Kinetics of the solvolyses of fluoro-substituted benzhydryl derivatives: Reference electrofuges for the development of a comprehensive nucleofugality scale

Article abstract of DOI:10.1002/ejoc.200901400

A series of m-fluoro-substituted benzhydryl chloridcjs, bromides, mesylates and Losylates 1-X to 5-X were prepared and subjected to solvolysis reactions in various solvents. The observed first-order rate constants k_s(25 °C) were found to follow the correlation equation log k_s(25 °C) = S_f(N_f + E_f), which allowed us to determine the electrofugalily parameters E_f for these destabilized benzhydrylium cations and the nucleofugality parameters N_f, S _f for a series of leaving group/ solvent combinations.

Full text of DOI:10.1002/ejoc.200901400

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901400
Kinetics of the Solvolyses of Fluoro-Substituted Benzhydryl Derivatives:
Reference Electrofuges for the Development of a Comprehensive Nucleofugality
Scale
Christoph Nolte[a] and Herbert Mayr*[a]
Keywords: Carbocations / Kinetics / Nucleophilic substitution / Linear free relationships / Solvent effects
A series of m-fluoro-substituted benzhydryl chlorides, bro-
mides, mesylates, and tosylates 1-X to 5-X were prepared
and subjected to solvolysis reactions in various solvents. The
observed first-order rate constants ks(25 °C) were found to
follow the correlation equation logks(25 °C) = sf(Nf + Ef),
which allowed us to determine the electrofugality param-
eters Ef for these destabilized benzhydrylium cations and the
nucleofugality parameters Nf, sf for a series of leaving group/
solvent combinations.
Introduction
The stabilization of benzhydryl cations (diarylcarbenium
ions)[1] can be modified widely by variation of substituents
in p- and m-position, while the steric shielding of the carbo-
cation center is kept constant. For that reason, benzhy-
drylium ions have not only been used to construct the most
comprehensive nucleophilicity scale presently available,[2]
but also for the development of a nucleofugality scale.[3] In
order to compare the leaving group abilities of tosylate and
bromide in solvents of high ionizing power, we had studied
the solvolyses of mono- to tetra(m-chloro)-substituted
benzhydrylium derivatives.[3a,3b] However, as mentioned in
a previous report,[3a] several researchers were suffering from
severe skin irritations when working in a laboratory where
these compounds were used. For that reason we had to
abandon the m-chloro-substituted compounds as references
and replace them by the corresponding fluoro derivatives 1-
X to 4-X with one to four m-fluoro substituents (Scheme 1).
The highly electrophilic benzhydrylium ions generated
from these precursors have recently been employed to study
the fastest bimolecular reactions in the electronic ground
state we are aware of, i.e., the reaction of 4+ with methanol,
which proceeds with a reaction time of 2.6 ps, correspond-
ing to a time in which light propagates less than 1 mm.[4]
We now report on the synthesis and characterization of
compounds 1-X to 5-X and the kinetics of their solvolysis
reactions in order to determine the electrofugality param-
eters of 1+–4+.
Scheme 1. Benzhydrylium derivatives employed in this study.
Results and Discussion
Synthesis of the Precursors
The fluoro-substituted benzhydrols (1–3)-OH and 5-OH
were synthesized by the reactions of the fluorinated phenyl-
magnesium bromides with fluorinated benzaldehydes
(Table 1) as described in detail in the Supporting Infor-
mation. For the synthesis of the symmetrical tetrafluoro-
substituted benzhydrol 4-OH, 3,5-difluorophenylmagne-
sium bromide was combined with 0.5 equiv. of ethyl for-
mate.
Table 1. Synthesis of the fluoro substituted benzhydrols (1–5)-OH.
