and separated from the dissociated
CF3CH2OH molecule H-bonded to one water molecule. (Cartesian
Computational
*
Computational results at the B3LYP/6-31þG level for the
enthalpy of dissociation of the protonated substrates CH3ꢀꢀ
YHþ (YH ¼ H2O, MeOH, CF3CH2OH and NH3), all of which
correspond to stable bonded ions in the gas phase, are shown
in Table 1 together with corresponding free energies of
dissociation at 258C. (The electronic energies, enthalpies and
free energies of neutrals, complexes and cations are given in
Hartrees in the accompanying Supplementary Table S4.) The
column headed ‘Onsager model’ contains results for aqueous
solution using a continuum model for the dielectric of the
medium;[27–29] results in the column headed ‘Solvated model’ are
for the gas phase with the ions specifically solvated by n water
molecules through hydrogen bonds (n ¼ 1 for the protonated
ethers, 2 for the protonated alcohol and 3 for the protonated
amine).
coordinates of optimised structures of TrꢀꢀY and TrꢀꢀYHðH2OÞþ
n
*
at the B3LYP/6-31þG level of theory are given in the
accompanying Supplementary Table S5.)
DISCUSSION
Extrapolation of kinetics results to [H3Oþ] ¼ 0 as shown in Figs
1–3 indicates unexpected reactivity for all three unprotonated
methoxy-substituted trityl TFE ethers, that is reaction with
trifluoroethoxide as nucleofuge (presumably with electrophilic
assistance due to H-bonding with a solvent molecule); we are
aware of no other dialkyl ethers which have been shown to
Table 1. Enthalpies and free energies (258C) of heterolytic bond dissociation of protonated species CH3–YHþ
*
(YH ¼ H2O, MeOH, CF3CH2OH and NH3) calculated at the B3LYP/6-31þG level
Gas phasea
DHo (kJ molꢀ1 DGo (kJ molꢀ1
Onsager model[27–29]b
DH-0-- (kJ molꢀ1 DG-0-- (kJ molꢀ1
Solvated modela
DHo (kJ molꢀ1 DGo (kJ molꢀ1
)
CH3–YHþ
)
)
)
)
)
25
25
25
CH3–OHþ2
282
241
290
234
399
279
238
286
282
403
458.6
420.1
364
407
CH3–O(H)CHþ3
CH3–O(H)CH2CFþ3
CH3–NHþ3
334
331
374
278
326
316
441.4
445.2
550.6
520.1
a Standard state ¼ ideal gas at 1 atm.
bStandard state ¼ pure solute at 1 mol dmꢀ3 in water.
J. Phys. Org. Chem. 2008, 21 614–621
Copyright ß 2008 John Wiley & Sons, Ltd.
