Stabilities of trityl-protected substrates: The wide mechanistic spectrum of trityl ester hydrolyses

Article abstract of DOI:10.1002/chem.200902669

Ionization rates of para-substituted triphenylmethyl (trityl) acetates, benzoates, and para-nitrobenzoates have been determined in aqueous acetonitrile and aqueous acetone at 25 °C. Conventional and stoppedflow techniques have been used to evaluate rate constants ranging from 1.38 × 10^-5 to 2.15 × 10²S^-1 by conductimetry and photospectrometry methods. The varying stabilities of the differently substituted tritylium ions account for a gradual change of reaction mechanism. Poorly stabilized carbocations are generated slowly by the ionization of their covalent precursors and trapped fast by water. Better stabilized carbocations are generated more rapidly and accumulate, so that ionization and trapping by water can be observed as separate steps in a single experiment. Finally, highly stabilized tritylium ions do not react with water, and only the rates of their formation could be measured. The ionization rate constants correlate linearly with Winstein's ionizing powers Y; the low slopes (0.17 + parameters is excellent for symmetrically substituted tritylium derivatives, deviations for unsymmetrically substituted systems are observed. The failing rate-equilibrium relationship between the rates of ionizations (log k_ion) and the stabilities of the carbocations in aqueous solution (pK_R+) may be explained by the late " development of resonance between a p-amino group and the carbocationic center of the tritylium ion during the ionization process.

Full text of DOI:10.1002/chem.200902669

FULL PAPER
DOI: 10.1002/chem.200902669
Stabilities of Trityl-Protected Substrates: The Wide Mechanistic Spectrum of
Trityl Ester Hydrolyses
Markus Horn and Herbert Mayr*[a]
Dedicated to Professor Rudolf Knorr on the occasion of his 75th birthday
Abstract: Ionization rates of para-sub-
stituted triphenylmethyl (trityl) ace-
tates, benzoates, and para-nitroben-
zoates have been determined in aque-
ous acetonitrile and aqueous acetone
at 258C. Conventional and stopped-
flow techniques have been used to
evaluate rate constants ranging from
1.38ꢀ10ꢀ5 to 2.15ꢀ102 sꢀ1 by con-
ductimetry and photospectrometry
methods. The varying stabilities of the
differently substituted tritylium ions ac-
count for a gradual change of reaction
mechanism. Poorly stabilized carboca-
tions are generated slowly by the ioni-
zation of their covalent precursors and
trapped fast by water. Better stabilized
carbocations are generated more rapid-
ly and accumulate, so that ionization
and trapping by water can be observed
as separate steps in a single experi-
ment. Finally, highly stabilized tritylium
ions do not react with water, and only
the rates of their formation could be
measured. The ionization rate con-
stants correlate linearly with Winsteinꢁs
ionizing powers Y; the low slopes
(0.17<m<0.58) indicate non-carbocat-
ion-like transition states. While the cor-
relation between the ionization rates
and Hammett-Brownꢁs s+ parameters
is excellent for symmetrically substitut-
ed tritylium derivatives, deviations for
unsymmetrically substituted systems
are observed. The failing rate–equilib-
rium relationship between the rates of
ionizations (log kion) and the stabilities
of the carbocations in aqueous solution
(pKR+) may be explained by the late
development of resonance between a
p-amino group and the carbocationic
center of the tritylium ion during the
ionization process.
Keywords: kinetics · linear free-en-
ergy relationships
·
protecting
groups · solvolysis · tritylium ions
Introduction
cleavage of trityl ethers often requires conditions which also
lead to the deprotection of other acid-labile groups, like gly-
cosides, Khorana introduced 4-methoxy- and the 4,4’-dime-
thoxytrityl derivatives, which are more acid-labile.[6] 4-Me-
thoxy-substituted tritylium systems have been studied exten-
sively by Maskill,[7] who determined rate constants of acidic
detritylations of amines[7a] and trifluoroethanol.[7b] Destabi-
lized trityl compounds, like the heptafluorotrityl system,
were designed to serve as acid-stable protecting groups, for
example, for the g-carboxy group of glutamic acid.[8]
While the qualitative trend that the cleavage of trityl
esters is facilitated by electron-donating substituents and im-
peded by acceptor groups is well-known, there are only a
few kinetic studies on the solvolyses of donor-substituted tri-
tylium derivatives, probably because many of these reactions
proceed very quickly and require special experimental tech-
niques, which were not generally available in the period
when most kinetic investigations of solvolysis reactions were
being performed.