Product
Grignard reagent
Aldehyde reagent
1-OH
2-OH
3-OH
4-OH
5-OH
PhMgBr
(3-FC6H4)CHO
(3-FC6H4)CHO
(3-FC6H4)CHO
0.5 HC(O)(OEt)
PhCHO
(3-FC6H4)MgBr
(3,5-F2C6H3)MgBr
(3,5-F2C6H3)MgBr
(3,5-F2C6H3)MgBr
[a] Department Chemie, Ludwig-Maximilians-Universität
München
Standard reagents (SOCl2, PBr3) were used to convert
the benzhydrols (1–5)-OH into the benzhydryl chlorides (1–
2)-Cl and benzhydryl bromides (1–5)-Br. Attempts to con-
vert the benzhydrols (1–4)-OH to the corresponding tosyl-
Butenandtstrasse 5-13 (Haus F), 81377 München, Germany
Fax: +49-89-218077717
E-mail: herbert.mayr@cup.uni-muenchen.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901400.
Eur. J. Org. Chem. 2010, 1435–1439
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C. Nolte, H. Mayr
SHORT COMMUNICATION
ates with p-toluenesulfonyl chloride/pyridine, p-toluenesul- Table 2. Solvolysis rate constants (25 °C) of the benzhydryl deriva-
tives (1–5)-X in different solvents.
fonyl anhydride/triethylamine, or p-toluenesulfonyl anhy-
dride/sodium hydride were unsuccessful.[5] Therefore, the
benzhydryl tosylates (1–4)-OTs were synthesized according
to a procedure by Cheeseman and Poller[6] by treatment of
Solvent[a]
X
Electrofuge
ks [s–1]
90A10W
TsO
1
1.16ϫ10–2
4.24ϫ10–4
5.59ϫ10–2[b]
2.42ϫ10–3
1.10ϫ10–4
3.87ϫ10–2
1.37ϫ10–3
5.92ϫ10–5
1.47ϫ10–3
1.59ϫ10–4
2.14[b]
2
the corresponding benzhydryl bromides (1–4)-Br with silver 80A20W
tosylate in dichloromethane. The benzhydryl mesylates (1–
TsO
1
2
3
4)-OMs were synthesized in the same manner by treatment
of the corresponding benzhydryl bromides with silver mes-
ylate. Only the tetrafluorinated benzhydryl mesylate 4-OMs
was obtained as a pure solid. The other mesylates (1–3)-
OMs could not be isolated as pure substances and were
obtained as yellowish oils that could neither be distilled nor
80A20W
OMs
1
2
3
60A40W
50A50W
60AN40W
Br
Br
OTs
1
2
1
2
9.53ϫ10–2
4.26ϫ10–3
1.45ϫ10–4
4.82ϫ10–2
2.52ϫ10–3
8.04ϫ10–5
4.57[b]
brought to crystallization. Nevertheless, it was possible to
investigate their solvolysis reactions by using diluted solu-
3
4
tions, in analogy to a procedure by Bentley.[7] The benzhy-
dryl sulfonates used in this study are sensitive to moisture,
and great care has to be taken to exclude traces of moisture
during synthesis and handling of these compounds.
60AN40W
60AN40W
OMs
Br
2
3
4
4-Me[c]
H[d]
1
1.44ϫ10–1[b]
4.59ϫ10–3
1.18ϫ10–4
1.59ϫ10–4
2.67ϫ10–4
8.22ϫ10–2
3.35ϫ10–3
1.88ϫ10–4
4.34ϫ10–2
1.70ϫ10–3
9.12ϫ10–5
4.07ϫ10–2
1.94ϫ10–3
8.15ϫ10–5
3.37ϫ10–2
1.35ϫ10–3
5.27ϫ10–5
9.47ϫ10–4
2.30ϫ10–5
3.98ϫ10–5
8.33ϫ10–1
2.07ϫ10–2
1.13ϫ10–3
5.51ϫ10–5
5.75ϫ10–4
1.90ϫ10–4
7.99ϫ10–2
1.73ϫ10–3
9.21ϫ10–2
1.78ϫ10–3
7.27ϫ10–2
1.49ϫ10–3
2.36ϫ10–3
2.54ϫ10–5
2.10ϫ10–2
3.87ϫ10–4
2
5
Kinetics
60AN40W
100E
Cl
OTs
1
1
When compounds (1–5)-X were dissolved in aqueous or
alcoholic media, an increase of conductivity due to the gen-
eration of HX was observed. Because calibration experi-
ments showed a proportionality between conductivity (G)
and the concentration of HX in the concentration range
investigated, the observed monoexponential increase of
conductivity (G) [Equation (1)] indicated the operation of a
first-order rate law.
