Saccharide-accelerated hydrolysis of boronic acid imines

Article abstract of DOI:10.1039/b202793c

Twenty substituted N-benzylidineaniline derivatives have been synthesised and their kinetic behaviour investigated. The rate of hydrolysis of the boronic acid imines was found to be accelerated by added saccharide. Catalytic activity was only observed below the pK_a of the boronic acid. Altering the concentration or type of saccharide revealed a Bronsted-like linear free energy relationship, indicating that intramolecular general acid catalysis was operating. Structure-activity relationship studies demonstrated that the system's electronic demands were independent of the boronic acid moiety.

Full text of DOI:10.1039/b202793c

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Saccharide-accelerated hydrolysis of boronic acid imines
James H. Hartley, Marcus D. Phillips and Tony D. James*
Department of Chemistry, University of Bath, Bath, UK BA2 7AY.
E-mail: T.D.James@bath.ac.uk
Received (in London, UK) 19th March 2002, Accepted 18th April 2002
First published as an Advance Article on the web 23rd July 2002
Twenty substituted N-benzylidineaniline derivatives have been synthesised and their kinetic behaviour
investigated. The rate of hydrolysis of the boronic acid imines was found to be accelerated by added saccharide.
Catalytic activity was only observed below the pKa of the boronic acid. Altering the concentration or type of
saccharide revealed a Brønsted-like linear free energy relationship, indicating that intramolecular general acid
catalysis was operating. Structure–activity relationship studies demonstrated that the system’s electronic
demands were independent of the boronic acid moiety.
Introduction
The recognition of saccharides by boronic acids has received a
significant amount of attention in recent years. The ability of
boronic acid to bind rapidly and reversibly with 1,2- and 1,3-
diols in competitive solvents has been used in the design of sen-
sors for saccharides with read-out via photoinduced electron
transfer (PET) fluorescence quenching, colorimetric and circu-
lar dichroism (CD) techniques.1–3
The effect of boric and boronic acid on the rate of hydrolysis
of salicaldehyde-derived imines has been studied by Okuyama
et al.,4–6 and Rao and Philipp.7 Both acids have the effect of
enhancing the rate of hydrolysis of these imines. The effect
of adding D-fructose was studied in the latter work, where it
Scheme 1 Qualitative description for the pKa of boronic acid.
was found that the enhancement was removed on addition of
the saccharide.
With these examples, the boronic acid is added, rather than
being an integral part of the system. We decided to investigate
how the Lewis acidity of integrated boronic acids affects the
rate of hydrolysis of simple imines.8 It has been known for
over forty years that the boron atom in a boronic acid becomes
more acidic when bound to a saccharide.9 This is due to the
reduction in the O–B–O bond angle from 120ꢀ in unbound
boronic acid to approximately 108ꢀ when bound. This reduc-
tion in pKa is the basis of many of the sensors developed,
but its definition in this context is poorly defined. We feel it
is best explained by considering the boronic acid to have a
water molecule loosely associated to the boron atom. At high
pH, the associated water is deprotonated and a tetrahedral
boronate anion is formed. Saccharide binding enhances the
Lewis acidity of the boron atom,1,2 facilitating this deprotona-
tion (Scheme 1).
Results and discussion
Synthesis
Twenty imines were synthesised, these are split into two types
depending on the side of substitution. Type I imines are substi-
tuted on the benzylidine ring and type II imines are substituted
on the aniline ring (Fig. 1). The boronic acid derivatives were
Fig. 1 The two types of imine, designated by substituted ring; Y ¼ electron-donating or electron-withdrawing substituent.
1228
New J. Chem., 2002, 26, 1228–1237
DOI: 10.1039/b202793c
This journal is # The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2002

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[saccharide] ꢁ [imine] and it should be noted that K in the
equation is equal to the dissociation constant, quoted in units
of M. The inverse of this value yields KS , the binding constant,
in units of Mꢂ1
.
k1K þ k2½saccharideꢃ
K þ ½saccharideꢃ
kobs
¼
ð1Þ
Scheme 2 Synthetic procedure for type I boronic acid imines.
Reagents and conditions: (i) 1,3-propanediol, HC(OMe)3 , r.t., 2 h; (ii)
Y–C6H4CHO, ethanol–C6H6 , reflux in Dean–Stark apparatus, 24 h.
Kinetic experiments
The conditions for the kinetic runs were chosen such that the
system obeyed pseudo-first order reaction kinetics. Although
this kinetic description was valid for the majority of com-
pounds over the whole kinetic run, there were a number of
anomalous compounds.y The absorption of these compounds
increased initially before a maximum was passed, after which
time their behaviour was pseudo-first order.
Scheme 3 Synthetic procedure for type II boronic acid imines.
Reagents and conditions: (i) Y–C6H4NH2 , ethanol–C6H6 , reflux in
Dean–Stark apparatus, 24 h; (ii) 1,3-propanediol, ethanol–C6H6 ,
reflux in Dean–Stark apparatus, 24 h.
Saccharide dependence
The effect of different saccharide types and the effect of differ-
ent concentrations of D-fructose with boronic acid imine 2 was
explored. The observed rate constants and calculated pKa for
different saccharides and concentrations of D-fructose are
given in Tables 2 and 3.
synthesised according to Scheme 2 and Scheme 3. It was found
that type I boronic acid imines could be conveniently formed
from a common precursor, protected 3-aminobenzeneboronic
acid. However, the protected precursor for type II imines, pro-
tected 3-formylbenzeneboronic acid, did not react as efficiently
as the free acid. For this reason, the order of synthesis was
reversed, with imine formation preceding protection by 1,3-
propanediol. It should be noted that the protecting group
was added for ease of characterisation of the target com-
pounds and was chosen for its low binding constant (KS)10
with the boronic acid substrates, which should ensure rapid
and complete displacement by added saccharide. Type I and
II non-boronic acid imines were synthesised by condensation
of the appropriate aldehyde and amine with azeotropic
removal of water for 24 h.
log ðKc ꢄ ½Pꢃf þ 1Þ ¼ ꢂDpH
ð2Þ
pKa ¼ 8:86 ꢂ DpH
The concentration dependence of boronic acid imine 2 with
D-fructose is shown in Fig. 2. This saturation curve is what one
would expect if complexation catalysis were occurring and it
indicates that binding of saccharide causes an increase in the
rate of hydrolysis of the boronic acid imine 2. Assuming a sim-
ple 1:1 binding event, the binding constant for the system can
be calculated. The curve was fitted using eqn. (1) to give values
for KS of 340 Mꢂ1, k1 of 7.5 ꢅ 10–4 sꢂ1 and k2 of 2.15 ꢅ 10ꢂ3
s
ꢂ1, with an r value of 0.998.
Complexation catalysis mechanism
Linear free energy relationship
The system under investigation can currently be considered in
the manner shown in Scheme 4. This complexation catalysis
mechanism11 is a simplification of the actual mechanism since
it assumes no reversibility in either k1 or k2 . However, the
excess of water, acting as a reagent, compared to the low con-
centration of imine ensures that this is still a good description
of the system under investigation. The saccharide does not
have to involve itself chemically in the hydrolysis of imines
but merely facilitates the reaction by providing a micro-envir-
onment which is different from that in the unbound state.
Uncomplexed boronic acid imines react to form products via
the uncatalysed route described by k1 . In the presence of sac-
charides, boronic acids are bound with a binding constant KS ,
resulting in the complexed boronic acid imine reacting to form
products via the catalysed route described by k2 . This mechan-
ism gives rise to eqn. 1, which describes the relationship
between the three constants and how they affect the overall
observed rate constant, kobs . This equation is suitable when
Treating the intramolecular boronic acid in the same manner
as a general acid of the same pKa , we were able to obtain
meaningful information by plotting a linear free energy rela-
tionship of the pKa values from Tables 2 and 3 against the
logarithm of the observed rate constant to give the Brønsted-
like correlation shown in Fig. 3. The linear curve fit gave gra-
dients of 0.245 and 0.242, with r values of 0.998 and 0.996,
respectively. The linear free energy relationship shown in
Fig. 3 suggests that the pKa of the boronic acid moiety is influ-
ential in the enhancement in the observed rate of hydrolysis of
y Anomalous behaviour: certain compounds did not obey pseudo-first
order kinetics for the whole of the experiment. These compounds (5, 9,
15, 17 and 21) displayed an initial increase in absorption before assum-
ing a normal first order decay curve. Reeves first noticed this phenom-
enon for 2112 and assigned it to the carbinolamine ether, formed when
imines appended with electron-withdrawing substituents were stored in
anhydrous alcohols, reverting back to the imine on introduction to
aqueous conditions before being hydrolysed. This increase in the con-
centration of the absorbing species accounts for the observed initial
increase in measured absorption. The kinetics of these compounds
were analysed in two ways. In the first method, the period over which
the absorption increased was ignored and only the data after the max-
imum was reached were used in the calculation of the rate constant.
