Prototropic processes in benzaurins. 19F and 1H NMR spectra of fluoro- and methylsubstituted 4-hydroxyphenyl-diphenylcarbinols, related fuchsones and benzaurins

Article abstract of DOI:10.2478/s11532-011-0003-0

Tautomerism of benzaurins and hydration are studied. ¹H and ¹⁹F chemical shifts have been determined for a number of substituted 4-hydroxyphenyl-diphenyl carbinols containing fluorine in a 3-, 3*- or 4*-position, and for similar comp

Full text of DOI:10.2478/s11532-011-0003-0

Cent. Eur. J. Chem. • 9(2) • 2011 • 253-264
DOI: 10.2478/s11532-011-0003-0
Central European Journal of Chemistry
Prototropic processes in benzaurins. 19F and 1H
NMR spectra of fluoro- and methylsubstituted
4-hydroxyphenyl-diphenylcarbinols, related
fuchsones and benzaurins
Research Article
Poul Erik Hansen1*, Alexsander S. Peregudov2*, Dimitrii N. Kravtsov2#,
Antonina I. Krylova2, Galina M. Babakhina2, Ludmila S. Golovchenko2#,
Valentina M. Pachevskaya
1Department of Science, Systems and Models, Roskilde University,
P.O. Box 260, DK-4000 Roskilde, Denmark
2A.N. Nesmeyanov Institute of Organo-Element Compounds,
Russian Academy of Science, 117813 Moscow, Russia
Received 19 May 2010; Accepted 20 December 2010
1H and 19F chemical shifts have been determined for a number of
Abstract:
Tautomerism of benzaurins and hydration are studied.
substituted 4-hydroxyphenyl-diphenyl carbinols containing fluorine in a 3-, 3*- or 4*-position, and for similar compounds
containing additional methyl groups in a position of 3, 3** or 4**. The same data have been obtained for the fuchsones prepared by
dehydration of the above carbinols. On this basis chemical shifts of fluorine in different positions have been evaluated as a monitor of the
transformation of 4-hydroxyphenyl group to the semiquinone moiety. The 19F NMR can be used to monitor the transformation of 4**-
fluorobenzaurinandtherelated3,3*-disubstitutedand3,3*,5,5*-tetramethylsubstitutedcompoundstothecorrespondingcarbinolsduetothe
addition of a water molecule and to study the tautomerism of the two latter benzaurins as well as that of 3,3*,4**trifluorobenzaurin.
Furthermore, fluorine and methyl group chemical shifts are sensitive to syn-anti-isomerism in substituted fuchsones.
The prototropic process of these compounds may be slow or fast on a 1H NMR time scale depending on the solvent and may be
catalyzed by water or carbonic acids. On the basis of kinetic and thermodynamic data obtained by dynamic NMR studies, a mechanism
for the process has been proposed.
Keywords: 19F NMR • Prototropic tautomerism • Syn-anti isomerism • Fluoro- and methyl substituted benzaurins • Fuchsones
© Versita Sp. z o.o.
atoms in the potential with two wells, [4-10] or the
mesomeric structure arising due to the presence of only
one well [11,12]. Examples of prototropic transfer for
1. Introduction
Prototropic tautomerism as illustrated below has attracted
much attention for intermolecular [1-3], but especially for
intramolecular cases [4-14]. In the latter category
other systems with the oxygen atoms as cation accepting
centres are nitrone-hydroxylamine tautomerism in the
methyl ester of N-hydroxyindolecarbonic acid [13] and
the enol forms the tautomerism of 3-hydroxyflavone [14].
of β-dicarbonyl compounds (X=O) [4-14] may serve as
Investigations of the prototropic tautomerism in
a model for the intermolecular case studied herein. The systems involving remote cation accepting oxygen atoms
prototropic transitions in these systems proceed at high (intermolecular exchange) are more rare. Tautomerism of
rates because the oxygen atoms are sterically drawn nitrone-hydroxylamine type in 4-hydroxypyrimidine oxide
together, and the geometry of the six-membered chelate [15] and nitroso-oxime tautomerism in 4-nitrosophenol
ring is optimal for the formation of the intramolecular and related substituted compounds were based on
hydrogen bond. It should be noted that in the literature NMR evidence. A quantitative investigation of the proton
the possible structure of these compounds is discussed transfer rate in these non-degenerated tautomeric
as a fast migration of the proton between the two oxygen systems was not conducted [16,17].
* E-mail: poulerik@ruc.dk
# Deceased: The paper is dedicated to the memory of Professors D.N. Kravtsov, L.S. Golovchenko and E.V. Borisov
253