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´
M. C. LOPEZ ET AL.
second-order term in the rate law. Our working hypothesis is that
this strong curvature is a medium effect (MMTrOTFE was
investigated at ionic strength ¼ 3 mol dmꢀ3 and [H3Oþ] up to
2.66 mol dmꢀ3) and further consideration will be postponed until
a proper acidity function analysis is complete.[17,30]
Leaving group effect upon heterolysis in protonated
substituted trityl alcohols, TFE ethers and amines in
aqueous solution
We see from Scheme 2 that kf ¼ k1/Ka for the protonation/
dissociation of substituted trityl alcohols where kf is the
experimental second-order rate constant of the forward reaction
and Ka is the acidity constant of the protonated alcohol (equal to
the reciprocal of the equilibrium constant K for the pre-
equilibrium shown in Scheme 2). Since kobs ¼ kr þ kf [H3Oþ] for
the equilibration of Scheme 2, kf is determinable. We have an
experimental value of kf ¼ 16.5 dm3 molꢀ1 sꢀ1 for DMTr alcohol
(258C, aqueous perchloric acid, 2% acetonitrile, ionic strength ¼
1 mol dmꢀ3).[9,10] From an estimated value of Ka ꢄ 104 mol dmꢀ3
for the putative DMTrꢀꢀOHþ2 in Scheme 2 based upon literature
data (pKa ¼ ꢀ1.74,[18] ꢀ1.98,[31] ꢀ2.12[32,33] and ꢀ3.8[34] for OH3þ,
MeOHþ2 , EtOHþ2 and Me3COHþ2 , respectively), we estimate k1 ꢄ
1.7 ꢂ 105 sꢀ1 for DMTrꢀꢀOHþ2 . (This replaces our earlier estimate
of 830 sꢀ1 based upon a simplistic value for the pKa of
DMTrꢀꢀOHþ2 ).[7]
Figure 4. Brønsted-type plot of log k (sꢀ1) where k represents k, k1 and
ko in Scheme 4 against the pKa of the conjugate acid (YHþ2 ) of the
leaving groups YH in Scheme 4. YHþ2 ¼ NHþ4 (pKa ¼ 9.21;[51] ko ¼
3.5 ꢂ 10ꢀ5 sꢀ1); CF3CH2OH2þ (pKa ¼ ꢀ5.6; ko ¼ 7 ꢂ 106 sꢀ1); H3Oþ (pKa ¼
ꢀ1.74;[18] ko ¼ 1.7ꢂ105 sꢀ1); MeONH3þ (pKa ¼ 4.60;[52] ko ¼ 0.20 sꢀ1);
PhCH2NHþ3 (pKa ¼ 9.34;[51] ko ¼ 4.2 sꢀ1); CH3CH2CH2NH3þ (pKa ¼ 10.53;[51]
ko ¼ 48 sꢀ1); PhNH3þ (pKa ¼ 4.62;[53] ko ¼ 41 sꢀ1); 4-NO2C6H4NHþ3
(pKa ¼ 1.11;[53] ko ¼ 38 sꢀ1); 4-MeC6H4NHþ3 (pKa ¼ 5.07;[53] ko ¼ 37 sꢀ1);
4-MeOC6H4NHþ3 (pKa ¼ 5.29;[53] ko ¼ 45 sꢀ1); 4-FC6H4NHþ3 (pKa ¼ 4.52;[53]
ko ¼ 43 sꢀ1). ko values from references[7,8,50]
To calculate the analogous parameter k in the reaction of
DMTrOTFE in Scheme 1, we need an estimate of the acidity
constant of its conjugate acid, DMTrO(H)TFEþ. This can be done
stepwise starting from the value for DMTrOHþ2 (pKa ꢄ ꢀ4, see
above), and incorporating perturbations due to conversion first to
DMTrO(H)CH2CHþ3 , then to DMTrO(H)CH2CF3þ. From pKa values of
ꢀ2.1 and ꢀ3.6 for EtOHþ2 and Et2OHþ, respectively,[32,33,35,36] we
estimate pKa ꢄ ꢀ5.5 for DMTrO(H)CH2CHþ3 . Then, from pKa values
for ethanol (15.9)[37] and trifluoroethanol (12.4),[38] we arrive at a
undergo hydrolysis by an uncatalysed SN1 mechanism. The
uncatalysed route requires incorporation of an extra reaction
channel into the mechanism of Scheme 1, and the predicted rate
law is then given by
Rate ¼ kobs ½Tr0OTFEꢃ where kobs ¼ ko þ kH ½H3Oþꢃ
(2)
value of pKa ꢄ ꢀ9 for DMTrO(H)TFEþ, that is Ka ꢄ 109 mol dmꢀ3
.
This allows determination of the catalytic rate constant kH and,
according to the mechanism of Scheme 1, kH ¼ k/Ka where Ka is
the acid dissociation constant (acidity constant) of the proto-
nated ether, that is the reciprocal of the equilibrium constant K
for the pre-equilibrium shown in Scheme 1. However, the simple
linear relationship between the observed pseudo-first-order
rate constant and hydronium ion concentration, expected on
the basis of Scheme 1 and Eqn 2, is observed only for TMTr TFE
ether (Fig. 1). Upwards curvature is observed for the dimethoxy
analogue (Fig. 2), and is even stronger for MMTr TFE ether (Fig. 3).