The second method involved the use of the kinetic modelling software
Gepasi v3.21.13–15 The reaction was defined as a consecutive two-step
reaction, the first step being the conversion of the carbinolamine ether
to the imine, and the second being the hydrolysis of the imine. The
results of these two methods are shown in Table 1 and clearly show
it was justified to ignore the induction period in the calculations, since
the observed rate constants calculated by the Gepasi software were the
same as the less rigorous pseudo-first order calculation.
Scheme 4 Proposed complexation catalysis mechanism.
New J. Chem., 2002, 26, 1228–1237
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Table 1 Rate constants for the decomposition of carbinolamine ether (kcarb) and subsequent imine hydrolysis (kobs) applying pseudo-first order
(P-FO) and Gepasi (Gep) methods
Compound
kcarb ꢅ 10ꢂ3/sꢂ1 (Gep)
kobs ꢅ 10ꢂ4/sꢂ1 (Gep)
kobs ꢅ 10ꢂ4/sꢂ1 (P-FO)
Non-boronic acids
15
17
21
9
6.3 ꢆ 0.2
47.7 ꢆ 0.3
69.5 ꢆ 2.9
7.3 ꢆ 0.3
2.12 ꢆ 0.07
4.65 ꢆ 0.17
6.45 ꢆ 0.03
5.50 ꢆ 0.08
2.42 ꢆ 0.05
16.50 ꢆ 0.02
6.81 ꢆ 0.11
2.13 ꢆ 0.08
4.64 ꢆ 0.17
6.45 ꢆ 0.03
5.41 ꢆ 0.08
2.58 ꢆ 0.08
16.46 ꢆ 0.07
6.81 ꢆ 0.12
Boronic acids
5
10.0 ꢆ 1.0
34.9 ꢆ 1.7
35.1 ꢆ 5.5
9 + D-fructose
5 + D-fructose
Table 2 Observed rate constants for the hydrolysis of 2 (4.0 ꢅ 10ꢂ5
M) in the presence of differing concentrations of D-fructose
Rate constant ꢅ 10ꢂ4/sꢂ1
Calculated pKa
a
[D-Fructose]/M
0
7.47 ꢆ 0.09
10.91 ꢆ 0.04
13.40 ꢆ 0.10
14.45 ꢆ 0.04
15.50 ꢆ 0.04
16.17 ꢆ 0.03
16.82 ꢆ 0.07
17.70 ꢆ 0.03
17.96 ꢆ 0.11
18.28 ꢆ 0.02
17.86 ꢆ 0.06
8.86
8.14
7.88
7.72
7.60
7.50
7.43
7.36
7.31
7.26
7.21
0.001
0.002
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.010
a
Fig. 2 Observed rate constant vs. [D-fructose] for the hydrolysis of 2
in 33% MeOH–66% H2O, pH 7.77, observed at 320 nm.
Manipulating data obtained for the boronic acid by Lorand and
Edwards,9 concentration values were converted into pKa values. The
equation used to obtain binding constants was rearranged to provide
an equation which, given the known binding constants of phenylboro-
nic acid with saccharides, afforded shifts in pKa of the boronic acid.
This method yielded the original values Lorand and Edwards would
have worked from. The rearranged equation is shown in eqn. (2),
where [P]f is the final concentration of saccharide, Kc is the binding
constant, and the value 8.86 is the literature value for the pKa of phe-
nylboronic acid.
Table 3 Observed rate constants for the hydrolysis of 2 (5.0 ꢅ 10ꢂ5
M) in the presence of different polyols (0.01 M). Binding constants
are from Lorand and Edwards9
Rate
Binding
Calculated
a
Polyol
constant ꢅ 10ꢂ4/sꢂ1 constant/Mꢂ1 pKa
D-Fructose
Mannitol
21.6
18.1
11.9
10.3
10.1
8.5
4370
2275
276
7.21
7.49
8.29
8.43
8.54
8.86
Fig. 3 Linear free energy relationship for 2 between the rate of imine
hydrolysis and the pKa of the boronic acid, calculated using eqn. (2).
D-Galactose
D-Mannose
D-Glucose
172
110
1,3-Propanediol
0.88
a
compound 2 in the presence of 0.01 M D-fructose. The plateau
region is indicative of an intramolecular process. Examples
from the literature include the work of Kirby and Brown,
who recently reported intramolecular general acid catalysis
of the hydrolysis of dialkyl acetals of benzaldehyde,17,18 and
Okuyama et al. with the intramolecular general base catalysis
of imines by tertiary amino groups.19 An important point to
note in the latter example is the observed Brønsted correlation
between the pKa of the tertiary amino group and the logarithm
of the rate constant. This is due to the fact that the tertiary
amino group is able to reach around and coordinate via a
water molecule to the imine bond. This water molecule then
deprotonates, the resultant hydroxide ion being delivered to
the imine in an intramolecular fashion resulting in the
observed general base catalysis.
See footnote in Table 2.
the remote imine bond and that general acid catalysis is occur-
ring. The value of the gradient would suggest an early, reac-
tant-like transition state.16
pH dependence
To further probe this system, the pH dependence of 2 with and
without D-fructose present was determined. As a control, N-
benzylidineaniline was also examined. The results are shown
in Fig. 4 and show a plateau region from pH 7 to 8.9 for
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boronic acid, formation of the anionic tetrahedral species
removes the neutral unbound boronic acid imine from the sys-
tem and the catalytic pathway cannot be followed.
The results presented here show that the mechanism of
hydrolysis of boronic acid imines in the presence of saccharides
proceeds by intramolecular general acid catalysis
Structure–activity relationship
To examine how the effect of the boronic acid pKa was trans-
mitted, a structure–activity relationship (SAR) study was per-
formed. The behaviour of the twenty boronic and non-boronic
acid imines was explored in the presence and absence of D-fruc-
tose. The results of our SAR experiments are shown in Table 4
for type I imines and in Table 5 for type II imines. The results
are shown graphically in Fig. 5 for type I imines and in Fig. 6
Fig. 4 Semi-logarithmic pH rate plot for the hydrolysis of selected
imines: N-benzylidineaniline (L); compound 2 (˘); compound 2 in
the presence of 0.01 M D-fructose (S).
for type II imines. Both the positive (r+ve) and negative (r
)
ꢂve
gradients of the Hammett plots were obtained and are
recorded in Table 6. The gradients of the data plotted in Fig.
5 and 6 give information about the electronic demands at the
reaction centre. Both graphs show a discontinuity in the Ham-
mett correlation, the downward break indicative of a change in
the rate-determining step of the reaction.20 One can see from
further examination of the graphs that no effect was observed
on the position of the changeover in the rate-determining step
and that the reaction parameter r was the same within each
type (I or II) regardless of saccharide interaction.
The structure–activity relationship studies indicate that the
system’s electronic demands are independent of the boronic
acid moiety—irrespective of any saccharide interaction.
Structure–activity relationships of N-benzylidineaniline deri-
vatives have been previously examined and a change in the
rate-determining step of the reaction was observed, with the
hydrogen-substituted compounds having the highest reactiv-
ity.21,22 This was also observed in the hydrolysis of salicylidi-
neanilines derivatives and a simplified reaction sequence has
been used to explain this kinetic behaviour.20 Based on the
sequence proposed by Hoffmann; the first step involves addi-
tion of a proton to the imine nitrogen, the second, addition
of water to the protonated imine and the third involves the
decomposition of this species into the products of hydrolysis
via the tetrahedral carbinolamine intermediate proposed by
Jencks and co-worker23,24 (Scheme 6).
The intramolecular process observed in the pH titration
operates in the region pH 7 to 8.9, above which a rapid change
in behaviour is observed. It should be noted that the pKa of
unbound phenylboronic acid is 8.86. This rapid drop-off in
enhanced behaviour at the pKa of the unbound boronic acid
shows that the neutral trigonal species is the active form in
the intramolecular process. Above pH 8.9, the boronic acid
becomes inactive through the formation of a tetrahedral anio-
nic boronate species. This can be represented by the complexa-
tion catalysis mechanism shown in Scheme 5. Binding D-
fructose at a pH below the pKa of the unbound boronic acid
allows the intramolecular general acid catalytic pathway repre-
sented by k2 to operate. At a pH above the pKa of the unbound
For this mechanism, it has been shown that general acid cat-
alysis can operate, in agreement with our findings.22
Kinetic isotope effect
The solvent deuterium kinetic isotope effect (KIE) was exam-
ined for a range of boronic and non-boronic acid imines in
the presence of D-fructose, the results are displayed in
Table 7. From these, it can be seen that both type I and II
boronic acid imines have a significant KIE in the presence of
Scheme 5 Observed mechanism in the hydrolysis of boronic acid imi-
nes in the presence of saccharide at physiological pH.