The triphenylmethyl (trityl) cation was the first carbocation
ever recognized.[1] Since then, the trityl group has found nu-
merous applications in organic chemistry. It has been used
as a hydride acceptor[2] and as a catalyst in Lewis acid initi-
ated reactions.[3] Stabilized tritylium ions, covalently bound
to nucleosides and peptides, have served as mass tags for im-
proving the sensitivity in MALDI-TOF mass spectrometry.[4]
Most important in synthetic chemistry, however, is their
use as protecting groups for OH and NH functionalities.[5–8]
The unsubstituted parent residue has long been employed to
protect alcohols, carboxylic acids, and amines.[5] Because the
[a] M. Horn, Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universitꢂt Mꢃnchen
Butenandtstr. 5–13, 81377 Mꢃnchen (Germany)
Fax : (+49)89-2180-77717
E-mail: Herbert.Mayr@cup.uni-muenchen.de
Swain and co-workers determined solvolysis rates of trityl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902669.
acetate in aqueous alcohols and acetone at 258C.[9] Bunton
Chem. Eur. J. 2010, 16, 7469 – 7477
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7469

proved that the alkyl–oxygen bond (rather than the acyl–
oxygen bond) is cleaved in the rate-determining step during
the hydrolysis of trityl acetate.[10] Hammond reported rates
of solvolysis of trityl benzoate in ethanolic ethyl methyl
ketone at 558C, and found the exclusive formation of the
ethyl trityl ether.[11] Smith studied the decomposition of tris-
ACHTUNGTRENNUNG(p-tolyl)methyl benzoate in ethanolic methylene chloride,
and detected strong common ion rate depression.[12] In the
course of their work on ion pairs, Swain[13] and Winstein[14]
investigated the rate of equilibration of carbonyl-18O-labeled
trityl benzoate in pure acetone.
In view of the thousands of kinetic investigations of SN1
reactions yielding less stabilized carbenium ions, we were
surprised that no systematic investigation concerning the
heterolyses of donor-substituted trityl esters had yet been
undertaken. Because such information is essential for select-
ing trityl derivatives with tailor-made stabilities, we set out
to study the ionization rates of trityl carboxylates, including
dimethylamino- and methoxy-substituted derivatives, which
are of particular importance as protecting groups (Table 1).
Scheme 1. Hydrolysis of a trityl acetate (R=Me), benzoate (R=Ph), or
p-nitrobenzoate (R=p-NO2C6H4).
bocations are generated almost quantitatively before
they are trapped by water, both steps of the reaction se-
quence can easily be followed by photospectrometry.
D) kion fast, kw not detectable. The solvolysis scheme is re-
duced to the ionization step, because the generated tri-
tylium ions are so stable that they do not react with
water under the reaction conditions. Photospectrometry
is a convenient method for monitoring the ionization.
Table 1. The tritylium systems studied in this work with corresponding
pKR+ values.
[b]
R1, R2, R3[a]
Abbreviation
pKR+
H, H, H
Me, H, H
Me, Me, H
Me, Me, Me
MeO, H, H
MeO, MeO, H
MeO, MeO, MeO
Me2N, H, H
Me2N, MeO, H
Me2N, Me2N, H
Tr+
ꢀ6.63
ꢀ5.41
ꢀ4.71
ꢀ3.56
ꢀ3.40
ꢀ1.24
0.82
MeTr+
Me2Tr +
Me3Tr +
(MeO)Tr+
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
3.88[c]
Results
N
R
G
4.86[d]
6.94[d]
AHCTUNGTRENNUNG
Only triphenylmethyl acetate, benzoate, and p-nitroben-
zoate, that is, the unsubstituted parent compounds, have
been isolated as pure substances. Because of their low stabil-
ity, the esters of the donor-substituted tritylium systems
were generated in acetonitrile directly before the kinetic
measurements by mixing the colored tritylium tetrafluoro-
borates with tetra-n-butylammonium acetate or benzoate.
Usually, one equivalent of the ammonium carboxylate was
sufficient to decolorize the solution. As mentioned above,
different kinetic methods were employed depending on the
relative magnitudes of kion and kw.
[a] For the location of the substituents see Scheme 1. [b] From ref. [16].
[c] From ref. [17]. [d] From ref. [18].
Kinetic methods: If acyl cleavage is excluded, the hydrolyses
of trityl esters follow Scheme 1, which includes four scenar-
ios (A to D, below) depending on the relative magnitudes of
kion and kw. As discussed later, common ion return, kꢀion
,
does not occur in the concentration range of interest, and
will therefore be neglected in the following discussion.
A) kion !kw. In the classical SN1 reaction, carbocations are
generated as short-lived intermediates, which are trap-
ped immediately by the solvent. The progress of the re-
actions can be followed conveniently by conductimetry.
B) kion ꢁkw. When the formation and consumption of the
intermediates proceed with comparable rates, small con-
centrations of the tritylium ions are detectable, and the
course of the reaction can be followed by conductimetry
or photospectrometry.