Absence of a rectilinear correlation between kobs/[H3Oþ] and
[H3Oþ] for MMTrOTFE (the correlation is an irregularly shaped
curve which defied mathematical fitting) established that the
upward curvature in Fig. 3 is not simply due to the intrusion of a
Thus, with kH ¼ 6.9 ꢂ 10ꢀ3 dm3 molꢀ1 sꢀ1, we obtain k ꢄ 7 ꢂ
106 sꢀ1 which is only about 40 times greater than the value of
k1 ꢄ 1.7 ꢂ 105 sꢀ1 for DMTrꢀꢀOHþ2 (see above) following the
improvement in the nucleofuge by replacing ꢀꢀOHþ2 by
ꢀꢀO(H)TFEþ. However, reduction of the concentration of the
protonated reactive intermediate through reduction of the
base strength of the substrate (a factor of about 105, see above)
more than compensates for this modest rate constant ratio, and
DMTrOTFE has a much lower experimental catalytic rate constant
than DMTrOH. The ratio for uncatalysed CꢀꢀO heterolysis
reactions of DMTrꢀꢀOTFE and DMTrꢀꢀOH is immeasurably high
as the latter shows no detectable reactivity in the absence of acid.
Heterolytic cleavage of the CꢀꢀN bond of DMTrꢀꢀNH2Rþ in
Scheme 3 comprises uncatalysed and catalysed channels but
Scheme 4. Comparison of rates of unimolecular heterolyses of DMTr–YHþ in aqueous solution for YH ¼ H2O, CF3CH2OH and NH3. k1 in
Eqn (i) ꢄ 1.7 ꢂ 105 sꢀ1 (see the text); k in Eqn (ii) ꢄ 7 ꢂ 106 sꢀ1 (see the text); ko in Eqn (iii) ¼ 3.67 ꢂ 10ꢀ5 sꢀ1 for R ¼ H;[20]
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J. Phys. Org. Chem. 2008, 21 614–621

HYDROLYSIS OF SUBSTITUTED TRITYL TFE ETHERS
dissociation free energies. In view of the relatively small effect of
the methoxy-substituents, we also assumed that computations
on the parent trityl compounds (R ¼ Ph3C) would adequately
model our experimental results for the 4,40-dimethoxy deriva-
tives, and, as a preliminary, we investigated the much simpler ions
with R ¼ CH3 and included RꢀꢀO(H)Meþ to model projected
experimental results using Tr’ꢀꢀOMe.
Scheme 5. Dissociation of protonated species CH3–YHþ and Tr–YHþ
All four ions CH3ꢀꢀYHþ correspond to stable bonded species,
and the bond dissociation enthalpies and free energies (258C) are
shown in Table 1. For the three analogues of compounds for
which we have experimental results, the decreasing order of
bond strengths in the gas phase (NH3 ꢁ H2O > CF3CH2OH), both
with and without using the specific solvation model, corresponds
very well to the increasing order of reactivity found in solution
(NH3 ꢅ H2O < CF3CH2OH). Agreement using the Onsager model
in solution is less satisfactory so this was not considered
further.[27–29] Results predicted for CH3ꢀꢀO(H)CHþ3 in the gas
phase indicate reactivity lower than for CH3ꢀꢀOHþ2 (but still much
greater than for CH3ꢀꢀNHþ3 ). Inclusion of specific water molecules
of solvation, however, inverts the order for CH3ꢀꢀO(H)CH3þ
and CH3ꢀꢀOHþ2 but CH3ꢀꢀO(H)CHþ3 is still predicted to be more
stable (less reactive) than CH3ꢀꢀO(H)CH2CFþ3 .
only the former is directly comparable with the heterolyses of
DMTrꢀꢀOHþ2 and DMTrꢀꢀO(H)TFEþ, that is the ko component of
Eqn (iii) in Scheme 4. Comparison of Schemes 3 and 4 shows that
[19,20]
ko ¼ (k1 /k?1 )kd, and ko ¼ 3.67 ꢂ 10ꢀ5 sꢀ1 for DMTrꢀꢀNH3þ.