Prototropic processes in benzaurins. 19F and 1H NMR spectra
of fluoro- and methylsubstituted 4-hydroxyphenyl-
diphenylcarbinols, related fuchsones and benzaurins
Thesocalleddegeneratesystems(Zisthesymmetric fuchsones
(4-diphenylmethylene-2,5-cyclohexadien-
framework of the tautomeric system) are most suitable 1-ones) (Scheme 1) containing fluorine or methyl
for the investigation of the influence of different outer and group tags in appropriate positions are used as model
inner structural factors on the mechanism of tautomeric compounds .
transformations. Degenerate systems can be studied by
NMR. The use of isotopic perturbation of equilibrium is
2. Experimental Procedure
well demonstrated for intramolecularly hydrogen bonded
systems [18-20]. NMR has in general the advantage of
having a number of reporter atoms which makes it useful 2.1 Compounds
in the study of degenerate systems. Furthermore, NMR The hydroxyphenyl carbinols 1, 3, 5, 7, 9, 11,
studies allow a broad range of solvents to be used, and 13 were obtained by the reactions of substituted
the effects of water addition can easily be monitored 4-hydroxybenzophenones with the corresponding
as well.
arylmagnesium bromides. Fuchsones 2, 4, 6, 8,
In literature there are two examples of such 10, 12, 14 were obtained by the dehydration of
degenerated tautomeric systems, the structures of the corresponding substituted 4-hydroxyphenyl-
which are discussed on the basis of NMR data. The first diphenylcarbinols.
3,3*,5,5*-tetramethyl-4**-
fluorobenzaurin (15), 3,3*-dimethyl-4**-fluorobenzaurin
(16) and 4**-fluorobenzaurin (18) have been
prepared by condensation 4-fluorobenzotrichloride
with 2,6-dimethylphenol, 2-methylphenol and phenol,
respectively.3,3*,4**-trifluorobenzaurin(17)wasobtained
by the reaction of 4-fluorophenylmagnesium bromide
with 3,3*-difluoro-4,4*-dihydroxybenzophenone.
example is hydrogalvinoxyl:
Me3C
CMe3
O
HO
C
Me3C
CMe3
The typical methods of synthesis of the obtained
In aqueous acetone-d6 or in aqueous DMSO-d6 compounds are presented below.
1
dynamic changes in the H and 13C NMR spectra with
Diphenyl-(3-fluoro-4-hydroxyphenyl)-carbinol
changes in the concentration of all three components (1): To the solution of Grignard reagent prepared from
of the mixture – hydrogalvinoxyl, solvent and water 10.16 g (0.065 M) of PhBr and 1.56 g (0.066 GA) of
were observed [21]. The authors have interpreted these Mg in 50 mL of absolute THF and stirred in the argon
results due to cluster formation (for a more detailed current the solution of 3.5 g (0.016 M) of 3-fluoro-4-
discussion see below) [21]. Another example is ethyl hydroxybenzophenone in 15 mL of the same solvent
ester of 3*,3**,5*,5**-tetrabromophenolphtalein [22].
was added. The same solvent was added absolute
Benzaurins represent prototropic systems with THF and stirred in the argon current the solution of
remote cation-accepting centers. This type of benzaurin 3.5 g (0.016 M) of 3-fluoro-4-hydroxybenzophenone
tautomerism can be studied by the NMR technique in15mLofAfterhavingbeenboiledandstirredfor5hours,
provided that reference data are available. In order to the reaction mixture was cooled to room temperature
facilitate the detection of tautomerism reporter groups and
are introduced into benzaurins at the 3,3* and 4** of NH4Cl . The organic layer was separated, washed
positions (Fig. 1).
with water and dried over Na2SO4. The yellow viscous
decomposed with a 5% aqueous solution
The substituents in positions 3 and 3* are necessary substance which remained after the distillation of
to monitor the prototropic process in the framework of a the solvent was dissolved in a 5% aqueous NaOH
simple two-site exchange, whereas the indicator in the solution, filtered and precipitated with a 5% aqueous
position 4** will help to detect a possible transformation solution of NH4Cl. This procedure was repeated twice.
of substituted benzaurins to substituted bis-(4- The precipitate was washed with water and dried over
hydroxyphenyl)-phenylcarbinols as a result of addition Na2SO4. 1.77 g (37%) of (1) was obtained as a yellow
of a H2O molecule [24]. Substitutents in these positions solid. M.p. 126-1280C. C19H15FO2 (MW 294): calcd. C
have only a small steric effect.
77.55, H 5.10, F 6.46; found C 76.75, H 5.36, F 5.92.
Fluorine atoms or the methyl group are used as
( 3 - F l u o r o p h e n y l ) - ( 4 - h y d r o x y p h e n y l ) -
indicators [25,26], whereas the CF3-group seems less phenylcarbinol (3) was obtained from PhMgBr and 3*-
suitable due to the lower synthetic accessibility of the fluoro-4-hydroxybenzophenone using a similar method
corresponding model compounds.
with a 96% yield as a dark yellow solid. M.p. 125 -
In the present investigation 4-hydroxyphenyl- 127 0C. C19H15FO2 (MW 294): calcd. C 77.55, H 5.10, F
diphenylcarbinols and corresponding substituted 6.46; found C 77.45, H 5.38, F 5.39.
254