Scenario A, kion !kw: Because CH3CO2H, PhCO2H, and p-
nitrobenzoic acid, which were generated in the hydrolyses,
are weak acids, tertiary amines (usually triethylamine) were
added to increase the sensitivity of the conductimetric meas-
urements by forming ionic ammonium carboxylates. Only
relative conductivities krel were needed for the evaluation of
the kinetic experiments, and we did not calibrate the con-
ductivity cell to determine absolute values of k. In order to
examine the relationship between reaction progress and
C) kion @kw. In the so-called SN2C+ mechanism, which was
first proposed by Ingold and co-workers,[15] carbocations
are formed in a fast ionization process and trapped in a
slow subsequent reaction. Because the intermediate car-
conductivity of the solution, a stock solution of (MeO)Tr
ꢀ
OAc in acetonitrile was added portionwise to 50:50 (v/v)
acetonitrile/water containing triethylamine (!Et3NH+
AcOꢀ). The solvolysis was complete within a few seconds
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Chem. Eur. J. 2010, 16, 7469 – 7477

Trityl Ester Hydrolyses
FULL PAPER
after each addition, and the resulting conductivities were
plotted against the concentrations of the dissolved trityl
ester. The linear correlation in the relevant concentration
range of the kinetic runs (Figure 1) allowed us to directly
relate the conductivity and the progress of the hydrolysis.
Figure 3. Time-dependent absorption of (MeO)3Tr + during the solvolyses
of (MeO)3Tr OAc (c0 =6.66ꢀ10ꢀ5 molLꢀ1
(stopped-flow photospectrometry, l=484 nm, 258C).
) in aqueous acetonitrile
ꢀ
rate constants for both steps, kion and kw. In all cases the
measured curves could be reasonably fitted (Tables 2 and 3;
for details see the Supporting Information).
At the maxima of the curves shown if Figure 3, ionization
and trapping proceeded with the same rate. Whereas the
Figure 1. Plot of relative conductivities Grel versus concentrations of
ꢀ
(MeO)Tr OAc; 50:50 (v/v) acetonitrile/water, 258C, [Et3N]=4.62ꢀ
10ꢀ3 molLꢀ1
.
ꢀ
Figure 2 shows a typical exponential increase of conduc-
tivity due to the rate-determining ionization of a trityl ester.
Analogous first-order kinetics were observed for the hydrol-
yses of all other trityl carboxylates, implying that common
ion return did not take place.[19] First-order rate constants
kion were evaluated by least-squares fitting of the curves to
ionization of (MeO)3Tr OAc was accelerated by a factor of
eight when going from 90AN10W (90:10 (v/v) acetonitrile/
water) to 50AN50W, the trapping rate only increased by a
factor of 1.4. This trend leads to a higher, as well as earlier,
maximum absorbance in 50AN50W, in which the maximum
carbocation concentration (25% of initial substrate) was
reached after 0.22 s. In 90AN10W, the maximum of the car-
bocation concentration was reached after 0.63 s, and corre-
sponded to 7.2% of the initial substrate.
the mono-exponential function Gt =G0ACHTGNUTRENNUNG
(1ꢀeꢀkt)+C.
ꢀ
Table 2. Rate constants for the solvolyses of (MeO)3Tr OAc in aqueous
acetonitrile at 258C; determined by conductimetry and photometric mon-
itoring of the intermediate carbocation.
From conductivity in the
presence of piperidine
From Gepasi-Fit of the
solvent[a]
absorbance of (MeO)3Tr +
kion [sꢀ1
]
kion [sꢀ1
]
kw [sꢀ1
]
90AN10W
80AN20W
60AN40W
50AN50W
6.80ꢀ10ꢀ1
1.58
3.86
5.15ꢀ10ꢀ1
1.13
2.50
5.01
7.13
7.12
7.22
5.56
4.09
[a] 90AN10W=90:10 (v/v) acetonitrile/water, etc.
ꢀ
Figure 2. Conductivity Grel versus time for the solvolysis of MeTr OAc
(c0 =1.06ꢀ10ꢀ3 molLꢀ1) in 60:40 (v/v) acetonitrile/water at 258C, 5 equiv
of NEt3.
ꢀ
Table 3. Rate constants for the solvolyses of (MeO)3Tr OBz in aqueous
acetonitrile at 258C; determined by conductimetry and photometric mon-
itoring of the intermediate carbocation.
Scenario B, kion ꢁkw: The similarities of the rates of ioniza-
From conductivity in the
presence of piperidine
From Gepasi-Fit of the
tion and quenching of the carbocation during the hydrolyses
Solvent[a]
absorbance of (MeO)3Tr +
ꢀ
ꢀ
kion [sꢀ1
]
kion [sꢀ1
]
kw [sꢀ1
]
of (MeO)3Tr OAc and (MeO)3Tr OBz, gave rise to sub-
stantial transient concentrations of (MeO)3Tr +, which could
be visualized by photospectrometry. No amine was added in
the experiments of Figure 3. Numerical treatment of the
time-dependent concentrations of (MeO)3Tr + with the help
of the computer program GEPASI[20] delivered individual
90AN10W
80AN20W
60AN40W
50AN50W
3.79
6.45
2.34
3.94
6.18
9.01
5.08
6.99
7.46
8.01
1.12ꢀ101
1.38ꢀ101
[a] 90AN10W=90:10 (v/v) acetonitrile/water, etc.