Table 4 SAR results for the hydrolysis of type I boronic and non-boronic acid imines in the presence and absence of D-fructose
Compound
s Value
kobs ꢅ 10ꢂ4/sꢂ1
log kobs
kobs ꢅ 10ꢂ4/sꢂ1 (D-Fructose)
log kobs (D-Fructose)
Boronic acids
6
ꢂ0.27
ꢂ0.14
ꢂ0.06
0.00
4.66 ꢆ 0.04
6.67 ꢆ 0.04
7.54 ꢆ 0.13
7.47 ꢆ 0.09
4.49 ꢆ 0.02
2.58 ꢆ 0.08
4.31 ꢆ 0.04
6.32 ꢆ 0.07
7.06 ꢆ 0.12
4.64 ꢆ 0.17
2.13 ꢆ 0.08
ꢂ3.33
ꢂ3.18
ꢂ3.12
ꢂ3.13
ꢂ3.35
ꢂ3.59
ꢂ3.37
ꢂ3.20
ꢂ3.15
ꢂ3.33
ꢂ3.67
10.47 ꢆ 0.05
15.28 ꢆ 0.03
18.22 ꢆ 0.05
17.86 ꢆ 0.06
10.98 ꢆ 0.04
6.81 ꢆ 0.12
—
ꢂ2.98
ꢂ2.82
ꢂ2.74
ꢂ2.75
ꢂ2.96
ꢂ3.17
—
3
4
2
7
0.24
0.71
5
14
Non-boronic acids
ꢂ0.27
ꢂ0.14
0.00
16
N-Benzylidineaniline
—
—
7.21 ꢆ 0.04
—
—
ꢂ3.14
—
—
17
15
0.24
0.71
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Table 5 SAR results for the hydrolysis of type II boronic and non-boronic acid imines in the presence and absence of D-fructose
Compound
s Value
kobs ꢅ 10ꢂ4/sꢂ1
log kobs
kobs ꢅ 10ꢂ4/sꢂ1 (D-Fructose)
log kobs (D-Fructose)
Boronic acids
10
13
ꢂ0.27
ꢂ0.14
0.00
4.16 ꢆ 0.03
7.77 ꢆ 0.01
9.87 ꢆ 0.12
10.24 ꢆ 0.09
7.17 ꢆ 0.03
5.41 ꢆ 0.08
3.07 ꢆ 0.04
5.25 ꢆ 0.19
6.87 ꢆ 0.04
7.06 ꢆ 0.12
6.45 ꢆ 0.03
ꢂ3.38
ꢂ3.11
ꢂ3.01
ꢂ2.99
ꢂ3.14
ꢂ3.27
ꢂ3.51
ꢂ3.28
ꢂ3.16
ꢂ3.15
ꢂ3.19
11.06 ꢆ 0.06
20.72 ꢆ 0.13
26.00 ꢆ 0.15
27.66 ꢆ 0.12
18.94 ꢆ 0.11
16.46 ꢆ 0.07
—
ꢂ2.96
ꢂ2.68
ꢂ2.59
ꢂ2.56
ꢂ2.72
ꢂ2.78
—
8
11
0.12
0.24
12
9
18
0.71
Non-boronic acids
ꢂ0.27
ꢂ0.14
ꢂ0.06
0.00
19
20
—
—
—
—
N-Benzylidineaniline
21
7.21 ꢆ 0.04
—
ꢂ3.14
—
0.24
Fig. 5 Hammett plot for type I boronic acid imines at 20 ꢀC; buffer
solution only (L); buffer solution with 0.01 M D-fructose (˘).
Scheme 6 Kinetic description for the hydrolysis of N-(2-hydroxy-5-
methylbenzylidine)aniline derivatives.20
Table 7 Solvent kinetic isotope effect for a range of boronic acid and
non-boronic acid imines in the presence of 0.01 M D-fructose. Note:
the apparent pH of solvents was equilibrated using a correction factor
of pD ¼ pH + 0.4
Compound
s Value
Type
kH/kD
6
10
ꢂ0.27
ꢂ0.27
0.00
I
2.30
2.51
2.28
2.83
1.76
2.06
1.30
II
2
I
8
0.00
0.71
II
5
I
9
N-Benzylidineaniline
0.71
0.00
II
Control
D-fructose as compared with the non-boronic acid imine deri-
vative N-Benzylidineaniline. In addition, type I imines display
a smaller KIE than type II imines.
Fig. 6 Hammett plot for type II boronic acid imines at 20 ꢀC; buffer
solution only (L); buffer solution with 0.01 M D-fructose (˘).
Conclusions
Table 6 r Values obtained from the Hammett plots derived from the
data in Tables 4 and 5
Intramolecular general acid catalysis should be dependent on
the strength of the general acid involved, however there is little
evidence to support this in the literature.17,18,25 With boronic
acid imines, we have shown that the strength of the intramole-
cular general acid controls the rate of hydrolysis. The strength
of a boronic general acid (pKa) can be varied by adding differ-
ent amounts of saccharide (or indeed different types) without
changing either the general acid or the gross structure of the
molecule.
Compound type and conditions
r+ve
r
ꢂve
Type I boronic acid
0.80
0.91
0.79
1.38
1.37
1.40
–0.63
–0.57
–0.73
–0.39
–0.30
–0.16
Type I boronic acid + D-fructose
Type I non-boronic acid
Type II boronic acid
Type II boronic acid + D-fructose
Type II non-boronic acid
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The acidity of the boron atom could be communicated to
the imine bond via a proton-transfer mechanism through sol-
vent water.26–29 Only the neutral bound boronic acid has the
ability to operate in this manner—above the pKa of the free
boronic acid the enhanced mechanism is lost and a purely
intermolecular process takes over.
pH measurements > pH 7, aqueous buffer solutions of pH
7.00 and 10.00 were used for calibration. For pH measure-
ments < pH 7, aqueous buffer solutions of pH 4.00 and 7.00
were used for calibration.
The deuterated buffer solutions were made up as follows.
0.05 M NaCl was prepared in a solution of CH3OD in D2O
(33% CH3OD w/w) and stored under an N2 atmosphere.
The pH was measured and a correction factor of 0.411 was
added to give an apparent pH of 8.12. For comparison, a
non-deuterated buffer was made up as follows. 0.05 M NaCl
was prepared in a solution of CH3OH in H2O (33% CH3OH
w/w) and stored under an N2 atmosphere. The pH was mea-
sured and adjusted with 0.01 M NaOH to give an apparent
pH of 8.04.
Experimental
General procedures
1H and {1H}-13C NMR spectra were recorded on a Bruker
AC-300 (300.13 and 75.47 MHz, respectively) spectrometer.
All chemical shifts (d) were recorded relative to tetramethylsi-
lane as the internal standard. The multiplicities of the spectro-
scopic data are presented in the following manner: s ¼ singlet;
Kinetic measurements
d ¼ doublet;
t ¼ triplet;
q ¼ quintet;
m ¼ multiplet;
1.25 cm3 of an appropriate buffer solution was transferred by
glass syringe into a quartz cuvette. This cuvette was placed
within a thermostatted cuvette holder in the spectrophot-
ometer and left for 10 min for temperature equilibration. After
this time, 5 mL of a 0.0100 M stock solution of imine was intro-
duced into the cuvette to give an initial imine concentration of
4.0 ꢅ 10ꢂ5 M. The cuvette was inverted three times to ensure
mixing before being re-inserted into the spectrophotometer.
UV WinLab32 was used for data collection—this was started
as soon as the sample chamber was closed. The period of time
between introducing the analyte to the cuvette and beginning
data collection was never more than 5 s. Data were collected
for 1 h at intervals of 6 s to give a total of 601 data points.
Data were recorded at an appropriate wavelength to study
the disappearance of the imine absorption peak—this was
usually 320 nm.