2
3
100E
OMs
OTs
OMs
Br
1
2
3
80E20W
80E20W
80E20W
100M
2
3
4
2
3
G = Gϱ(1 – e–k t) + C
(1)
s
4
1
The first-order rate constants ks were obtained by fitting
the time-dependent conductivities G to the monoexponen-
tial function (1). Because all solvolyses studied in this work
follow first-order rate laws, common-ion return[8] (k–1 in
Scheme 2) obviously does not occur, and the ks values listed
in Table 2 correspond to the ionization rate constants k1
defined in Scheme 2.
2
5
OTs
1
2
3
4
100M
80M20W
100TFE
Br
Br
OTs
1
2
3
4
100TFE
100TFE
OMs
Br
3
4
1
Scheme 2. Simplified solvolysis scheme.
2
5
The Eyring and Arrhenius activation energies were deter-
mined for 1-Br and 3-OTs in 80E20W as representative sys-
tems (Table 3). Both compounds exhibit activation param-
eters, which are typical for solvolysis reactions.[3,9]
3
100TFE
Cl
1
2
[a] Mixtures of solvents are given as (v/v); solvents: A = acetone,
AN = MeCN, E = ethanol, M = methanol, TFE = 2,2,2-trifluoro-
ethanol, W = water. [b] Stopped-flow kinetics. [c] 4-Methylbenz-
hydryl. [d] Benzhydryl.
Correlation Analysis
In previous work we have demonstrated that Equa-
tion (2) can be used to correlate solvolysis rates of sub-
strates, which differ widely in reactivity.[3] In this equation,
carbocations are characterized by the electrofugality pa-
rameter Ef, while the nucleofuge-specific parameters Nf and
sf refer to combinations of leaving groups and solvents.
logks(25 °C) = sf(Nf + Ef)
(2)
sf, Nf: nucleofuge-specific parameters
Ef: electrofuge-specific parameter
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Eur. J. Org. Chem. 2010, 1435–1439

Kinetics of the Solvolyses of Fluoro Substituted Benzhydryl Derivatives
Table 3. Activation parameters for the solvolyses of 1-Br and 3-OTs
in 80E20W.
1-Br
3-OTs
∆H‡ [kJmol–1]
∆S‡ [Jmol–1 K–1]
Ea [kJmol–1]
lgA
84.2Ϯ0.7
–20.2Ϯ2.4
86.6Ϯ2.4
12.2Ϯ0.1
79.8Ϯ0.8
–28.9Ϯ2.7
82.2Ϯ0.8
11.7Ϯ0.1
The solvolysis rate constants ks in Table 2 and previously
reported solvolysis rate constants for benzhydryl derivatives
were subjected to a least-squares minimization according to
Equation (3), where Ef for (4-MeOC6H4)2CH+ was set to
0.00, and sf for the leaving group/solvent combination chlo-
ride/ethanol was set to 1.00.
∑∆2 = ∑(logks – logkcalcd.)2 = ∑[logks – sf(Nf + Ef)]2
(3)
Minimization of the deviation between calculated and ex-
perimental rate constants, i.e., ∑∆2 as defined by Equa-
tion (3), yielded the electrofugality parameters for the benz-
hydrylium ions 1+–4+ (Table 4) and the nucleofuge-specific
parameters Nf/sf for OTs, OMs, and Br in solvents of high
ionizing power (Table 5).