P. E. Hansen et al.
4**
3 **
2**
1
**
C
OH
O
HO
C
O
4
4
*
*
1
1
2
3
2
*
3
*
benzaurin
4**
3 **
2 **
1
**
C
O
4
1
4
*
*
1
3
2
*
2
3
*
fuchsone
Figure 1. Tautomeric scheme and numbering of compounds
F
F
H2O
HO
C
OH
HO
C
O
OH
X
X
X
X
X=CH3 16; X=F 17 and X=H 18
Figure 2. Water addition
( 4 - F l u o r o p h e n y l ) - ( 4 - h y d r o x y p h e n y l ) - fluoro-3-methyl-4-hydroxybenzophenone using a similar
phenylcarbinol (5) was obtained from PhMgBr and 4*- method with a 97% yield as an yellow solid. M.p. 68 –
fluoro-4-hydroxybenzophenone using a similar method 780C. C20H17FO2 (MW 308): calcd. C 77.92, H 5.52, F
1
with a 72% yield as an orange solid. M.p.110 - 1120C. 6.17; found C 77.45, H 5.38, F 5.39. H NMR (C6D6):
C19H15FO2 (MW 294): calcd. C 77.55, H 5.10, F 6.46; 2.17, 3H.
found C 77.57, H 5.51, F 6.24.
(4-Fluorophenyl)-(4-hydroxyphenyl)-(3-
(4-fluorophenyl)-(3-fluoro-4-hydroxyphenyl)- methylphenyl)-carbinol (11) was obtained from
phenylcarbinol (7) was obtained from PhMgBr and 3-CH3C6H4MgBr and 4*-fluoro-4-hydroxybenzophenone
3,4*-difluoro-4-hydroxybenzophenone using a similar using a similar method with a 84% yield as a pale yellow
0
method with a 21% yield as an orange solid. M.p. 113 - solid. M.p. 130 –132 C. C20H17FO2 (MW 308): calcd.
1190C. C19H14F2O2 (MW 312): calcd. C 73.08, H 4.49, F C 77.92, H 5.52, F 6.17; found C 77.75, H 5.61, F 5.59.
12.18; found C 72.20, H 4.45, F 10.21.
1H NMR (C6D6): 2.12, 3H;
(4-Fluorophenyl)-(4-hydroxy-3-methylphenyl)-
(4-Fluorophenyl)-(4-hydroxyphenyl)-(4-
phenylcarbinol (9) was obtained from PhMgBr and 4*- methylphenyl)-carbinol (13) was obtained from
255

Prototropic processes in benzaurins. 19F and 1H NMR spectra
of fluoro- and methylsubstituted 4-hydroxyphenyl-
diphenylcarbinols, related fuchsones and benzaurins
Hydroxyphenyl carbinols
Fuchsones
R1
R1
R2
C
OH
C
O
R4
OH
R3
R4
R2
R3
1 and 2 R1=R2=R3=H; R4=F
3 and 4 R1=R2=R4=H; R3=F
5 and 6 R1=R3=R4=H; R2=F
7 and 8 R1=R4=F; R2=R3=H
9 and 10 R1=F; R2=R3=H; R4=CH3
11 and 12 R1=F; R2=R4=H; R3=CH3
13 and 14 R1=F; R3=R4=H; R2=CH3
Benzaurins
Di(hydroxyphenyl) carbinols
R1
R1
R2
R2
H O
R2
C
O
OH
C
R2
R3
OH
R3
R3
H O
R3
15 R1=F; R2=R3=CH3
16 R1=F; R2=H; R3=CH3
17 R1= R3=F; R2=H
18 R1=F; R2=R3=H
19 R1=F; R2=R3=CH3
20 R1=F; R2=H; R3=CH3
21 R1= R3=F; R2=H
22 R1=F; R2=R3=H
Scheme 1. Investigated compounds. Even numbers are fuchsones.
4-CH3C6H4MgBr and 4*-fluoro-4-hydroxybenzophenone of the compound (8) was obtained as red crystals. M.p.
using a similar method with a yield of 65 % as a yellow 162 – 1640C. C19H12F2O (MW 294): calcd.: C 77.55, H
solid. M.p. 1010C. C20H17FO2 (MW 308): calcd C 77.92, 4.08, F 12.92; found C 77.41, H 4.24, F 12.05.
H 5.52, F 6.17; found C 77.90, H 5.96, F 4.89. 1H NMR
4*-Methyl-4**-fluorofuchsone (14) was obtained
(C6D6): 2.14, 3H;
by boiling a toluene solution of (4-fluorophenyl)-(4-
2,4*-Difluorofuchsone (8): 0.4 g (0.0013 M) of hydroxyphenyl)-(4-methylphenyl)-carbinol
(13)
for
(4-fluorophenyl)-(3-fluoro-4-hydroxyphenyl)-phenyl- 20 hours. After recrystallization from m-xylene 14 was
carbinol (7) was dissolved in 15 mL of acetic acid and obtained as orange-red crystals. M.p.78-800C. C20H15FO
heated until the boiling of the solvent. After removing (MW 290): calcd. C 82.76, H 5.17; found: C 82.16, H
acetic acid on the rotating evaporater, the remaining oil 5.93. 1H NMR (C6D6): 2.11, 3H.
was triturated with a small quantity of ether. 0.21 g (56%)
256