The data were analysed using Kaleidagraph 3.09, assuming
pseudo-first order reaction kinetics to give rate constants.34
The final absorption Ae was calculated by using the experimen-
tal data to fit an exponential curve of general formula
y ¼ ae(bx) + c, with values of a, b and c calculated by the
curve-fitting software. The value c represents the final absorp-
tion at infinite time, Ae . The curve-fitting software used the
non-linear Levenberg–Marquardt algorithm35,36 and reported
the accuracy of the curve fit by the coefficient of determination,
r2. Usually r2 was q 0.99, indicating a good fit of the data had
been achieved. Typically, each experiment was repeated three
times and the mean rate constant is reported with a standard
deviation, represented by a ꢆ value.
br ¼ broad signal. J Values are given in Hz. The {1H}-13C
NMR spectra were subject to the polarisation enhancement
that is nurtured during attached nucleus testing (PENDANT)
technique,30,31 resulting in primary and tertiary carbon atoms
having a different phase to secondary and quaternary carbon
atoms. The phase is presented in the following manner: (+)
positive phase; (ꢂ) negative phase. Due to quadrapolar relaxa-
tion, carbon atoms attached directly to a boron atom were not
observed in the spectra.
Electron impact (EI) mass spectra were recorded on a VG
ProSpec mass spectrometer. Liquid secondary ion (LSI) mass
spectra were recorded using a VG ZabSpec instrument. HRMS
measurements were also obtained from either the VG ProSpec
or VG ZabSpec spectrometers.
Elemental analyses were performed at the University of
North London and the University of Birmingham.
Thin-layer chromatography (TLC) was carried out on pre-
coated aluminium-backed silica gel plates supplied by Merck
KGaA, Darmstadt, Germany (Silica Gel 60 F254 , thickness
0.2 mm, Art. 5554). Visualisation was achieved by UV light
(254 nm).
Melting points were determined using a Gallenkamp melting
point apparatus and are reported uncorrected.
All reagents and solvents were used as supplied by the
Aldrich Chemical Co. Ltd., Lancaster Synthesis Ltd. and
Fisher Scientific Ltd.
All kinetic measurements were performed on a Perkin-Elmer
Lambda 20 UV/VIS spectrophotometer with data collected
via the UV WinLab software package32 on a PC running
Microsoft NT v4. A thermostatted cell holder was fitted and
connected to a Colora Kryo-Thermostat Wk 6, operating at
20 ꢀC.
Where the absorption increased initially, indicating hydroly-
sis of the carbinolamine ether to form the imine, rate data were
acquired after the maximum absorption had been passed.
These rate constants were also calculated by applying the
kinetic modelling software Gepasi v3.21.13–15 The model was
defined as being a two-step, irreversible consecutive reaction.
The combined concentration of carbinolamine ether, imine
and products was set to 4.0 ꢅ 10ꢂ5 M and the software varied
both the starting concentrations of carbinolamine ether and
imine, and also the kinetic rate constants k1 and k2 to fit the
observed data. The optimisation method chosen was the
Levenberg–Marquardt gradient descent method.14,15,35–39
Typically, standard deviations of less than 1% were reported
for the Gepasi kinetic rate constants. Acceptable convergence
to a minimum was usually obtained after approximately
1000 iterations.
Stock solutions of imines were prepared in 5.00 cm3 of
HPLC methanol to a concentration of 0.0100 M. These were
stored at 5 ꢀC in the dark until required.
The pH 7.77 buffer was prepared according to literature pro-
cedures33 as follows: 0.010000 M KCl, 0.002642 M KH2PO4
and 0.002642 M Na2HPO4 were prepared in a solution of
HPLC methanol in deionised water (33% MeOH w/w) to give
the appropriate buffer solution. This buffer solution was stored
and dispensed under an N2 atmosphere.
For experiments where the saccharide concentration rate
dependence was studied, a stock solution of the highest sac-
charide concentration to be used was prepared in pH 7.77 buf-
fer solution. Aliquots of this stock solution were then diluted
with pH 7.77 buffer to give the weaker concentrations.
For the pH dependence study, a 0.05 M NaCl stock solution
was prepared, with or without D-fructose present. The pH was
adjusted using dilute HCl and dilute NaOH, and pH values
read on a Hanna Instruments HI 9321 microprocessor pH
meter. Calibration of the pH meter was performed using
Fisher Scientific Analytical Reagents buffer solutions. For
Synthesis
3-[1,3,2]Dioxaborinan-2-yl-phenylamine (1).8 3-Aminobenze-
neboronic acid monohydrate (465 mg, 3.00 mmol) was dis-
solved in HC(OMe)3 (20 cm3) with stirring at room
temperature. Propane-1,3-diol (250 mg, 3.00 mmol) was
added, and the solution was stirred at room temperature for
New J. Chem., 2002, 26, 1228–1237
1233

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(3-[1,3,2]Dioxaborinan-2-yl-phenyl)(3-nitrobenzylidene)amine
2 h. The solvent was removed under reduced pressure to afford
crude 1 as a light brown oil. Chloroform (10 cm3) was added to
redissolve the oil and then n-hexane (20 cm3) was added. The
light brown precipitate formed was removed by filtration.
The filtrate solvent was removed under reduced pressure to
afford the amine 1 (450 mg, 85% yield) as a white solid, mp
79–81 ꢀC; dH (300 MHz, C2HCl3) 7.20–7.16 (2H, m, Ar-H),
7.12–7.08 (1H, m, Ar-H), 6.78–6.73 (1H, m, Ar-H), 4.15 (4H,
(5). Compound 5 was prepared according to the general proce-
dure for the synthesis of 3, except that 3-nitrobenzaldehyde
(151 mg, 1.00 mmol) was used in place of benzaldehyde. Pre-
cipitation of the crude product from a chloroform solution
with n-hexane afforded 5 (155 mg, 50%) as a bright yellow
microcrystalline solid, mp 96–97 ꢀC (Found: C, 61.87; H,
4.85; N, 8.88; C16H15BN2O4 requires: C, 61.97; H, 4.88; N,
9.03%. HRMS found: M+ m/z 310.1111; C16H15BN2O4
requires: m/z 310.1125); lmax (MeOH)/nm (e/dm3 molꢂ1
cmꢂ1) 314 (8630); nmax/cmꢂ1 1623 (st, C=N); dH (300 MHz,
C2HCl3) 8.73 (1H, s, N=CH), 8.58 (1H, s, Ar-H), 8.34–8.22
(2H, m, Ar-H), 7.72–7.60 (3H, m, Ar-H), 7.45–7.30 (2H, m,
3
t, JH–H 5.5, OCH2CH2), 3.80–3.40 (2H, br, Ar–NH2), 2.04
3
(2H, q, JH–H 5.5, OCH2CH2); dC (75 MHz, C2HCl3) 146.3
(ꢂ), 128.0 (+), 124.9 (+), 120.4 (+), 117.6 (+), 61.8 (ꢂ), 27.3
(ꢂ); m/z (LSI) 177 (100%, [M + H]+); Rf 0.32 (hexane–ethyl
acetate, 1:1).
3
3
Ar-H), 4.18 (4H, t, JH–H 5.5, OCH2CH2), 2.08 (2H, q, JH–
5.5, OCH2CH2); dC (75 MHz, C2HCl3) 157.0 (ꢂ), 150.2
Benzylidene(3-[1,3,2]dioxaborinan-2-yl-phenyl)amine (2).8
1
H
(250 mg, 1.40 mmol) was dissolved in HC(OMe)3 (3 cm3) with
stirring at room temperature. Benzaldehyde (160 mg, 1.50
mmol) was added and the reaction mixture was allowed to stir
at room temperature for 60 h. The solvent was removed under
reduced pressure to afford crude 2. This oil was trituated with
ether to afford 2 (329 mg, 88%) as a thick brown oil (Found: C,
72.36; H, 6.17; N, 5.38; C16H16BNO2 requires: C, 72.49, H,
6.08, N, 5.28%); lmax (MeOH)/nm (e/dm3 molꢂ1 cmꢂ1) 308
(8544); nmax/cmꢂ1 1631 (st, C=N); dH (300 MHz, C2HCl3)
8.44 (1H, s, N=CH), 7.87–7.81 (2H, m, Ar-H), 7.68–7.59
(2H, m, Ar-H), 7.51–7.45 (3H, m, Ar-H), 7.41–7.36 (1H, m,
(+), 148.7 (+), 138.1 (+), 134.1 (ꢂ), 132.3 (ꢂ), 129.8 (ꢂ),
128.6 (ꢂ), 125.5 (ꢂ), 125.0 (ꢂ), 124.3 (ꢂ), 123.5 (ꢂ), 62.1
(+), 27.4 (+); m/z (EI) 310 (100%, M+).