Chem. Eur. J. 2010, 16, 7469 – 7477
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7471

H. Mayr and M. Horn
ꢀ
ꢀ
ꢀ
Table 5. Ionization rates of (Me2N)Tr OAc (c0 =6.00ꢀ10ꢀ5 molLꢀ1) in
aqueous acetonitrile in the presence of variable amounts of (nBu)4N+
AcOꢀ (stopped-flow photospectrometry, l=461 nm, 258C).
When the solvolyses of (MeO)3Tr OAc and (MeO)3Tr
OBz were carried out in the presence of piperidine, the in-
termediate carbocations were trapped immediately by the
amine;[21] a transient absorption was not detectable. From
the mono-exponential increase of conductivity, the first-
order rate constants listed in the second columns of Tables 2
and 3 were obtained. The independence of kobs of the con-
centration of piperidine (Table 4) proved the ionization step
to be rate-determining. Tables 2 and 3 show that the conduc-
timetrically determined ionization rate constants in the pres-
ence of piperidine are generally 1.3 to 1.8 times bigger than
those derived from the absorbance of the intermediate car-
bocations.
A
]
kion [sꢀ1
]
50AN50W[a]
90AN10W[a]
1.32ꢀ10ꢀ4
3.21ꢀ10ꢀ4
1.87ꢀ10ꢀ3
3.73ꢀ10ꢀ3
6.78ꢀ10ꢀ3
1.01ꢀ10ꢀ2
1.35ꢀ10ꢀ2
7.40
7.41
7.29
7.34
7.32
7.22
7.22
1.08
1.07
1.02
1.04
1.03
1.05
1.04
[a] 90AN10W=90:10 (v/v) acetonitrile/water, 50AN50W=50:50 (v/v)
acetonitrile/water.
ꢀ
Table 4. Ionization rate constants of (MeO)3Tr OAc (c0 =8.33ꢀ
10ꢀ4 molLꢀ1) in the presence of variable amounts of piperidine (stopped-
flow conductimetry, 90:10 (v/v) acetonitrile/water, 258C).
piperidine [molLꢀ1
]
kobs [sꢀ1
]
5.18ꢀ10ꢀ3
1.04ꢀ10ꢀ2
1.55ꢀ10ꢀ2
2.07ꢀ10ꢀ2
6.74ꢀ10ꢀ1
6.79ꢀ10ꢀ1
6.65ꢀ10ꢀ1
6.80ꢀ10ꢀ1
Scenario C, kion @kw: The esters of (Me2N)Tr ionized very
rapidly compared to the reaction of the carbenium ion with
water, as shown in Figure 4. Both the increase and decrease
Figure 5. Time-dependent absorbance A for the ionization of (Me2N)-
(MeO)Tr OAc (c0 =5.03ꢀ10ꢀ5 molLꢀ1) in aqueous acetonitrile solutions
ꢀ
ous acetonitrile of different compositions gave solutions of
the tritylium ion according to the rate law At =A0 (1ꢀeꢀkt)+
C. While the resulting solutions of the carbocations are
fairly stable in the absence of base, a slow reaction with
water takes place in the presence of carboxylate ions, con-
verting this system into a scenario C case.
Figure 4. Solvolysis of (Me2N)Tr OAc (c0 =2.79ꢀ10ꢀ5 molLꢀ1) in 60:40
(v/v) acetonitrile/water, stopped-flow photospectrometry, l=461 nm,
ꢀ
ꢀ
For the synthesis of (Me2N)2Tr OAc, an ester of mala-
chite green, a large excess of (nBu)4N+AcOꢀ was needed.
Its ionization proceeded so rapidly, however, that the kinet-
ics of these reactions could only be followed by a stopped-
flow device in solvents of low ionizing power, that is, in
90AN10W and 80AN20W, but not in 60AN40W. Due to the
pKR+ value of 6.94, the subsequent reaction with water
would have needed strongly basic conditions, and could not
be observed even in the presence of high carboxylate con-
centrations.
258C; [(nBu)4N+OAcꢀ]=3.18ꢀ10ꢀ4 molLꢀ1
. The insert magnifies the
first stage of the reaction.
of the absorbance were separated by a relatively large time
gap, which allowed us to evaluate ionization rate constants
by fitting the first parts of the curves according to the
mono-exponential function At =A0ACHTGNUTRENNUNG
(1ꢀeꢀkt)+C. However,
conversion to the alcohol only went to completion when an
excess of carboxylate was used to quench the generated pro-
tons, and thus suppress the reionization of the triarylcarbi-
nol. Table 5 shows that an excess of AcOꢀ did not affect the
ionization rates.