P. E. Hansen et al.
2-Methyl-4*-fluorofuchsone (10) was obtained by
heating in the argon current a small quantity of carbinol
(9) without a solvent for 4 hours at 1100C . The red
product that formed had m.p. 60 – 620. C20H15FO (MW
290): calcd. C 82.76, H 5.17; found C 81.30, H 5.23. 1H
NMR (C6D6): 2.05, 3H; 2.09, 3H.
The heating of carbinols 1,3,5 and 11 for several
hours under an argon atmosphere led according to NMR
to the formation of the corresponding fucsones 2,4,6
and 12. The reaction mixture contains considerable
quantities of starting carbinols. The element analysis of
these products corresponds to the mixtures of fuchsone
– carbinol or fuchsone – water.
2.3 Analysis of spectra
The mean lifetimes were determined by correlating the
experimental PMR spectra to the theoretical curves. The
theoretical spectra were calculated by employing the
Bloch equations which were modified with regard to the
dynamic processes [27] of the 3-site exchange with 2:1:1
populations of the three states (in dioxane-d8, Tables 2
and 3) or a 2-site exchange with 1:1 populations (DMF-
d7, Table 4). The linewidth ν01/2 of 3 Hz for dioxane-d8
was used. In regard to DMF-d7, the linewidth ν01/2 of the
solvent signal at near 8 ppm wass used, which varied
from 3-4 Hz at a moderate temperature to 9 Hz at -500C.
The experimental error in the case τ values did not
exceed ±4% in their concentration and temperature
dependence.
3,3*,5,5*-Tetramethyl-4**-fluorobenzaurin
(15):
7.32 g (0.06 M) of 2,6-dimethylphenol were placed in a
three-necked flask, fitted with a stirrer, reflux condenser
and dropping funnel. The flask was heated to 850C, and
2.14 g (0.01 M) of 4-fluorobenzotrichloride were dropped
into the flask. The reaction mixture was stirred at 800C
for 7 hours and then decomposed with an aqueous
solution of sodium acetate. The by-products were
separated by water steam distillation. The remaining
brown substance was filtered, washed several times
with hot water and dried to constant weight. The product
was recrystallized from chlorobenzene and dried in the
pistol. 2.68 g (76.8%) of 15 was obtained as a red solid.
M.p. 220-2220C. C23H21FO2 (MW 348): calcd. C 79.31,
H 6.03, F 5,46; found C 79.41, H 5.88, F 4.98. 1H NMR:
(CDCl3) 2.02, 3H; 2.04, 3H and 2.28, 6H. (dioxane-d8)
2.06, 3H, 2.07, 3H and 2.34, 6H. (DMF-d7) 2.17, 12H.
(dioxane-d8+D2O, 2.05, 12H. (dioxane-d8+HCOOH)
2.28, 9H. (dioxane-d8+CF3COOH) 2.29, 12H.
In general, for the exchange reaction:
k1
nA + mB
pC + qD
k-1
the mean life time τA of the exchange species in state A
between two successive exchanges can be expressed
by the following relation [28]:
1/τA = 1/[A] d[A]/dt = kobs[A]n-1[B]m
where n and m are the orders of the exchange reaction
in A and B respectively. A similar expression can be
written for τB. Moreover, in our case kobs is equal to k1/2
[29]. Hence, knowing the τA and τB for some values of
[A] and [B], one can calculate n and m. In this work the
τA and τB values were obtained in varying [B] or [A] and
keeping, respectively, [A] or [B] constant (Table 2). For
a two-site exchange as demonstrated in Fig. 8, a similar
result was obtained using Spinworks 3.1.7 [30].
3 , 3 * - D i m e t h y l - 4 * * - f l u o r o b e n z a u r i n
(16) was obtained from 2-methylphenol and
4-fluorobenzotrichloride using a similar method with the
yield of 69% as a red solid. After recrystallization from
p-dichlorobenzene m.p. 268 – 2700C. C21H17FO2 (MW
3. Results and Discussions
320): calcd. C 78.75, H 5.31, F 5.93; found C 78.72,
1
H 5.19, F 5.31. H NMR: (dioxane-d8) 2.06, 3H; 2.31, 3.1
Substituted
4-hydroxyphenyl-
3H.
diphenylcarbinols and fuchsones.
The fluorine chemical shift (δ 19F) values of compounds
in the benzene solution have been determined
relative to external fluorobenzene in the same solvent
(Table 1).
2.2 NMR spectroscopy
1H NMR spectra were recorded at room temperature
at 400.1 MHz on a Bruker AMX-400 or at 300 MHz on
a Bruker AvanceTM 300, respectively. 19F NMR spectra
were recorded at 188.3 MHz on a Bruker WP-200
SY spectrometer. For 19F NMR, the fluorine chemical
shifts values were measured relative to the external
fluorobenzene dissolved in the same solvent as the
compounds. The stabilization of resonance conditions
regarding 19F NMR was performed using an external
D2O lock.
For the hydroxyphenyl carbinols the fluorine atom in
an ortho position to the hydroxy group resonates in the
range of –26.88 to –25.00 ppm as seen from the data
of compounds 1 and 7. Fluorines in 4*or 4** positions
fall in a different chemical shift range from -2.87 to -
3.41ppm(compounds5,7and9). Forthefluorofuchsones
6, 8, 10, 12 and 14a fluorine in para position fall in a
range from 1.97 to 3.71 ppm. For the fluorines next to
257