{3-[(3-[1,3,2]Dioxaborinan-2-yl-phenylimino)methyl]phenyl}-
methanol (6). Compound 6 was prepared according to the gen-
eral procedure for the synthesis of 3, except that p-
anisaldehyde (136 mg, 1.00 mmol) was used in place of benzal-
dehyde. Recrystallisation of the crude product from petroleum
ether (40–60) afforded 6 (170 mg, 57%) as a light cream micro-
crystalline solid, mp 62–63 ꢀC (HRMS found: M+ m/z
295.1373; C17H18BNO3 requires: m/z 295.1380); lmax
(MeOH)/nm (e/dm3 molꢂ1 cmꢂ1) 315 (23 246); nmax/cmꢂ1
1621 (st, C=N); dH (300 MHz, C2HCl3) 8.42 (1H, s, N=CH),
7.88–7.81 (2H, m, Ar-H), 7.66–7.55 (2H, m, Ar-H), 7.37 (1H,
3
Ar-H), 7.34–7.29 (1H, m, Ar-H), 4.19 (4H, t, JH–H 5.5,
3
OCH2CH2), 2.08 (2H, q, JH–H 5.5, OCH2CH2); dC (75
MHz, C2H3O2H) 163.2 (+), 152.7 (ꢂ), 138.0 (ꢂ), 133.4 (+),
133.3 (+), 130.6 (+), 130.1 (+), 127.5 (+), 125.0 (+), 63.8
(ꢂ), 29.2 (ꢂ); m/z (LSI) 266 (100%, [M + H]+).
3
t, JH–H 7.3, Ar-H), 7.31–7.27 (1H, m, Ar-H), 7.01–6.94 (2H,
m, Ar-H), 4.17 (4H, t, JH–H 5.5, OCH2CH2), 3.87 (3H, s,
3
3
Ar–OCH3), 2.07 (2H, q, JH–H 5.5, OCH2CH2); dC (75 MHz,
C2HCl3) 162.2 (ꢂ), 159.5 (+), 151.7 (ꢂ), 131.0 (+), 130.5
(+), 129.4 (ꢂ), 128.4 (+), 125.1 (+), 124.1 (+), 114.2 (+),
62.1 (ꢂ), 55.4 (+), 27.5 (ꢂ); m/z (EI) 295 (100%, M+).
(3-[1,3,2]Dioxaborinan-2-yl-phenyl)(4-methylbenzylidene)-
amine (3). A solution of p-tolualdehyde (120 mg, 1.00 mmol) in
absolute ethanol (5 cm3) was added to a stirred solution of 1
(177 mg, 1.00 mmol) in absolute ethanol (20 cm3). Benzene
(2 cm3) was added and the reaction vessel fitted with a
Dean–Stark side-arm adapter filled with absolute ethanol.
The reaction mixture was then stirred under reflux for 24 h,
after which time the solution was allowed to cool and the sol-
vent removed under reduced pressure. Recrystallisation of the
crude product with petroleum ether (40–60) afforded 3 (256
mg, 92%) as a light brown microcrystalline solid, mp 79–
80 ꢀC (Found: C, 73.16; H, 6.67; N, 4.98; C17H18BNO2
requires: C, 73.15; H, 6.50; N, 5.02%); lmax (MeOH)/nm (e/
dm3 molꢂ1 cmꢂ1) 308 (13 820); nmax/cmꢂ1 1618 (st, C=N);
dH (300 MHz, C2HCl3) 8.45 (1H, s, N=CH), 7.85–7.74 (2H,
m, Ar-H), 7.68–7.56 (2H, m, Ar-H), 7.44–7.26 (4H, m, Ar-
(4-Chlorobenzylidene)(3-[1,3,2]dioxaborinan-2-yl-phenyl)-
amine (7). Compound 7 was prepared according to the general
procedure for the synthesis of 3, except that 4-chlorobenzalde-
hyde (141 mg, 1.00 mmol) was used in place of benzaldehyde.
Recrystallisation of the crude product from petroleum ether
(40–60) afforded 7 (155 mg, 50%) as a bright yellow microcrys-
talline solid, mp 64–66 ꢀC (HRMS found: M+ m/z 299.0870.
C16H15BClNO2 requires: m/z 299.0884); lmax (MeOH)/nm
(e/dm3 molꢂ1 cmꢂ1) 319 (13 420); nmax/cmꢂ1 1623 (st, C=N);
dH (300 MHz, C2HCl3) 8.45 (1H, s, N=CH), 7.87–7.80 (2H,
m, Ar-H), 7.68–7.62 (1H, m, Ar-H), 7.61–7.56 (1H, m, Ar-
3
H), 7.47–7.41 (2H, m, Ar-H), 7.38 (1H, t, JH–H 7.4, Ar-H),
7.32–7.27 (1H, m, Ar-H), 4.18 (4H, t, JH–H 5.5, OCH2CH2),
3
3
H), 4.17 (4H, t, JH–H 5.5, OCH2CH2), 2.41 (3H, s, Ar–
3
3
2.07 (2H, q, JH–H 5.5, OCH2CH2); dC (75 MHz, C2HCl3)
CH3), 2.06 (2H, q, JH–H 5.5, OCH2CH2); dC (75 MHz,
C2HCl3) 160.1 (+), 151.6 (ꢂ), 141.7 (ꢂ), 133.9 (ꢂ), 131.2
(+), 129.5 (+), 128.8 (+), 128.4 (+), 125.1 (+), 124.2 (+),
62.1 (ꢂ), 27.5 (ꢂ), 21.7 (+); m/z (EI) 279 (100%, M+).
158.5 (+), 151.0 (ꢂ), 137.2 (ꢂ), 134.9 (ꢂ), 131.6 (+), 129.9
(+), 129.0 (+), 128.5 (+), 125.0 (+), 124.1 (+), 62.1 (ꢂ),
27.5 (ꢂ); m/z (EI) 299 (100%, M+).
(3-[1,3,2]Dioxaborinan-2-yl-phenyl)(3-methylbenzylidene)-
amine (4). Compound 4 was prepared according to the general
procedure for the synthesis of 3, except that m-tolualdehyde
(120 mg, 1.00 mmol) was used in place of benzaldehyde to
afford 4 (248 mg, 89%) as a light brown oil (HRMS found:
M+ m/z 279.1422; C17H18BNO2 requires: m/z 279.1431); lmax
MeOH)/nm (e/dm3 molꢂ1 cmꢂ1) 307 (12 028); nmax/cmꢂ1 1626
(st, C=N); dH (300 MHz, C2HCl3) 8.47 (1H, s, N=CH), 7.76
(1H, s, CH3CCHC), 7.71–7.57 (3H, m, Ar-H), 7.45–7.25
(3-[1,3,2]Dioxaborinan-2-yl-benzylidene)-phenyl-amine (8).8
Aniline (93.1 mg, 1.00 mmol) in absolute ethanol (5 cm3)
was added to a stirred solution of 3-formylbenzeneboronic
acid (150 mg, 1.00 mmol) in absolute ethanol (20 cm3). Ben-
zene (2 cm3) was added and the reaction vessel fitted with a
Dean–Stark side-arm adapter filled with absolute ethanol.
The reaction mixture was then stirred under reflux for 24 h.
The solution was allowed to cool and the solvent removed
under reduced pressure to afford a yellow oil. This oil was
redissolved in absolute ethanol (20 cm3) with stirring. To this,
a solution of 1,3-propanediol (76 mg, 1.0 mmol) in absolute
ethanol (5 cm3) was added, followed by a small amount of ben-
zene (2 cm3). The mixture was heated to reflux under Dean–
Stark conditions for 24 h, after which time the solution was
allowed to cool and the solvent removed under reduced
3
(4H, m, Ar-H), 4.18 (4H, t, JH–H 5.5, OCH2CH2), 2.42 (3H,
3
s, Ar–CH3), 2.07 (2H, q, JH–H 5.5, OCH2CH2); dC (75
MHz, C2HCl3) 160.4 (ꢂ), 151.5 (+), 138.5 (+), 136.4 (+),
132.2 (ꢂ), 131.4 (ꢂ), 129.0 (ꢂ), 128.7 (ꢂ), 128.5 (ꢂ), 126.4
(ꢂ), 125.2 (ꢂ), 124.1 (ꢂ), 62.1 (+), 27.5 (+), 21.4 (ꢂ); m/z
(EI) 279 (100%, M+).