Thus, whilst rate constants for heterolyses of DMTrꢀꢀO(H)TFEþ
and DMTrꢀꢀOHþ2 differ only by a factor of about 40, there is a rate
ratio of about 4 ꢂ 109 for fragmentation of DMTrꢀꢀOH2þ
compared with DMTrꢀꢀNHþ3 . Figure 4 includes a Brønsted-type
plot of log (k, k1 or ko) against the pKa of the conjugate acid of
the leaving group for DMTrYHþ (YH ¼ OH, OTFE and NH2)
together with results reported earlier for eight other sub-
strates:—DMTrꢀꢀNH2Rþ (Scheme 3) with R ¼ MeO, PhCH2
and CH3CH2CH2, and 4-X-C6H4 (X ¼ H, NO2, Me, MeO and F).
Literature pKa values were available for all 11 protonated leaving
groups YHþ2 except TFEOH2þ (see Fig. 4). A value of pKa ¼ ꢀ5.6 for
TFEOHþ2 may be estimated from the value for TFEOH (12.4)[38]
assuming that the difference between these two is the same as
the difference between values for EtOHþ2 and EtOH (ꢀ2.1 and
15.9);[32,33,18] similar results are obtained if the difference
between pKa values of H2O and H3Oþ is taken or between
MeOH and MeOHþ2 . As seen, results for five substrates which span
the whole wide range of reactivity lie on an excellent straight
line suggestive of a common mechanism. The high value of the
gradient (ꢀ0.79, R ¼ ꢀ0.99) is wholly compatible with the
dissociation of Tr0YHþ involving initial ionisation followed by
0
0
For the parent trityl analogues TrꢀꢀYHþ, results using the
solvated model for YH ¼ H2O, CH3OH and NH3 are given in
Table 2; (the ion TrꢀꢀO(H)CH2CFþ3 did not correspond to an
energy minimum). Heterolytic dissociation of TrꢀꢀNH3ðH2OÞþ is
3
still thermodynamically unfavourable whereas that of
TrꢀꢀO(H)CH3(H2O)þ is strongly favourable; between the two lies
TrꢀꢀOH2ðH2OÞþ whose dissociation is endothermic (positive
2
DHo) but overall favourable (negative DGo) when the entropy
term is included.
Computed structures of TrꢀꢀYHþ are shown in Fig. 5. Structural
parameters for TrNH3ðH2OÞþ (CꢀꢀN bond, 1.550 A; sum of angles
˚
3
at central C, 337.28) are in excꢀellent agreement with crystal-
lographic values fþor TrNHþ3 Cl (1.519 A and 334.88) and
˚
rate-determining separation of the ion–molecule pair,[9,10,12]
a
N-tritylglycine (TrNH2 CH2CO2 , 1.551 Aand 333.68).[40] In addition,
ꢀ
˚
detail included in Fig. 3 but not in Figs 1, 2 and 4, that is the bond
from the trityl residue to the nucleofuge is completely broken in
the transition structure for heterolysis/dissociation of Tr0YHþ.
Results for six substrates, however, lie above the linear correlation
(two are superimposed), that is these six substrates are more
reactive than anticipated. We have at present no explanation of
these anomalies but note that four are substituted anilines.