Prototropic processes in benzaurins. 19F and 1H NMR spectra
of fluoro- and methylsubstituted 4-hydroxyphenyl-
diphenylcarbinols, related fuchsones and benzaurins
Table 1. 19F a) chemical shifts of fuchsones, benzaurins and their corresponding carbinols.
δ19F, ppm
Solvent
δ19F, ppm
Solvent
Hydroxyphenyl carbinols
Fuchsones
1
3
-26.88
0.10
C6H6
C6H6
2
4
-13.25
0.59
C6H6
C6H6
5
-3.05
-25.00(3-F)
-3.41(4*-F)
-2.87
C6H6
6
3.02
-14.29;-14.41(2-F)
2.86; 2.87(4*-F)
1.97; 2.12
C6H6
7
C6H6
8
C6H6
9
C6H6
C6H6
10
12
C6H6
C6H6
11
-2.88
3.35
13
-3.01
C6H6
14
3.71
C6H6
Benzaurins
Di(hydroxyphenyl) carbinols
2.20
1.55
CHCl3
THF
15
1.03
Dioxane
DMF
19
no data available
2.88
1.90
Pyridine
THF
1.83;1.85
1.50;1.55
2.40
-4.57
-4.37
-4.16
THF
Dioxane
DMF
Dioxane
Pyridine
16
20
2.41
Pyridine
THF
-19.29(3,3*-F)
3.20(4**-F)
-18.97(3,3*-F)
-24.86(3,3*-F)
-3.41(4**-F)
THF
17
18
21
22
Pyridine
-23.09(3,3*-F)
Pyridine
3.66(4**-F)
2.35
-3.27(4*-F)
-4.39
THF
Dioxane
DMF
THF
Dioxane
DMF
2.40
3.00
2.87
-4.13
-3.97
-4.10
Pyridine
Pyridine
a) For 1H chemical shifts see experimental part
the C=O group the fluorine resonates in a range from respect to that of the methyl group in the corresponding
-13.25 to -14.41 ppm (compounds 2 and 8). This type carbinol; however, in going from carbinol to fuchsone
of fluorine is therefore an excellent reporter group to the neighboring electron-donating hydroxyl group is
monitor the change from a C=O to a C-OH functional transformed to the electron-accepting carbonyl group.
group, as is in a tautomeric equilibrium (Fig. 4) or by This may be connected to the dominating contribution
addition of water as seen in Fig. 2.
from the anisotropy effects.
The data in the experimental section indicates
that the sensitivity of δ1H values of the methyl group 3.1.1 Syn/anti
regarding the transformation of the carbinol to the For
2,4*-difluorofuchsone
8
and
4*-fluoro-2-
corresponding fuchsone is rather low. The changes methylfuchsone 10 two fluorine signals for the fluorine
in δ1H vary from -0.12 ppm for the methyl group in in the 4-fluorophenyl group are observed. For the former
position 2 (for numbering see Fig. 1) to 0.03 ppm for compound, two signals also appear for the fluorine which
the methyl group in position 3**, and the decrease is adjacent to the carbonyl group. This is consistent with
in absolute values depends on the position in the the existence as a mixture of syn- and anti-isomers, in
sequence: 2 > 4** > 3**. In two cases the changes in which the 4-fluorophenyl group can be oriented in the
the shieldings are unexpected. Thus, the shielding of direction of fluorine or in the direction of the methyl group
the methyl group in 4*-fluoro-2-methylfuchsone 10 and in position 2 or in the direction of the hydrogen atom in
4*-fluoro-4**-methylfuchsone 14 are decreased with position 6 (Fig. 3). This observation shows clearly that
258

P. E. Hansen et al.
the interconversion of the two isomers is slow on the 1.83 and 1.85 ppm (Table 1) in THF and at 1.50 and
NMR time-scale.
1.55 ppm in dioxane. According to the data obtained for
The δ 1H values of the methyl group in position 2 of fuchsones, this means that for the above compound the
fuchsone is likewise sensitive to the syn-anti isomerism, mutual transformation of syn- and anti-forms is slow in
as may be seen from the data of 10. The δ1H values of these solvents on the 19F NMR time scale (see Fig. 3 for
methyl groups in the position 3* of 2,3*-dimethylfuchsone an example).
and position 4* of 2,4*-dimethylfuchsone will be also
sensitive to the syn-anti isomerism. The methyl 3.2.1 Water addition
resonances are therefore useful in detecting the extent In addition to the two closely lying resonances described
of dimerisation and syn-anti isomerism.
above, a signal in the range from –3.27 to -4.57 ppm
Further the δ 1H values have been studied for appears in the spectra of 17 and 18 and the 3,3*-
the methyl groups in substituted 4-hydroxyphenyl- dimethylsubstituted analogue 16 in solvents such as
diphenylcarbinols 9, 11 and 13 as well as for the dioxane, DMF, pyridine and THF. This position is in
corresponding fuchsones 10, 12 and 14 containing the range close to that observed for the substituted
methyl groups in positions 2, 3** or 4** and fluorine diphenyl-(4-hydroxyphenyl)-carbinols 7, 9, 11 and 13
in position 4*. The results show that the use of only containing a 4-fluorophenyl group. It can be expected
a methyl indicator group for the study of benzaurin that the electron-donating effect of the additional HO-
tautomerism may be insufficient. The more suitable group in 4*-position will increase the electron density
approach is to use jointly, fluorine and methyl group tags on the carbon atom in 4**-position and in the fluorine
as reporters.
shielding (see above). Thus, the above signals ranging
from –3.27 to -4.57 ppm may be assigned to the carbinol
form of the corresponding benzaurin which was formed
as a result of the addition of a water molecule. Therefore,
19F NMR spectroscopy allows the monitoring of the
transformation of benzaurins and the corresponding
carbinols. As water addition readily occurs it may be
difficult to record the spectra of pure benzaurins.
3.2 Substituted benzaurins.
The tautomeric process of
4*-fluorobenzaurin
3,3*,5,5*-tetramehyl-
(15),
of
3,3*-dimethyl-4**-
fluorobenzaurin (16) and of 3,3*,4**-trifluorobenzaurin
(17) as shown in Fig. 4 were the focus of this work.
In this connection 15 - 17 and for comparison, the
4**-fluorobenzaurin 18 have been studied (Fig. 4). In
addition to a prototropic process as described in Fig. 4
water addition may also occur as shown in Fig. 2.
The δ19F values in different solvents for 15 – 18
and the corresponding carbinols, 20 - 22, which are
formed due to the addition of water molecule to 16-18,
are presented in Table 1. This Table shows that for
15 - 18 the fluorine resonances are observed in the
range from 3.66 to 1.03 ppm. According to the results
that were obtained for fuchsones, they may safely
be assigned to the benzaurin form. The slight shift to
lower frequency (higher field) may be connected with
the electron-donating effect of the hydroxyl group and
methyl substituents. It should be noted that in the case
of 3,3*-dimethyl-4**-fluorobenzaurin 16 the signal of
fluorine appears as two closely lying resonances at
F
3.2.2 Tautomerism
Ofspecialinterestis2,4*,4**-trifluorobenzaurin(17). The
19F NMR spectrum in THF consists of two resonances
in an estimated ratio of 2:1 at -19.29 and 3.20 ppm in
addition to resonances belonging to the carbinol (-3.41
and –24.86 ppm) and some very minor impurities. The
chemical shift of –19.29 ppm for the fluorine next to
the C=O/COH groups clearly shows that a prototropic
process is at play.
The absence of the carbinol resonance in the spectra
of solutions of 3,3*,5,5*-tetramethyl-4**-fluorobenzaurin
15 may be explained by the electron-donating effect of
twoadditionalmethylgroupswhichincreasestheelectron
density at the central carbon atom, whereby hindering
the attack of the hydroxyl anion. For 15 dissolved in
THF, dixoane or pyridine even addition of water to the
point of precipitation did not lead to the appearance of
a
19F signal corresponding to the carbinol. The same
C
O
result has been obtained for 16 in DMF.
C
O
The 1H NMR spectra of methyl-substituted
benzaurins have been studied in connection with the
possibility of prototropic tautomerism in benzaurins. The
corresponding data are presented in the experimental
section. The 1H NMR spectrum of 3,3*,5,5*-tetramethyl-
4**-fluorobenzaurin 15 in CDCl3 contains three signals
CH3
CH3
F
syn-
anti-
isomer
isomer
Figure 3. Syn- and anti-isomers as illustrated by 10.
259