Salt effects: When the trityl esters used for the kinetic stud-
ies were generated by combining tritylium tetrafluoro-
borates
with
tetra-n-butylammonium
carboxylates,
ꢀ
(nBu)4N+BF4 was produced as a byproduct. In order to ex-
amine the influence of this additional salt on the ionization
rates,[19,22] a series of experiments with variable concentra-
Scenario D, kion fast and kw not detectable: As illustrated in
Figure 5, the ionizations of (Me2N)
ꢀ
N
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Chem. Eur. J. 2010, 16, 7469 – 7477

Trityl Ester Hydrolyses
FULL PAPER
ꢀ
tion of (nBu)4N+BF4 was performed. Table 6 shows that
even large amounts of this salt did not affect the rates of
ionization. We therefore conclude that tetraalkylammonium
salts do not exert a positive salt effect. This finding is in line
with Hojoꢁs investigations of the solvolyses of adamantyl
halides in 50:50 (v/v) sulfolane/water, showing that small
concentrations of tetraalkylammonium salts hardly affected
the ionization rates, while larger concentrations (up to
1 molLꢀ1) caused slight retardations of the solvolyses.[23]
Table 9. Ionization rate constants of trityl para-nitrobenzoate in aqueous
acetonitrile (258C).
Solvent[a]
kion [sꢀ1
]
90AN10W
80AN20W
60AN40W
50AN50W
1.57ꢀ10ꢀ3
4.19ꢀ10ꢀ3
9.68ꢀ10ꢀ3
1.82ꢀ10ꢀ2
[a] 90AN10W=90:10 (v/v) acetonitrile/water, etc.
ꢀ
Table 6. Ionization rate constants of (Me2N)
(MeO)Tr OAc (c0 =5.03ꢀ
ꢀ
10ꢀ5 molLꢀ1) in the presence of variable amounts of (nBu)4N+BF4 (pho-
tospectrometry, l=506 nm, 90:10 (v/v) acetonitrile/water, 258C).
A
]
kion [sꢀ1
]
0
6.23
6.37
6.13
6.27
6.19
6.07ꢀ10ꢀ4
1.75ꢀ10ꢀ3
3.17ꢀ10ꢀ3
4.53ꢀ10ꢀ3
Summary of rate constants: Although a variety of differently
substituted trityl acetates (Table 7) and benzoates (Table 8)
have been investigated in aqueous acetonitrile, triphenyl-
methyl p-nitrobenzoate is the only ester of p-nitrobenzoic
acid that we have studied kinetically (Table 9).
Figure 6 illustrates the consistency of the different series
of rate constants, and shows that the ionization rates of dif-
ferently substituted trityl acetates in 50AN50W and
Figure 6. Correlation of ionization rates of trityl acetates in different sol-
vents with those of trityl benzoates in 90:10 (v/v) acetonitrile/water,
258C.
90AN10W correlate linearly
with the ionization rates of the
corresponding trityl benzoates.
The converging correlation
lines indicate that the differ-
ence in rates between the two
solvents decreases when better
stabilized carbocations are em-
ployed (Hammond effect). Sol-
volytic studies in aqueous ace-
tone were only performed with
esters of the unsubstituted tri-
phenylmethanol (Table 10).
Table 7. Ionization rate constants of trityl acetates in aqueous acetonitrile[a] (258C).
kion [sꢀ1
]
Scenario
90AN10W
80AN20W
60AN40W
50AN50W
Tr
1.47ꢀ10ꢀ5
1.03ꢀ10ꢀ4
3.23ꢀ10ꢀ4
1.30ꢀ10ꢀ3
1.20ꢀ10ꢀ3
4.04ꢀ10ꢀ2
6.80ꢀ10ꢀ1
1.08
5.88ꢀ10ꢀ5
3.59ꢀ10ꢀ4
1.21ꢀ10ꢀ3
4.98ꢀ10ꢀ3
4.53ꢀ10ꢀ3
1.15ꢀ10ꢀ1
1.58
2.70ꢀ10ꢀ4
1.46ꢀ10ꢀ3
5.62ꢀ10ꢀ3
1.77ꢀ10ꢀ2
1.50ꢀ10ꢀ2
3.06ꢀ10ꢀ1
3.86
5.57ꢀ10ꢀ4
3.01ꢀ10ꢀ3
9.59ꢀ10ꢀ3
3.33ꢀ10ꢀ2
2.40ꢀ10ꢀ2
4.41ꢀ10ꢀ1
5.56
A
A
A
A
A
A
B
C
D
D
MeTr
Me2Tr
Me3Tr
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
2.00
4.51
7.40
G
G
6.23
1.22ꢀ101
2.15ꢀ102[b]
2.49ꢀ101
3.93ꢀ101
[c]
[c]
R
1.28ꢀ102
–
–
[a] 90AN10W=90:10 (v/v) acetonitrile/water, etc. [b] Reaction was very fast, approximate value. [c] Reaction
was too fast to be measured.