1234
New J. Chem., 2002, 26, 1228–1237

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pressure. Trituration with petroleum ether (40–60) afforded 8
(245 mg, 92%) as a thick brown oil (Found: C, 72.26; H,
6.18; N, 5.38; C16H16BNO2 requires: C, 72.49, H, 6.08, N,
5.28%); lmax (MeOH)/nm (e/dm3 molꢂ1 cmꢂ1) 308 (11 352);
line (128 mg, 1.00 mmol) was used in place of aniline. Tritura-
tion with petroleum ether (40–60) afforded 12 (208 mg, 69%) as
a creamy yellow microcrystalline solid, mp 82–84 ꢀC (Found:
C, 64.07; H, 5.01; N, 4.60; C16H15BClNO2 requires: C,
64.15; H, 5.05; N, 4.68%); lmax (MeOH)/nm (e/dm3 molꢂ1
cmꢂ1) 302 (9648); nmax/cmꢂ1 1621 (st, C=N); dH (300 MHz,
C2HCl3) 8.43 (1H, s, N=CH), 8.22 (1H, s, CCHCB), 8.05–
7.96 (1H, m, Ar-H), 7.92–7.85 (1H, m, Ar-H), 7.45 (1H, m,
Ar-H), 7.38–7.31 (2H, m, Ar-H), 7.18–7.11 (2H, m, Ar-H),
4.18 (4H, t, JH–H 5.5, OCH2CH2), 2.08 (2H, q, JH–H 5.5,
OCH2CH2); dC (75 MHz, C2HCl3) 161.7 (+), 150.3 (ꢂ),
137.1 (+), 135.0 (+), 134.8 (ꢂ), 131.4 (ꢂ), 130.3 (+), 129.2
(+), 128.1 (+), 122.2 (+), 62.0 (ꢂ), 27.3 (ꢂ); m/z (EI) 299
(100%, M+).
n
max/cmꢂ1 1627 (st, C=N); dH (300 MHz, C2HCl3) 8.48 (1H,
s, N=CH), 8.24 (1H, s, Ar-H), 8.07–7.99 (1H, m, Ar-H),
7.92–7.86 (1H, m, Ar-H), 7.50–7.36 (3H, m, Ar-H), 7.26–7.19
3
(3H, m, Ar-H), 4.18 (4H, t, JH–H 5.5, OCH2CH2), 2.07 (2H,
3
q, JH–H 5.5, OCH2CH2); dC (75 MHz, C2HCl3) 160.9 (+),
3
3
152.3 (ꢂ), 136.8 (ꢂ), 135.4 (+), 135.0 (+), 130.3 (+), 129.2
(+), 128.1 (+), 125.8 (+), 120.9 (+), 62.1 (ꢂ), 27.5 (ꢂ); m/z
(LSI-MS) 266 (100%, [M + H]+).
(3-[1,3,2]Dioxaborinan-2-yl-benzylidene)(3-nitrophenyl)amine
(9). Compound 9 was prepared according to the general proce-
dure for the synthesis of 8, except that 3-nitroaniline (138 mg,
1.00 mmol) was used in place of aniline. Precipitation of the
crude product from a chloroform solution with n-hexane
afforded 9 (265 mg, 85%) as a bright yellow microcrystalline
solid, mp 102–104 ꢀC (Found: C, 61.84; H, 5.12; N, 9.08;
C16H15BN2O4 requires: C, 61.97; H, 4.88; N, 9.03%); lmax
(MeOH)/nm (e/dm3 molꢂ1 cmꢂ1) 256 (28 640); nmax/cmꢂ1
1628 (st, C=N); dH (300 MHz, C2HCl3) 8.49 (1H, s, N=CH),
8.26 (1H, s, CCHCB), 8.12–7.98 (3H, m, Ar-H), 7.95–7.88
(3-[1,3,2]Dioxaborinan-2-yl-benzylidene)-p-tolylamine (13).
Compound 13 was prepared according to the general proce-
dure for the synthesis of 8, except that p-toluidine (107 mg,
1.00 mmol) was used in place of aniline. Crude 13 was dis-
solved in n-hexane to remove a small amount of orange solid.
The solution was then concentrated under reduced pressure to
afford 13 (225 mg, 81%) as a clear oil (Found: C, 73.05; H,
6.38; N, 4.96; C17H18BNO2 requires: C, 73.15; H, 6.50; N,
5.02%); lmax (MeOH)/nm (e/dm3 molꢂ1 cmꢂ1) 315 (11 605);
3
n
s, N=CH), 8.22 (1H, s, CCHCB), 8.07–7.99 (1H, m, Ar-H),
max/cmꢂ1 1625 (st, C=N); dH (300 MHz, C2HCl3) 8.48 (1H,
(1H, m, Ar-H), 7.58–7.44 (3H, m, Ar-H), 4.19 (4H, t, JH–H
3
5.5, OCH2CH2), 2.08 (2H, q, JH–H 5.5, OCH2CH2); dC (75
MHz, C2HCl3) 163.1 (+), 153.4 (+), 148.9 (+), 137.6 (ꢂ),
135.3 (ꢂ), 134.7 (ꢂ), 130.7 (ꢂ), 129.9 (ꢂ), 128.3 (ꢂ), 127.6
(ꢂ), 120.3 (ꢂ), 115.5 (ꢂ), 62.1 (+), 27.4 (+); m/z (EI) 310
(30%, M+) 138 (100).
3
7.91–7.84 (1H, m, Ar-H), 7.45 (1H, t, JH–H 7.4, Ar-H),
3
7.23–7.11 (4H, m, Ar-H), 4.18 (4H, t, JH–H 5.5, OCH2CH2),
3
2.37 (3H, s, Ar–CH3), 2.08 (2H, q, JH–H 5.5, OCH2CH2); dC
(75 MHz, C2HCl3) 160.1 (+), 149.7 (ꢂ), 136.6 (+), 135.7
(ꢂ), 135.6 (ꢂ), 134.9 (+), 130.2 (+), 129.8 (+), 128.1 (+),
120.9 (+), 62.1 (ꢂ), 27.5, (ꢂ) 21.1 (+); m/z (EI) 279 (73%,
M+), 106 (100).
{4-[(3-[1,3,2]Dioxaborinan-2-yl-benzylidene)amino]phenyl}-
methanol (10). Compound 10 was prepared according to the
general procedure for the synthesis of 8, except that p-anisidine
(123 mg, 1.00 mmol) was used in place of aniline. Precipitation
of the crude product from a chloroform solution with n-hexane
afforded 10 (247 mg, 83%) as a light brown microcrystalline
solid, mp 83–85 ꢀC (HRMS found: M+ m/z 295.1371;
C17H18BNO3 requires: m/z 295.1380); lmax (MeOH)/nm (e/
dm3 molꢂ1 cmꢂ1) 330 (15 200); nmax/cmꢂ1 1620 (st, C=N);
dH (300 MHz, C2HCl3) 8.49 (1H, s, N=CH), 8.20 (1H, s,
CCHCB), 8.05–7.98 (1H, m, Ar-H), 7.89–7.82 (1H, m, Ar-
(4-Phenyliminomethylphenyl)methanol (14). p-Anisaldehyde
(136 mg, 1.00 mmol) in absolute ethanol (5 cm3) was added
to a stirred solution of aniline (93.1 mg, 1.00 mmol) in absolute
ethanol (20 cm3). Benzene (2 cm3) was added and the reaction
vessel was fitted with a Dean–Stark side-arm adapter filled
with absolute ethanol. The reaction mixture was then stirred
under reflux for 24 h. The mixture was allowed to cool and
then concentrated under reduced pressure to afford crude 14
as a creamy yellow solid. The crude product was recrystallised
from the minimum amount of petroleum ether (40–60) to
afford 14 (168 mg, 79%) as a white microcrystalline solid, mp
56–58 ꢀC [lit. 58–60 ꢀC]40 (HRMS found: M+ m/z 211.1001;
C14H13NO requires: m/z, 211.0997); lmax (MeOH)/nm (e/
dm3 molꢂ1 cmꢂ1) 309 (23 272); dH (300 MHz, C2H3O2H)
8.44 (1H, s, N=CH), 7.86 (2H, m, Ar-H), 7.45–7.33 (2H, m,
Ar-H), 7.28–7.15 (3H, m, Ar-H), 7.18–6.99 (2H, m, Ar-H),
3.86 (3H, s, Ar–OCH3); dC (75 MHz, C2HCl3) 162.3 (ꢂ),
159.8 (+), 152.4 (ꢂ), 130.6 (+), 129.3 (ꢂ), 129.2 (+), 125.6
(+), 120.9 (+), 114.2 (+), 55.5 (+); m/z (EI) 211 (100%, M+).