Prototropic processes in benzaurins. 19F and 1H NMR spectra
of fluoro- and methylsubstituted 4-hydroxyphenyl-
diphenylcarbinols, related fuchsones and benzaurins
F
F
X
X
X
X
C
OH
O
HO
C
O
Y
Y
Y
Y
X=Y=CH3 15; X= H; Y= CH3 16; X=H, Y=F 17; X=Y=H 18
Figure 4. Tautomers of 15 - 18
or trifluoroacetic acids are added, resulting in a
concentration of 4 mol L-1 of the above benzaurin in
dioxane-d8. A similar picture is found for 16.
F
CH3
CH3
It may be tentatively proposed that the prototropic
process is accelerated due to the formation of cyclic
reactive complexes containing two molecules of
benzaurin and one or more molecules of water (Fig. 5)
or other HO-acid. In these complexes, the molecules
of water or HO-acid can act as bridges for the transfer
of two hydrogen atoms from oxygen atoms of two HO-
groups to those of two carbonyl groups. The inspection
of molecular models show that in the case of benzaurin
or 4**-fluorobenzaurin, the syn and anti forms of 3,3*,4**-
trifuorobenzaurin and the anti form of 3,3*-dimethyl-4**-
fluorobenzaurin two molecules may be joined without
steric hindrance arising in the hydrogen-bonded complex
involving hydroxyl and carbonyl groups. In contrast,
O
O
O
O
C
C
F
H
n(H2O)
CH3
CH3
CH3
CH3
m(H2O)
H
CH3
CH3
Figure 5. Water catalysis model involving two molecules of 15.
3,3*,5,5*-tetramethyl-4**-fluorobenzaurin 15
steric
in the CH3 region, a doublet like feature at 2.02 and
2.04 ppm and a singlet like feature at 2.28 ppm, the
intensities of these signals being at a ratio of 1:1:2. On
the basis of the general considerations and the data on
the chemical shifts of methyl protons in 4-fluorophenyl-
(4-hydroxy-3-methylphenyl)-phenylcarbinol 9 and 4*-
fluoro-2-methylfuchsone 10, it may be concluded that
the doublet belongs to the methyl groups in the vicinity
of the carbonyl group, whereas the singlet arises from
the methyl groups in the ortho-position to the HO-group.
A similar picture is observed in dioxane-d8. These data
indicate that the prototropic process (Fig. 4) in benzaurin
15 is slow on the 1H NMR time scale in chloroform and
dioxane.
hindrance does not allow the formation of a complex
without water or carbonic acid participation.
1
A similar effect of water on the H and 13C NMR
spectra of a hydrogalvinoxyl in acetone-d6 has been
described [21]. The coalescence of 1H or 13C signals of
t-Bu groups as well as corresponding nuclei of aromatic
and methine moieties has been observed. The authors
[21]interpretedtheirresultsusingtheformationofathree-
components system (Fig. 6) in which the broadening of
signals takes place due to the increase in correlation
time caused by the transition of anisotropic state to a
liquid-crystal state and does not discuss the possible
tautomeric process similar to those shown in Fig. 4. We
carried out some kinetic experiments in dioxane-d8 as
well as in DMF-d7 to make the distinction between the
model as shown in Fig. 6 or in Fig. 5 or even a more
complicated one involving chains of solvent molecules.
However, only one broadened signal is observed in
1
the H NMR spectrum of 15 in DMF-d7. This indicates
that in this case the prototropic process on the 1H NMR
time scale occurs at a moderate rate. In addition it has
been determined that water and carbonic acids catalyze
the prototropic process in 3,3*,5,5*-tetramethyl-4**-
fluorobenzaurin (15) in dioxane-d8. Thus, the addition
of water resulting in a concentration of 14 mol L-1 in
dioxane-d8 leads to the appearance of only one peak
for the methyl groups in the 1H NMR spectrum of
this compound. The same is observed when formic
1
In dry dioxane-d8 the H NMR spectrum of 15 at
room temperature reveals one signal at 2.339 ppm (6H)
and two nearby signals at 2.071 (3H) and 2.059 (3H)
ppm (Me-protons), singlet at 6.971 ppm (2H - aromatic
protons), two signals at 7.172 (1H) and 7.303 (1H) ppm
from quinone protons, the last one is overlapped by
the multiplet (4H) from the p-FC6H4 group. In addition,
260