Discussion
Table 8. Ionization rate constants of trityl benzoates in aqueous acetonitrile[a] (258C).
As expected,[25] trityl benzoates
always ionized faster than the
kion [sꢀ1
]
Scenario
90AN10W
80AN20W
60AN40W
50AN50W
corresponding acetates
(cf.
Tr
5.34ꢀ10ꢀ5
2.56ꢀ10ꢀ4
1.26ꢀ10ꢀ3
5.43ꢀ10ꢀ3
4.45ꢀ10ꢀ3
1.61ꢀ10ꢀ1
3.79
1.67ꢀ10ꢀ4
8.08ꢀ10ꢀ4
3.55ꢀ10ꢀ3
1.51ꢀ10ꢀ2
1.30ꢀ10ꢀ2
3.34ꢀ10ꢀ1
6.45
5.14ꢀ10ꢀ4
2.78ꢀ10ꢀ3
1.05ꢀ10ꢀ2
4.55ꢀ10ꢀ2
3.86ꢀ10ꢀ2
6.67ꢀ10ꢀ1
1.12ꢀ101
1.40ꢀ101
6.95ꢀ101
9.99ꢀ10ꢀ4
5.01ꢀ10ꢀ3
1.71ꢀ10ꢀ2
6.97ꢀ10ꢀ2
5.56ꢀ10ꢀ2
9.30ꢀ10ꢀ1
1.38ꢀ101
2.04ꢀ101
1.02ꢀ102
A
A
A
A
A
A
B
Tables 7, 8, and 10). The high
polarity of water caused an in-
crease of ionization rates with
increasing amounts of water in
all solvent mixtures. Whereas
MeTr
Me2Tr
Me3Tr
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ꢀ
ꢀ
ꢀ
Tr OAc, Tr OBz, and Tr PNB
solvolyzed more slowly in aque-
ous acetone than in aqueous
T
5.37
8.35
C
D
T
E
3.36ꢀ101
4.70ꢀ101
[a] 90AN10W=90:10 (v/v) acetonitrile/water, etc.
Chem. Eur. J. 2010, 16, 7469 – 7477
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7473

H. Mayr and M. Horn
ties of s+ parameters in di- and triarylcarbenium ions has
Table 10. Ionization rate constants of several trityl esters in aqueous ace-
tone[a] (258C).
been discussed in detail previously.[27,28]
kion [sꢀ1
]
90A10W
80A20W
60A40W
50A50W
Winstein–Grunwald analysis: The ionizing power Y of a sol-
vent was introduced by Winstein and Grunwald.[30] In Equa-
tion (1) the parameter m is a measure of the sensitivity of
the rate of solvolysis to a change of the solvent; it has often
been used as a criterion for the determination of the mecha-
nism of a solvolysis reaction. Values below 0.5 were consid-
ered as evidence for SN2 reactions, whereas values close to 1
are usually found for typical SN1 reactions.[31]
1.38ꢀ10ꢀ5[c]
3.50ꢀ10ꢀ5[d]
1.49ꢀ10ꢀ3
1.99ꢀ10ꢀ4
2.87ꢀ10ꢀ4
1.08ꢀ10ꢀ2
6.40ꢀ10ꢀ4
6.95ꢀ10ꢀ4
3.25ꢀ10ꢀ2
ꢀ
Tr OAc
–
ꢀ
Tr OBz
9.31ꢀ10ꢀ6
3.63ꢀ10ꢀ4
[b]
ꢀ
Tr PNB
[a] 90A10W=90:10 (v/v) acetone/water, etc. [b] PNB=p-nitrobenzoate.
[c] A rate constant of 1.45ꢀ10ꢀ5 sꢀ1 has been reported in ref. [9]. [d] A
rate constant of 3.33ꢀ10ꢀ5 sꢀ1 has been reported in ref. [24].
acetonitrile when the water portion was low (10 vol%
water), the opposite reactivity order was found in solvents
with a high fraction of water (50 vol%). In line with the
larger dependence of Winstein–Grunwaldꢁs ionizing power
Y (see later) on the percentage of water in aqueous acetone
than in aqueous acetonitrile, the ionization rates of the trityl
esters depend more strongly on the composition of acetone/
water than of acetonitrile/water mixtures.