3
H), 7.44 (1H, t, JH–H 7.7, Ar-H), 7.28–7.22 (2H, m, Ar-H),
4.18 (4H, t, JH–H 5.5, OCH2CH2), 3.83 (3H, s, Ar–OCH3),
3
3
2.08 (2H, q, JH–H 5.5, OCH2CH2); dC (75 MHz, C2HCl3)
158.9 (+), 158.1 (ꢂ), 145.1 (ꢂ), 136.4 (+), 135.6 (ꢂ), 134.8
(+), 130.0 (+), 128.1 (+), 122.2 (+), 114.4 (+), 62.0 (ꢂ),
55.5 (+), 27.4 (ꢂ); m/z (EI) 295 (100%, M+).
{3-[(3-[1,3,2]Dioxaborinan-2-yl-benzylidene)amino]phenyl}-
methanol (11). Compound 11 was prepared according to the
general procedure for the synthesis of 8, except that m-anisi-
dine (123 mg, 1.00 mmol) was used in place of aniline. The pro-
duct 11 (266 mg, 90%) was afforded as a light yellow oil
(Found: C, 69.35; H, 6.26; N, 4.80; C17H18BNO3 requires: C,
69.18; H, 6.15; N, 4.75%); lmax (MeOH)/nm (e/dm3 molꢂ1
cmꢂ1) 306 (9550); nmax/cmꢂ1 1626 (st, C=N); dH (300 MHz,
C2HCl3) 8.47 (1H, s, N=CH), 8.22 (1H, s, CCHCB), 8.07–
7.98 (1H, m, Ar-H), 7.92–7.85 (1H, m, Ar-H), 7.45 (1H, t,
3JH–H 7.7, Ar-H), 7.33–7.25 (1H, m, Ar-H), 6.85–6.75 (3H,
(3-Nitrobenzylidene)phenylamine (15). Compound 15 was
synthesised according to the general procedure for the synth-
esis of 14, except 3-nitrobenzaldehyde (151 mg, 1.0 mmol)
was used in place of p-anisaldehyde. Recrystallisation from
petroleum ether (40–60) afforded 15 (120 mg, 53%) as a bright
yellow microcrystalline solid, mp 62–63 ꢀC (HRMS found: M+
m/z 226.0749; C13H10N2O2 requires: m/z 226.0742); lmax
(MeOH)/nm (e/dm3 molꢂ1 cmꢂ1) 310 (9670); nmax/cmꢂ1
3
m, Ar-H), 4.18 (4H, t, JH–H 5.5, OCH2CH2), 3.84 (3H, s,
3
Ar–OCH3), 2.07 (2H, q, JH–H 5.5, OCH2CH2); dC (75 MHz,
C2HCl3) 161.0 (ꢂ), 160.3 (+), 153.7 (+), 136.8 (ꢂ), 135.3
(+), 135.0 (ꢂ), 130.3 (ꢂ), 129.9 (ꢂ), 128.1 (ꢂ), 112.9 (ꢂ),
111.8 (ꢂ), 106.6 (ꢂ), 103.9 (ꢂ), 62.1 (+), 55.4 (ꢂ), 27.5 (+);
m/z (EI) 295 (75%, M+), 123 (100).
3
1616 (st, C=N); dH (300 MHz, C2H3O2H) 8.77 (1H, t, JH–H
1.8, Ar-H), 8.67 (1H, s, N=CH), 8.37–8.31 (1H, m, Ar-H),
8.32–8.26 (1H, m, Ar-H), 7.73 (1H, m, Ar-H), 7.45–7.38 (2H,
m, Ar-H), 7.33–7.26 (3H, m, Ar-H); dC (75 MHz, C2HCl3)
157.2 (+), 150.9 (ꢂ), 148.7 (ꢂ), 137.9 (ꢂ), 134.2 (+), 129.8
(+), 129.4 (+), 126.9 (+), 125.6 (+), 123.5 (+), 121.0 (+);
m/z (EI) 226 (100%, M+).
(4-Chlorophenyl)(3-[1,3,2]dioxaborinan-2-yl-benzylidene)-
amine (12). Compound 12 was prepared according to the gen-
eral procedure for the synthesis of 8, except that 4-chloroani-
New J. Chem., 2002, 26, 1228–1237
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(3H, m, Ar-H), 7.30–7.23 (1H, m, Ar-H), 7.09–6.99 (3H, m,
(4-Methylbenzylidene)phenylamine (16). Compound 16 was
synthesised according to the general procedure for the synth-
esis of 14, except p-tolualdehyde (120 mg, 1.0 mmol) was used
in place of p-anisaldehyde. Recrystallisation from petroleum
ether (40–60) afforded 16 (163 mg, 83%) as a white solid, mp
43–44 ꢀC [lit. 44–45 ꢀC]23 (HRMS found: M+ m/z 195.1052;
C14H13N requires: m/z 195.1048); lmax (HPLC MeOH)/nm
(e/dm3 molꢂ1 cmꢂ1) 304 (16 635); dH (300 MHz, C2H3O2H)
8.49 (1H, s, N=CH), 7.85–7.76 (2H, m, Ar-H), 7.45–7.16
(7H, m, Ar-H), 2.40 (3H, s, Ar–CH3); dC (75 MHz, C2HCl3)
160.4 (+), 152.3 (ꢂ), 141.9 (ꢂ), 133.7 (ꢂ), 129.6 (+), 129.2
(+), 128.9 (+), 125.8 (+), 121.1 (+), 21.7 (+); m/z (EI) 195
(100%, M+).
Ar-H), 2.36 (3H, s, Ar–CH3); dH (300 MHz, C2HCl3) 8.49
(1H, s, N=CH), 8.01–7.93 (2H, m, Ar-H), 7.55–7.49 (3H, m,
Ar-H), 7.39–7.31 (1H, m, Ar-H), 7.15–7.07 (3H, m, Ar-H),
2.45 (3H, s, Ar–CH3); dC (75 MHz, C2HCl3) 160.4 (+), 152.3
(ꢂ), 139.2 (ꢂ), 136.5 (ꢂ), 131.6 (+), 129.3 (+), 129.0 (+),
127.0 (+), 121.9 (+), 118.2 (+), 21.7 (+); m/z (EI) 195
(100%, M+).
Benzylidene(4-chlorophenyl)amine (21). Compound 21 was
synthesised according to the general procedure for the synth-
esis of 18, except 4-chloroaniline (128 mg, 1.00 mmol) was used
in place of p-anisidine. Recrystallisation from petroleum ether
(40–60) afforded 21 (70.8 mg, 33%) as a white solid, mp 59–
60 ꢀC [lit. 61–61.5 ꢀC]41 (Found: C, 72.40; H, 4.75; N, 6.56;
C13H10ClN requires: C, 72.39; H, 4.67; N, 6.49%; HRMS
found: M+ m/z 215.0492; C13H10ClN requires: m/z
(4-Chlorobenzylidene)phenylamine (17). Compound 17 was
synthesised according to the general procedure for the synth-
esis of 14, except 4-chlorobenzaldehyde (141 mg, 1.0 mmol)
was used in place of p-anisaldehyde. Recrystallisation from
petroleum ether (40–60) afforded (175 mg, 81%) as a white
solid, mp 62–63 ꢀC [lit. 60–62 ꢀC]23 (Found: C, 72.55; H,
4.44; N, 6.65; C13H10ClN requires: C, 72.39; H, 4.67; N,
6.49%; HRMS found: M+ m/z 215.0507; C13H10ClN requires:
m/z 215.0502); lmax (MeOH)/nm (e/dm3 molꢂ1 cmꢂ1) 309
(12 257); dH (300 MHz, C2HCl3) 8.42 (1H, s, N=CH), 7.89–
7.81 (2H, m, Ar-H), 7.49–7.36 (4H, m, Ar-H), 7.29–7.18 (3H,
m, Ar-H); dC (75 MHz, C2HCl3) 158.8 (+), 151.7 (ꢂ), 137.4
(ꢂ), 134.8 (ꢂ), 130.0 (+), 129.3 (+), 129.1 (+), 126.3 (+),
121.0 (+); m/z (EI) 215 (100%, M+).
215.0502); lmax (MeOH)/nm (e/dm3 molꢂ1 cmꢂ1
) 311
(11 456); dH (300 MHz, C2HCl3) 8.43 (1H, s, N=CH), 7.92–
7.86 (2H, m, Ar-H), 7.52–7.45 (3H, m, Ar-H), 7.39–7.32 (2H,
m, Ar-H), 7.19–7.12 (2H, m, Ar-H); dC (75 MHz, C2HCl3)
160.8 (+), 150.5 (ꢂ), 136.0 (ꢂ), 131.7 (+), 131.5 (ꢂ), 129.3
(+), 128.9 (+), 122.3 (+); m/z (EI) 215 (100%, M+).