Table 4. Electrofugality (Ef) parameters of fluoro-substituted benz-
hydryl cations.
Benzhydryl cation
Substituents
Ef
1
2
3
4
3-fluoro
–7.53
–9.25
–10.88
–12.60
3,3Ј-difluoro
3,3Ј,5-trifluoro
3,3Ј,5,5Ј-tetrafluoro
Table 5. Nucleofugality parameters Nf /sf for leaving groups X in
various solvents.
Solvent
X = OTs
9.73/0.94[a]
OMs
Br
TFE
9.84/1.00[b]
7.69/0.83
7.48/0.82
–
5.81/0.80
5.85/0.84
–
6.19/0.95[a]
5.23/0.99
60AN40W
80E20W
100M
100E
80A20W
90A10W
7.97/0.82
7.44/0.80[a]
7.33/0.82
4.36/0.95[a]
4.23/0.99[a]
6.08/0.78[a]
5.99/0.83[a]
5.38/0.89[a]
[c]
[c]
[c]
Figure 1. Plot of logks for the solvolysis reaction of various substi-
tuted benzhydryl derivatives vs. electrofugality Ef: (a) bromides, (b)
tosylates, (c) mesylates. Data points with filling were taken from
Table 2, data points without filling were taken from previously pub-
lished data.[3a,3b] Mixtures of solvents are given as (v/v); solvents:
A = acetone, AN = MeCN, E = ethanol, M = methanol, TFE =
2,2,2-trifluoroethanol, W = water.
[a] These parameters revise previously published values from ref.[3a]
[b] Solvolyis data not included into the total correlation as only
two rate constants were available for this leaving group/solvent sys-
tem. [c] See ref.[3a]
Figure 1 illustrates the high quality of these correlations
for benzhydryl bromides (a), tosylates (b) and mesylates (c).
Some of the nucleofuge-specific parameters Nf/sf in nicely with the experimental values of 2.97ϫ10–5 s–1 and
Table 5 have previously been reported. The small deviation 1.74ϫ10–6 s–1, respectively, reported by Nishida.[10b] The
of the new parameters, which are based on a larger set of closely similar nucleofugalities of TsO and MsO in different
experimental data, confirms the solidity of the previously solvents is in line with the previously reported similar mag-
reported set of nucleofugality parameters.[3a,3b] From the nitude of the leaving-group abilities of these two sulfonate
electrofugality parameters in Table 4 and the nucleofugality groups.[7] The slightly lower nucleofugality of mesylate can
parameters for Cl– in MeOH (Nf = 2.95, sf = 0.98)[3a] and be explained by the better delocalization of negative charge
EtOH (Nf = 1.87, sf = 1.00)[3a] one can calculate the meth- by tosylate. Depending on the solvent, the nucleofugality of
anolysis rate constant for 1-Cl (3.18ϫ10–5 s–1) and the eth- bromide is 2.5–3.8 orders of magnitude smaller than that
anolysis rate constant for 1-Cl (2.14ϫ10–6 s–1), which agree of TsO or MsO.
Eur. J. Org. Chem. 2010, 1435–1439
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C. Nolte, H. Mayr
SHORT COMMUNICATION
In line with the similar magnitude of Hammett’s σm con- tuted benzhydryl cations 1+–4+ are suggested to replace the
stants for Cl (0.37) and F (0.34),[11] the m-fluoro-substituted skin-irritating chloro-substituted analogues as references in
benzhydrylium ions 1+–4+ have similar electrofugalities as the high electrophilicity and low electrofugality range for
the corresponding chloro-substituted benzhydrylium quantifying weak nucleophiles and strong nucleofuges,
ions.[3a] Remarkable is the almost constant increment of respectively.