log kion ¼ log k0 þ mY
ð1Þ
In Figures 8 and 9, ionization rate constants of trityl ace-
tates and benzoates are plotted against the ionizing powers
Y of aqueous acetonitrile.[32] The slopes of the linear correla-
tions represent the m parameters as defined by Equa-
tion (1). It can easily be seen that m decreases with increas-
ing solvolysis rates, that is, with increasing stabilization of
the carbocation. This trend may be explained by a Ham-
mond shift[33] towards the reactants as the exothermicity of
the reactions is increased. The remarkably small m parame-
ters, particularly in the case of donor-substituted systems, in-
dicate non-carbocation-like transition states, which is sup-
ported by the full free-energy diagrams in Figure 11 of the
subsequent paper in this issue.[39] A similar behavior has re-
cently been found for the ionizations of benzhydryl carboxy-
lates.[25] The fact that the ionization rates of trityl benzoates
Hammett analysis: The Hammett–Brown parameters spþ
were designed for reactions with a positively-charged center
developing at a position which is in conjugation with the
substituents under consideration.[26] Figure 7 shows that the
Figure 7. Plot of logkion versus Sspþ for ionizations of substituted trityl
acetates in 90:10 (v/v) acetonitrile/water, 258C; the line is drawn through
filled circles, logkion =ꢀ1.99 Ssþp ꢀ4.80, R2 =0.9995; spþ =0 (H), ꢀ0.31 (p-
Me), ꢀ0.78 (p-OMe), and ꢀ1.70 (p-NMe2) from reference [29].
three symmetrical systems Tr, Me3Tr, and (MeO)3Tr, corre-
late perfectly linearly with Ssþp, and deviations from the cor-
relation line are most significant for systems which are un-
symmetrically substituted with strong electron-donating
groups. The small value of the reaction constant (1=ꢀ1.99)
is due to the propeller-like arrangement of the phenyl rings,
which inhibits full conjugation of the carbocationic center
with all three aryl rings. Most significantly, tritylium ions
containing one or two dimethylamino groups deviate posi-
tively from the correlation line. The problem of the additivi-
Figure 8. Plot of logkion of trityl acetates versus ionizing powers Y of
aqueous acetonitrile, 258C; Y=ꢀ1.23 (90AN10W), ꢀ0.14 (80AN20W),
1.00 (60AN40W) and 1.50 (50AN50W) from ref. [32].
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Trityl Ester Hydrolyses
FULL PAPER
Figure 11. Plot of logkion of trityl esters versus Y of aqueous acetone,
258C; Y=ꢀ1.856 (90A10W), ꢀ0.673 (80A20W), 0.796 (60A40W), and
1.398 (50A50W) from reference [34].
Rate-equilibrium relationships: Intuitively, one would
expect a good correlation between the ionization rates of
trityl esters and the stabilities of the corresponding tritylium
ions in aqueous solution, pKR+. Such a correlation has been
reported for solvolyses of benzhydryl chlorides by Deno.[35]
As can be seen in Figure 12, there are two separate corre-
lation lines between logkion and pKR+, one for the methyl-
and methoxy-substituted compounds, and one for the dime-
thylamino-substituted systems. From the slope of the corre-
lation for the methyl- and methoxy-substituted compounds
(0.62) one might infer that more than half of the carbocation
character is developed in the solvolysis transition states.
Consideration of the full data set shows, however, that this
conclusion is too simplistic. Although (MeO)3Tr + and
(Me2N)Tr+ differ by a factor of 1.1ꢀ103 in their thermody-
namic stabilities in water (from pKR+), the ionization rates
of the corresponding carboxylates are almost identical. The
unexpected low reactivities of the dimethylamino-substitut-
ed trityl derivatives indicate that the product-stabilizing res-
onance of the amino group develops late on the reaction co-
ordinate, and contributes only slightly to the stabilization of
Figure 9. Plot of logkion of trityl benzoates versus ionizing powers Y of
aqueous acetonitrile, 258C.
are generally less sensitive to solvent polarity than those of
trityl acetates may also be attributed to earlier transition
states of the benzoate hydrolyses.
Figure 10 shows that the m value of triphenylmethyl p-ni-
trobenzoate is considerably smaller than that of the corre-
sponding benzoate, which seems to exclude the rationaliza-
tion of the different m parameters by steric arguments, but
supports an explanation by electronic effects. However, be-
cause trityl p-nitrobenzoates and benzoates have similar m
values in aqueous acetone, much smaller than trityl acetates
(Figure 11), an unambiguous rationalization for the absolute
magnitude of the m values appears not to be possible.
Figure 10. Plot of logkion of trityl esters versus ionizing powers Y of aque-
ous acetonitrile, 258C.
Figure 12. Plot of logkion for trityl acetates in 90:10 (v/v) acetonitrile/
water, 258C, versus pKR+
.
Chem. Eur. J. 2010, 16, 7469 – 7477
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7475

H. Mayr and M. Horn
the transition state. This is another example of Bernasconiꢁs
“Principle of Non-Perfect Synchronization”,[36] and empha-
sizes the role of intrinsic barriers for these reactions.