P. E. Hansen et al.
a singlet due to the OH-proton is are observed at the 13-15 moles of H2O leads to the coalescence of the
7.585 ppm. All signals are rather sharp. This spectrum Me and of the CH signals. The spectra are reproduced
corresponds to the slow prototropic process. The for different samples with the same ratio of water to
spectral pattern does not depend on concentration of 15 compound 15. The above data show that the prototropic
in the range from 0.03 M to 0.12 M and on temperature process is catalyzed by water.
(up to 800C). Some changes in chemical shifts have
The analysis of the kinetic data (Table 2) performed
been observed.
in the framework of dynamic NMR method (three-site
The addition of surplus water, up to 4 moles with exchange) [23] (see Experimental Procedure) reveals
respect to 15, does not change the spectrum very that in dioxane-d8 the reaction is second order in 15 and
much with one exception as the signal of the OH-proton 6.5 in H2O. These data suggest that the transition state
disappears. The addition of 10 moles of H2O gives rise includes two molecules of 15 and 6-7 bridging molecules
to the broadening of methyl signals as well as of those of water (m+n=6-7) (Fig. 5).
of CH-aromatic and quinone protons. The addition of
- -
- -
t Bu
t Bu
H
C
...
O
...
...
...
...
... ...
... ...
...
H
S olv
...
O
H
O
H
- -
- -
t Bu
t Bu
n
Figure 6. Hydroxygalvinoxyl and suggested three component system from [4]
Figure 7. 1H spectrum of 15 at -50oC.
Table 2. The concentration dependence of mean life time τ for system 15 + H2O in dioxane-d8 at 200C
τ×103 , sec
Concentration of 15, M
Concentration of H2O, M
0.05
0.05
0.1
0.5
0.05
1.0
17.2
1.94
8.7
Table 3. The temperature dependence of mean life time τ for system 15 + 10 M H2O in dioxane-d8
τ×103 , sec
τ×103 , sec
T, K
T, K
293
310
320
325
17.2
11.0
8.0
7.3
6.3
335
345
350
355
360 [a]
5.8
5.1
4.8
4.5
4.2
330
[a]near collapse
261

Prototropic processes in benzaurins. 19F and 1H NMR spectra
of fluoro- and methylsubstituted 4-hydroxyphenyl-
diphenylcarbinols, related fuchsones and benzaurins
Figure 8. 1H spectrum of 15 with 2.5 moles of water added; (a) experimental traces, (b) simulated traces for temperatures from 223 K to 263 K.
262

P. E. Hansen et al.
Table 4. The temperature dependence of mean life time τ for the solution of 15 in DMFA-d7 with 2.5 moles of water added.
T, K
τ×103 , sec
T, K
τ×103 , sec
240
245
250
255
260
25.0
19
13.5
9.4
263
273
280
288
295
5.8
2.6
1.8
1.6
1.0
6.9
For the analysis of the temperature dependence the
At room temperature the width of the averaged Me
system involving 0.05 M 15 and 0.5 M H2O in dioxane-d8 signal does not depend on the concentration of 15 in the
was selected because for this system the full dynamic range from 0.03 to 0.15 M. The above data suggest that
picture from three Me signals at room temperature to in DMF-d7 the mechanism is monomolecular in 15, but
one broad signal at 900 was observed (Table 3).
The following thermodynamic parameters of the two molecules of water are involved in the process or
from the present study it cannot be excluded that one or
process have been obtained.
that it may involve close connected ionic pairs or ionic
pairs disconnected by the solvent.
Ea=4.4±0.2 kcal mol-1, ∆H≠ = 3.8±0.2 kcal mol-1,
∆S≠ = -38e.u., ∆G≠293 = 15.0±0.2 kcal mol-1.
4. Conclusions
The large negative entropy of activation suggests
that the transition state has a greater steric hindrance
in comparison with the initial starting state. This is
consistent with the proposed mechanism.
The 1H NMR spectrum of the solution of 15 in DMF-
d7 at room temperature reveals one broad signal of
Me-groups at 2.15 and one broad signal of CH-protons
at 7.20 ppm. On lowering the temperature to –500 the
methyl signals split into two relatively broad signals at
2.001(6H) and 2.302(6H) ppm. The CH-signals split into
three relatively broad signals at 6.97(2H), 7.18(1H) and
7.38 ppm(1H) (Fig. 7).
1H NMR spectra of 15 in DMF-d7 and 2.5 moles of
water per mole benzaurin at different temperatures are
shown in Fig. 8a. A comparison of experimental and
simulated spectra is shown in Fig. 8b. The following
thermodynamic parameters have been obtained for
11 temperatures from the analysis of the temperature
dependence of rate constants (Table 4):
The benzaurins 16 –18 appear to add water to form
carbinols in solvents like dioxane, THF and pyridine.
Fuchsones 8 and 10 exist on syn and anti forms in
benzene, and the conversion rate is slower than 10
times per second. For the less hydrophilic compound,
15, no carbinol formation is observed. Compounds 15 –
18 are shown to be prototropic (see Fig. 4) in DMF. 17
is also found to be prototropic in solvents like THF and
pyridine. For 15 a prototropic exchange is found in DMF
and in solvents such as dioxane. In the latter case this
is observed only after adding considerable amounts of
water or carbonic acids. Kinetic experiments revealed
that a chain of 6-7 bridging water molecules are involved
in the process. Thermodynamic parameters show that
the transition state is sterically more hindered than the
initial state.
For 15 in DMF kinetic experiments, the process
is monomolecular or possibly involves one or two
molecules of water.
Ea=8.45±0.24 kcal mol-1, R= -0.996
∆H≠=7.85±0.2 kcal mol-1, ∆S≠=-18 e.u.,
∆G≠293 =13.6±0.2 kcal mol-1 .
5. Acknowledgements
This investigation was conducted within the framework
of INTAS, project № 96-1021. We would like to
thank Professor John Lindon, Imperial College for his
assistance.
Addition of 18 moles of water
temperatures:
based on 9
Ea=6.98±0.14 kcal mol-1, R= -0.998:
∆H≠=6.44±0.15 kcal mol-1, ∆S≠=-21 e.u.,
∆G≠293 =12.6±0.2 kcal mol-1.
263