–1.7 per m-F substituent on the electrofugality Ef of the
benzhydrylium ions (Table 4). In accord with this observa-
Experimental Section
tion, Figure 2 shows a linear correlation between Ef and ∑σ
with a slope of –4.91, which corresponds to Hammett ρ
values from –4.06 to –5.08 for reaction series with 0.78 Ͻ sf
Ͻ 0.99 (Table 5). From the three different rate constants for
the reaction of 5-Br in TFE, 60AN40W and 80E20W an elec-
trofugality of Ef = –9.00 was calculated. The almost iden-
tical Ef values of the symmetrical (2) and unsymmetrical
difluoro-substituted system (5) also illustrates the additivity
of substituent effects. This behavior contrasts that of donor
Benzhydryl Derivatives: Syntheses and characterization of the sub-
strates (1–5)-X are described in the Supporting Information.
Kinetics: Hydrolysis or alcoholysis of the benzhydryl derivatives (1–
5)-X with X = Cl, Br, OMs, OTs led to the formation of the benzhy-
drols [(1–5)-OH] or benzhydryl ethers (1–5-OR) along with the
strong acids HX. The generation of HX resulted in an increase of
conductivity. Calibration experiments for two representative sys-
tems showed that the initial concentration of benzhydryl bromide
substituents, where a levelling effect is observed,[10e,12] i.e., or tosylate correlates linearly with the final conductance, in agree-
ment with previous results. Therefore, the solvolysis rate constants
can be determined reliably by conductimetry. Most reactions were
monitored with a conventional conductimeter. The temperature of
the solutions during all kinetic studies was kept constant at 25.0 °C
(Ϯ0.1 °C) by using a circulating bath thermostat. Fast solvolysis
reactions, e.g., solvolysis of 1-OTs in 80% aqueous acetone, have
been measured in a stopped-flow conductometer by mixing 1 equiv.
of the benzhydryl derivative in acetone or MeCN with 10 equiv.
of aq. acetone or MeCN to give solvent mixtures of the desired
composition. Details of the kinetic measurements are given in the
Supporting Information.
the second electron-donor group has generally a smaller
cation-stabilizing effect than the first donor group. From
the observation that replacement of one H by F has a sim-
ilar effect in the comparison 3+ Ǟ 4+ as in the comparison
Ph2CH+ Ǟ 1+ one may conclude that nonadditivity of sub-
stituent effects in benzhydrylium systems is specific for sub-
stituents with +M effects.[10] The unsymmetrical difluoro-
substituted system 5, which exhibits a similar reactivity as
the symmetrical difluoro-substituted system 2, was not in-
cluded into the series of reference electrofuges.
Supporting Information (see footnote on the first page of this arti-
cle): Preparative procedures, product characterization, details of the
kinetic experiments.
Acknowledgments
We thank Dipl.-Ing. Johannes Ammer for assistance during the
preparation of the manuscript and the Deutsche Forschungsge-
meinschaft (Ma673/20-3) for financial support.
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hydrylium ions (Table 4) with Hammett σ constants (from ref.[11]).
Conclusions
The solvolyses of the fluoro-substituted benzhydryl bro-
mides, tosylates and mesylates (1–5)-X in various aqueous
and alcoholic solutions follow first-order kinetics with rate-
determining ionization and no common-ion return.[8] All
rate constants follow the correlation logks = sf(Nf + Ef)
[Equation (2)], which confirms previously reported nucleo-
fugality parameters Nf, sf for bromide and tosylate in vari-
ous solvents and allows to determine nucleofugalities for
mesylate as well as electrofugalities Ef of the fluoro-substi-
tuted benzhydrylium ions 1+–5+. The fluorine effects are
roughly additive, and the solvolysis rates are retarded by a
factor of 18 to 59 per m-fluorine. Because the Ef values of
1+–4+ (Table 4) are similar to those of the corresponding
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Received: December 2, 2009
Published Online: February 4, 2010
Eur. J. Org. Chem. 2010, 1435–1439
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