Conclusion
Hydrolyses of donor-substituted tritylium carboxylates in
aqueous acetonitrile and acetone cover a wide mechanistic
spectrum: from conventional SN1 reactions with slow ioniza-
tion and rapid trapping of the intermediate carbocations by
water, through reactions in which the carbocations can be
observed by the appearance and disappearance of color
(carbocation watching),[37] to reactions where the carboca-
tions are formed as persistent species. From the small Win-
stein m values one can derive non-carbocation-like transi-
tion states despite the fact that we are dealing with well-de-
fined ionization processes.
Most important for the use of tritylium ions as tailor-
made protecting groups in organic syntheses is the finding
that the well-known thermodynamic stability parameters
pKR+ cannot be used to predict kinetic stability and the ease
of deprotection of strongly donor-substituted derivatives.
While the relative hydrolysis rates of methyl- and methoxy-
substituted tritylium esters correlate well with pKR+, the ex-
pected further acceleration from the trimethoxy- to the di-
methylamino-substituted system is not observed. The p-(di-
methylamino)trityl protecting group is released at almost
the same rate as the tri-p-methoxytrityl group, although the
latter tritylium ion is less stabilized by a factor of 1.1ꢀ103 in
aqueous solution. According to Scheme 2, a correlation
exists between the reaction times t99 for 99% ionization of
trityl acetates and the semiquantitative reaction times re-
ported for complete detritylations of 5’-O-trityluridines
(turidine).[6a]
Because Tables 7 and 8 provide a quantitative comparison
of the ionization rates of all p-methyl- and methoxy-substi-
tuted trityl systems, it is now possible to fine-tune the stabil-
ities of trityl-protected OH and NH functionalities. We are
currently extending our investigations on the nucleofugali-
ties of various O-, N-, and S-centered leaving groups,[38]
which will be combined with the data of the present investi-
gation in order to provide absolute lifetimes for differently
substituted trityl ethers, esters, and amides in solvents of dif-
ferent ionizing powers. A quantitative basis for the use of
tritylium ions as protecting groups in bioorganic chemistry is
thus emerging.
Scheme 2. Detritylation times for acetates and uridines. [a] Relative rate
constants for the ionizations of acetates in 50:50 (v/v) acetonitrile/water,
258C. [b] Time for 99% ionization of trityl acetate in 50:50 (v/v) acetoni-
trile/water at 258C. [c] Time for “complete” hydrolysis of 5’-protected ur-
idine derivatives in 80% AcOH at RT, from reference [6a].
procedures (see Supporting Information). All synthesized compounds
1
were characterized by H and 13C NMR spectroscopy and melting points.
Kinetics: Typically, each run was repeated at least once, the reported rate
being the arithmetic mean. The error was usually less than 3%. The tem-
perature in all runs was kept constant at 258C using a circulating water
bath. For conductimetry, reactions with half-times >10 s were followed
by conventional conductimetry using a Tacussel CD810 or a Radiometer
MeterLab CDM230, both instruments being equipped with Pt electrodes.
Reactions with half-times <10 s were followed by a Hi-Tech Scientific
SF-61 DX2 stopped-flow device (cell volume 21 mL, Pt electrodes), con-
trolled by the Hi-Tech KinetAsyst3 software. Initial concentrations of
substrates were between 10ꢀ4 and 10ꢀ3 molLꢀ1, and 5 to 15 equivalents of
triethylamine were used as additive. In the case of tri(p-methoxy)trityl
ester solvolyses, 16 to 18 equivalents of piperidine were added. For pho-
tospectrometry, an Applied Photophysics SX.18MV-R stopped-flow reac-
tor was used. Initial concentrations of substrates were between 10ꢀ5 to
10ꢀ4 molLꢀ1
.
Experimental Section
Acknowledgements
Chemicals: Acetonitrile (VWR, ꢂ99.9%), acetone (VWR, ꢂ99.8%),
tetra-n-butylammonium acetate (Fluka, ꢂ99%) and tetra-n-butylammo-
nium benzoate (Fluka, ꢂ99%) were used as purchased. Water was puri-
fied by using a Millipore MilliQ (final specific resistance ꢂ18.2 MWcm).
Trityl alcohols and tritylium tetrafluoroborates, as well as trityl acetate,
benzoate, and p-nitrobenzoate, were synthesized according to standard
We thank Dr. Armin Ofial for help during the preparation of this manu-
script. Financial support by the Deutsche Forschungsgemeinschaft (Ma
673/20-3) and the Fonds der Chemischen Industrie is gratefully acknowl-
edged.
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Trityl Ester Hydrolyses
FULL PAPER
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Received: September 28, 2009
Revised: February 24, 2010
Published online: June 16, 2010
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7477