The enormous element effect upon the rate of heterolysis of
the ions DMTrꢀꢀOHþ2 and DMTrꢀꢀNHþ3 is quite remarkable given
that the CꢀꢀO and CꢀꢀN bond dissociation enthalpies
in CH3ꢀꢀOH and CH3ꢀꢀNH2 are 385 and 356 kJ molꢀ1, respect-
ively.[39] However, these bond dissociation enthalpies correspond
to gas phase homolysis and the present reactions are heterolyses
in aqueous solution. Consequently, we have calculated the
dissociation enthalpies and free energies for the heterolytic
reactions in Scheme 5 to provide a basis for comparison of the
kinetic effects being observed.
the computations reproduce the CꢀꢀN bond length observed
˚
experimentally for Ph3CꢀꢀNH2 (CꢀꢀN ¼ 1.486 A computationally
compared with 1.481 A crystallographically)[41] and the
˚
elongation upon protonation of the nitrogen, which lends
credibility to the computational protocol. For TrꢀꢀOH2ðH2OÞþ,
2
˚
the CꢀꢀO bond is 1.620 A (appreciably longer than the value
˚
˚
1.446 A presently calculated for TrOH, and 1.448 A obtained
crystallographically[42]), and there is an appreciably greater
degree of planarisation (sum of angles at central C ¼ 344.28) than
in the less reactive tritylammonium ion (337.28) in accordance
with the Bu¨rgi–Dunitz principle.[43–46]
The solvated protonated trityl TFE ether does not correspond
to a stable bonded ion and, correspondingly, the computed
structure comprises the propeller-shaped trityl carbocation (fully
planar at the central carbon) well separated from the
trifluoroethanol molecule hydrogen-bonded to a water molecule
˚
(the central carbon atom being 3.536 A from the oxygen). This
suggests that the acid-catalysed fragmentation of Tr0ꢀꢀOTFE in
aqueous solution is concerted with proton transfer rather than
following a pre-equilibrium as shown in Scheme 1. This leads to
the prediction of general as opposed to specific acid catalysis. If
confirmed experimentally, this would be wholly in line with the
observation by Bunton of general acid catalysis in the
protonation/dissociation of tropyl alcohol to give the tropylium
ion,[11] and general base catalysis in the hydration of some
triarylmethyl carbenium ions.[47–49]
Computational comparison of leaving group effects upon
heterolysis of R-YHR where R ¼ CH3 and Ph3C, and
YH ¼ H2O, CH3OH, CF3CH2OH and NH3
Assuming that reactivity parallels thermodynamic driving force
for the set of closely related compounds reacting by the same
generic meþchanism, we anticipated the kinetic reactivity of
RꢀꢀO(H)TFE , RꢀꢀOHþ2 and RꢀꢀNHþ3 to parallel heterolytic bond
J. Phys. Org. Chem. 2008, 21 614–621
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

´
M. C. LOPEZ ET AL.
þ
*
Figure 5. Optimised structures of solvated complexes, Tr–YHðH2OÞn , at the B3LYP/6-31þG level.
4-Methoxytrityl 2,2,2-trifluoroethyl ether
EXPERIMENTAL
4-Methoxytrityl tetrafluoroborate (51 mg, 0.14 mmol) was
dissolved in 2,2,2-trifluoroethanol (2 cm3, excess) and triethyl-
amine (two drops) was added. The mixture was stirred overnight
at room temperature and then evaporated to dryness. The
residue was chromatographed on silica gel (20% ethyl acetate/
petrol) to give a colourless oil (40 mg, 76%; dH 3.38 (2H, q, J
8.5, CH2), 3.71 (3H, s, OCH3), 6.77 (2H, d, J 9, C-30H, C-50H),
7.10–7.40 (12H, m, ArH); dC 55.28 (OCH3), 61.68 (CꢀꢀO), 62.37
(CH2), 87.82 (CF3), 113.45 (C-3, C-5), 127.38 (C-40), 128.12 (C-30,
C-50), 128.27 (C-20, C-60), 130.39 (C-2, C-6), 134.22 (C-1), 143.25
(C-10), 159.03 (C-4)).