Prototropic processes in benzaurins. 19F and 1H NMR spectra
of fluoro- and methylsubstituted 4-hydroxyphenyl-
diphenylcarbinols, related fuchsones and benzaurins
References
[1]
[16]
A.I. Kol’tsov, G.M. Kheifets, Usp. Khim. 40, 1646
(1971) (In Russian)
A.R.Katritsky, Usp.Khim. 41, 700 (1972)
(In Russian)
H.G. Hansson, Acta Chem. Scand. 17, 2155
(1963)
J. Zawadiak, M. Mrzyczek, Spectrochim. Acta A.
75, 925 (2010)
J.C. Sloop, D.L. Bumgardner, G. Washington,
W.D. Loehle, S.S. Sankar, A.B. Lewis, J. Fluorine
Chem. 127, 780 (2006)
N.V. Belova, V.V. Seleznev, H. Oberhammer,
G.V. Girichev, J. Mol. Struct. 978, 282 (2010)
V. Bertolasi, P. Gilli, V. Ferretti, G. Gilli, J. Am.
Chem. Soc. 113, 4917 (1991)
A.J. Vila, C.M. Lagier, A.C. Olivieri, J. Phys. Chem.
95, 5069 (1991)
S. Bolvig, P.E. Hansen, Magn. Reson. Chem. 34,
467 (1996)
E.I. Beloborodova, A.V. Gribanov, B.A. Ershov,
A.I. Kol’tsov, A.A. Petrov, I.L. Ushakova, Khim. Fiz.
19, 3 (2000) (In Russian)
S. Bratan, F. Strohbusch, Chem. Ber. 105, 2284
(1972)
G.K.H. Madsen, B.B. Iversen, F.K. Larsen,
M. Kapon, G.M. Reisner, F.H. Herbstein, J. Am.
Chem. Soc. 120, 10041 (1998)
R.M. Acheson, C.J.Q. Brookes, D.P. Dearnaley,
B. Quest, J. Chem. Soc. (C), 504 (1968)
B.J. Schwartz, L.A. Peteanu, C.B. Harris, J. Phys.
Chem. 96, 3591 (1992)
(a)H. Uffmann, Tetrahedron Letters, 4631 (1966);
(b) H. Uffmann, Naturforsch. 226, 491 (1967)
H. Metzger, Tetrahedron Letters 18, 203 (1964)
M. Saunders, M.H. Jaffe, P. Vogel, J. Am. Chem.
Soc. 93, 2558 (1971)
[2]
[3]
[4]
[5]
[17]
[18]
[19]
C.L. Perrin, Y.J. Kim, J. Am. Chem. Soc. 120,
12641 (1998)
[20]
[21]
P.E. Hansen, Magn. Reson. Chem. 31, 27 (1993)
S.V. Bukharov, O.E. Zgadzai, V.V. Syakaev, Dokl.
Akad. Nauk 346, 51 (1996) (In Russian)
A.C. Chiverton, S. Fortier, J.W. Bovenkamp,
D. Thoraval, G.W. Buchanan, B.A. Dawson, Can.
J. Chem. 69, 1298 (1991)
J. Sandstrom, Dynamic NMR Spectroscopy
(Academic Press, London, 1982)
P. Ramart-Lucas, Bull. Soc. Chim. France 8, 928
(1942)
R.W. Taft, E. Price, I.P. Fox, I.C. Lewis,
K.K. Andersen, G.T. Davis, J. Am. Chem. Soc. 85,
3146 (1963)
S.H. Marcus, W.P. Reynolds, S.I. Miller, J. Org.
Chem. 31, 1872 (1966)
J.A. Pople, W.G. Schneider, H.J. Bernstein, High-
Resolution Nuclear Magnetic Resonance (McGraw-
Hill, Ney York, 1959)
J.J. Delpuech, Bull. Soc. Chim. France 2697,
(1964)
[22]
[6]
[7]
[23]
[24]
[25]
[8]
[9]
[10]
[26]
[27]
[11]
[12]
[28]
[29]
[30]
[13]
[14]
[15]
J. Soulati, K.L. Henold, J.P. Oliver, J. Amer. Chem.
Soc. 93, 5654 (1971)
Kirk Marat, Spinworks 3.1.7 (University of
Manitoba, Manitoba, 2010) http://www.umanitoba.
ca/chemistry/nmr/spinworks/index.html
B.A.Y. Jones, A.R. Katritzky, J.M. Logovski, Chem.
and Ind. 870 (1960)
264