Acknowledgements
T. D. J. wishes to acknowledge the Royal Society for support
through the award of a University Fellowship. J. H. H. wishes
to acknowledge the EPSRC for support through the award of
a Studentship. M. D. P. wishes to acknowledge the EPSRC for
support through the award of a Studentship. We would also
like to thank the University of Bath for support.
[4-(Benzylideneamino)phenyl]methanol (18). p-Anisidine (123
mg, 1.00 mmol) in absolute ethanol (5 cm3) was added to a stir-
red solution of benzaldehyde (106 mg, 1.00 mmol) in absolute
ethanol (20 cm3). Benzene (2 cm3) was added and the reaction
vessel was fitted with a Dean–Stark side-arm adapter filled
with absolute ethanol. The reaction mixture was then stirred
under reflux for 24 h. The mixture was allowed to cool and
then concentrated under reduced pressure to afford crude 18
as an off-white solid. The crude product was recrystallised
from the minimum amount of petroleum ether (40–60) to
afford 18 (131 mg, 62%) as a white microcrystalline solid, mp
69–70 ꢀC [lit. 70–71 ꢀC]41 (HRMS found: M+ m/z 211.0999;
C14H13NO requires: m/z 211.0997); lmax (MeOH)/nm (e/
dm3 molꢂ1 cmꢂ1) 330 (16 952); dH (300 MHz, C2H3O2H)
8.56 (1H, s, N=CH), 7.93–7.86 (2H, m, Ar-H), 7.51–7.45
(3H, m, Ar-H), 7.30–7.23 (2H, m, Ar-H), 6.99–9.93 (2H, m,
Ar-H), 3.81 (3H, s, Ar–OCH3); dC (75 MHz, C2HCl3) 158.5
(+), 158.3 (ꢂ), 144.9 (ꢂ), 136.5 (ꢂ), 131.1 (+), 128.8 (+),
128.6 (+), 122.3 (+), 114.4 (+), 55.5 (+); m/z (EI) 211 (80%,
M+), 196 (100, [M ꢂ CH3]+).
References
1
J. H. Hartley, T. D. James and C. J. Ward, J. Chem. Soc., Perkin
Trans. 1, 2000, 19, 3155.
2
3
T. D. James and S. Shinkai, Top. Curr. Chem., 2002, 218, 159.
S. Arimori, M. L. Bell, C. S. Oh, K. A. Frimat and T. D. James, J.
Chem. Soc., Perkin Trans. 1, 2002, 803.
4
5
6
H. Matsuda, H. Nagamatsu, T. Okuyama and T. Fueno, Bull.
Chem. Soc. Jpn., 1984, 57, 500.
H. Nagamatsu, T. Okuyama and T. Fueno, Bull. Chem. Soc. Jpn.,
1984, 57, 2502.
H. Nagamatsu, T. Okuyama and T. Fueno, Bull. Chem. Soc. Jpn.,
1984, 57, 2508.
7
8
9
G. Rao and M. Philipp, J. Org. Chem., 1991, 56, 1505.
J. H. Hartley and T. D. James, Tetrahedron Lett., 1999, 40, 2597.
J. O. Edwards and J. P. Lorand, J. Org. Chem., 1959, 24, 769.
10 M. N. Khan and R. Yusoff, J. Phys. Org. Chem., 2001, 14, 74.
11 M. Page and A. Williams, Organic and Bio-organic Mechanisms,
Addison Wesley Longman, London, 1997.
Benzylidene-p-tolylamine (19). Compound 19 was synthe-
sised according to the general procedure for the synthesis of
18, except p-toluidine (107 mg, 1.00 mmol) was used in place
of p-anisidine, to afford 19 (148 mg, 76%) as a brown oil
(HRMS found: M+ m/z 195.1056; C14H13N requires: m/z
12 R. L. Reeves, J. Org. Chem., 1965, 30, 3129.
13 P. Mendes, Comput. Appl. Biosci., 1993, 9, 563.
14 P. Mendes, Trends Biochem. Sci., 1997, 22, 361.
15 P. Mendes and D. B. Kell, Bioinformatics, 1998, 14, 869.
16 J. N. Brønsted and K. Pedersen, Z. Phys. Chem., 1924, 108, 185.
17 C. J. Brown and A. J. Kirby, Chem. Commun., 1996, 2355.
18 C. J. Brown and A. J. Kirby, J. Chem. Soc., Perkin Trans. 2, 1997,
1081.
19 T. Okuyama, H. Shibuya and T. Fueno, J. Am. Chem. Soc., 1982,
104, 730.
20 J. Hoffmann, J. Klicnar, V. Sterba and M. Vecera, Coll. Czech.
Chem. Commun., 1970, 35, 1387.
195.1048); lmax (MeOH)/nm (e/dm3 molꢂ1 cmꢂ1
) 315
(8900); dH (300 MHz, C2H3O2H) 8.49 (1H, s, N=CH), 7.91–
7.83 (2H, m, Ar-H), 7.50–7.43 (3H, m, Ar-H), 7.22–7.10 (4H,
m, Ar-H), 2.33 (3H, s, Ar–CH3); dC (75 MHz, C2HCl3) 159.7
(+), 149.5 (ꢂ), 136.4 (ꢂ), 135.9 (ꢂ), 131.3 (+), 129.9 (+),
128.8 (+), 121.0 (+), 21.2 (+); m/z (EI) 195 (100%, M+).
Benzylidene-m-tolylamine (20). Compound 20 was synthe-
sised according to the general procedure for the synthesis of
18, except m-toluidine (107 mg, 1.00 mmol) was used in place
of p-anisidine, to afford 20 (174 mg, 89%) as a light brown oil
(HRMS found: M+ m/z 195.1039; C14H13N requires: m/z
) 311
(9602); nmax/cmꢂ1 1629 (st, C=N); dH (300 MHz, C2H3O2H)
8.50 (1H, s, N=CH), 7.93–7.86 (2H, m, Ar-H), 7.52–7.45
21 A. V. Willi, Helv. Chem. Acta, 1956, 39, 1193.
22 A. V. Willi and R. E. Robertson, Can. J. Chem., 1953, 31, 361.
23 E. H. Cordes and W. P. Jencks, J. Am. Chem. Soc., 1962, 84, 832.
24 W. P. Jencks, Prog. Phys. Org. Chem., 1964, 2, 63.
25 A. J. Kirby and A. Parkinson, J. Chem. Soc., Chem. Commun.,
1994, 707.
26 N. Agmon, Chem. Phys. Lett., 1995, 244, 456.
27 T. J. F. Day, U. W. Schmitt and G. A. Voth, J. Am. Chem. Soc.,
2000, 122, 12 027.
195.1048); lmax (MeOH)/nm (e/dm3 molꢂ1 cmꢂ1
1236
New J. Chem., 2002, 26, 1228–1237

View Article Online
34 Kaleidagraph, Synergy Software, Reading, PA, USA, 1997.
35 K. Levenberg, Q. Appl. Math., 1944, 2, 164.
36 D. W. Marquardt, SIAM J., 1963, 11.
37 P. Mendes, Trends Biochem. Sci., 1997, 22, 361.
38 S. M. Goldfield, R. E. Quant and H. F. Trotter, Econometrica,
1966, 34, 541.
28 D. Marx, M. E. Tuckerman, J. Hutter and M. Parrinello, Nature
(London), 1999, 397, 601.
29 M. Tuckerman, K. Laasonen, M. Sprik and M. Parrinello, J.
Chem. Phys., 1995, 103, 150.
30 J. Homer and M. C. Perry, J. Chem. Soc., Chem. Commun., 1994,
373.
31 J. Homer and M. C. Perry, J. Chem. Soc., Perkin Trans. 2, 1995,
533.
39 G. A. F. Seber and C. J. Wild, Nonlinear Regression, John Wiley
and Sons, New York, 1989.
32 UV WinLab, Perkin-Elmer, Norwalk, CT, USA, 1997.
33 D. D. Perrin and B. Dempsey, Buffers for pH and Metal Ion Con-
trol, Chapman and Hall, London, 1974.
40 R. A. Benkeser and D. C. Snyder, J. Organomet. Chem., 1982,
225, 107.
41 J. D. Margerum and J. A. Sousa, Appl. Spectrosc., 1965, 19, 91.
New J. Chem., 2002, 26, 1228–1237
1237