Our kinetics methods, general experimental procedures and
instrumentation have already been described.[7,9,10,20–22]
PREPARATIONS
Trityl 2,2,2-trifluoroethyl ether
Trityl bromide (66 mg, 0.2 mmol) was dissolved in acetone (1 cm3)
and 2,2,2-trifluoroethanol (2 cm3) was added. After addition of
triethylamine (two drops), the product precipitated out and the
mixture was stirred for 1 h at room temperature. The precipitated
compound was filtered off and dried in vacuo to yield the title
compound as white crystals (61 mg, 89%; mp 123–1258C; found:
C, 73.46; H, 4.90; C21H17OF3 requires C, 73.67; H, 5.00; dH 3.65 (2H,
q, J 8.5, CH2), 7.20–7.40 (15H, m, ArH); dC 61.75 (CꢀꢀO), 62.44 (CH2),
87.89 (CF3), 127.56 (C-40), 128.15 (C-30, C-50), 128.56 (C-20, C-60),
142.68 (C-10)).
4,4(-Dimethoxytrityl 2,2,2-trifluoroethyl ether
4,40-DMTr tetrafluoroborate (200 mg, 0.62 mmol) was dissolved in
2,2,2-trifluoroethanol (4 cm3, excess) and triethylamine (five
drops) was added. The mixture was stirred for 21 h at room
temperature and then evaporated to dryness. The residue was
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 614–621

HYDROLYSIS OF SUBSTITUTED TRITYL TFE ETHERS
extracted between water (10 cm3) and dichloromethane (10 cm3).
The organic phase was separated, dried (Na2SO4), filtered and
evaporated to give an oil (135 mg, 56%; dH 3.45 (2H, q, J 8.5, CH2),
3.80 (6H, s, 2 ꢂ OCH3), 6.84 (4H, d, J 9, C-30H, C-50H), 7.10-7.50 (5H,
m, ArH), 7.32 (4H, d, J 9, C-20H, C-60H); dC 55.28 (2 ꢂ OCH3), 61.60
(CꢀꢀO), 62.29 (CH2), 87.78 (CF3), 113.23 (C-3, C-5), 127.20 (C-40),
127.99 (C-30, C-50), 129.18 (C-2, C-6), 130.03 (C-20, C-60), 134.81
(C-1), 143.77 (C-10), 158.88 (C-4)).
[20] J. Crugeiras, H. Maskill, J. Chem. Soc. Perkin Trans. 2 1998, 1901–1907.
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[26] Gaussian 03, Revision C.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr, T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V.
Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson,
H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M.
Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E.
Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
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J. A. Pople, Gaussian Inc., Wallingford, CT, 2004.
4,4(,400-Trimethoxytrityl 2,2,2-trifluoroethyl ether
4,40,400-TMTr tetrafluoroborate (29.5 mg, 0.07 mmol) was dis-
solved in 2 cm3 (excess) of 2,2,2-trifluoroethanol and two drops of
triethylamine were added. The mixture was stirred for 6 h at room
temperature and then extracted between water (10 cm3) and
ether (10 cm3). The organic phase was separated, dried (Na2SO4),
filtered and evaporated to give an oil (24.19 mg, 80%; dH 3.40 (2H,
q, J 8.5, CH2), 3.75 (9H, s, 3 ꢂ OCH3), 6.80 (6H, d, J 9, C-3H, C-5H),
7.25 (6H, d, J 9, C-2H, C-6H); dC 55.27 (3 ꢂ OCH3), 61.54 (CꢀꢀO),
113.39 (C-3, C-5), 129.73 (C-2, C-6), 135.32 (C-1), 158.75 (C-4)).
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Acknowledgements
˜
We thank the Turkish Government (ID), the University of A Coruna
and the Xunta de Galicia (MCL and HM) for financial support. We
also thank a referee for some perceptive and helpful comments.
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J. Phys. Org. Chem. 2008, 21 614–621
Copyright ß 2008 John Wiley & Sons, Ltd.
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