Examination of pinanediol-boronic acid ester formation in aqueous media: Relevance to the relative stability of trigonal and tetrahedral boronate esters

Article abstract of DOI:10.1039/d0ob00201a

The interaction of pinanediol with 2-fluorophenylboronic acid and several other substituted phenylboronic acids was studied in 40% vol. aqueous acetonitrile by ¹H and ¹¹B NMR, potentiometric and spectrophotometric titrations at variable pH values. The experimental results reveal the formation of a very stable trigonal ester (K_trig ≈ 2 × 10⁴ M^-1) and a significantly less stable tetrahedral hydroxocomplex (K_tet ≈ 5 × 10³ M^-1) in contrast to the traditionally observed inverted order of stabilities K_trig < K_tet. Comparison of the crystal structure of the trigonal ester isolated from aqueous acetonitrile with the DFT simulated structure of the respective hydroxocomplex shows that an unusual order of stabilities K_trig > K_tet is observed in spite of the existence of the usual strain release effect in the O-B-O angle considered responsible for the typically observed increased stability of the tetrahedral hydroxocomplex. A complementary study of the stability of the six-membered cyclic boronate esters of chromotropic acid demonstrated the order K_trig ? K_tet although the strain was absent in these esters. The results for m-, p-substituted phenylboronic acids show that the stability of both five- and six-membered trigonal esters formed with pinanediol and chromotropic acid, respectively, is insensitive to electronic effects but the electron accepting substituents stabilize the hydroxocomplexes. It follows from the whole set of results that K_tet can be much larger than K_trig in the absence of the strain, but with a sufficiently acidic diol, and that the presence of the strain does not necessarily make K_tet larger than K_trig for a less acidic diol with a purely saturated hydrocarbon backbone. Thus, the electronic effects manifested in the acidity of the diol appear to be more significant than the strain release effect in determining the K_tet/K_trig ratio.

Full text of DOI:10.1039/d0ob00201a

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Examination of pinanediol - boronic acid ester formation in aqueous media:
relevance to the relative stability of trigonal and tetrahedral boronate esters
Mayte A. Martínez-Aguirre,† Marcos Flores-Alamo,† Felipe Medrano‡ and Anatoly K.
Yatsimirsky*†
†Facultad de Química, Universidad Nacional Autónoma de México, 04510 México D.F., México
Email: iatsimirski46@comunidad.unam.mx
‡ Departamento de Ciencias químico-biológicas, Universidad de Sonora, Rosales y Luis Encinas
Johnson s/n. Centro 83000. Hermosillo, Sonora. México.
Abstract
The interaction of pinanediol with 2-fluorophenylboronic and several other substituted
phenylboronic acids was studied in 40% vol. aqueous acetonitrile by 1H and 11B NMR,
potentiometric and spectrophotometric titrations at variable pH. The experimental results reveal a
formation of a very stable trigonal ester (Ktrig  2×104 M-1) and a significantly less stable
tetrahedral hydroxocomplex (Ktet  5×103 M-1) in contrast to traditionally observed inverted order
of stabilities Ktrig < Ktet. Comparison of the crystal structure of trigonal ester isolated from
aqueous acetonitrile with DFT simulated structure of the respective hydroxocomplex shows that
the unusual order of stabilities Ktrig > Ktet is observed in spite of the existence of a usual strain
release effect in the O-B-O angle considered responsible for the typically observed increased
stability of the tetrahedral hydroxocomplex. A complementary study of stability of the
six-membered cyclic boronate esters of chromotropic acid demonstrated the order Ktrig << Ktet
although the strain was absent in these esters. Results for m-, p-substituted phenylboronic acids
show that stability of both five- and six-membered trigonal esters formed with pinanediol and
chromotropic acid, respectively, is insensitive to electronic effects but the electron accepting
substituents stabilize the hydroxocomplexes. It follows from the whole set of results that Ktet can
be much larger than Ktrig in the absence of the strain, but with a sufficiently acidic diol, and that
the presence of the strain does not necessarily make Ktet larger than Ktrig for a low acidic diol with
purely saturated hydrocarbon backbone. Thus, the electronic effects manifested in acidity of the
diol appear to be more significant than the strain release effect in determining the Ktet/Ktrig ratio.
1

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Introduction
The formation of boronic acid diol esters is important for molecular recognition of
sugars,1 self-assembly of stimuli responsive supramolecular structures 2,3,4,5 and as a type of
bioorthogonal chemical reactions for bioconjugation.6 The process is pH-dependent and generally
is interpreted in terms of Scheme 1.1,2 Typically Ktet >> Ktrig and therefore as a rule only
formation of hydroxyboronate esters (hydroxocomplexes of boronic acid esters) shown at the
right side of Scheme 1 is observed in water.
OH
R'
OH
R
B
H+
-
+
+
OH
OH
OH
R''
B
Ka
Ktet
OH
OH
OH
R'
R'
OH
O
O
E
H+
Ktrig
Ka
-
B
R
+
O
R
B
R
B
+
R'
O
OH
R''
R''
R''
D
K'tet
Ka
-
R'
O
OH
OH
H+
R
B
+
+
R''
OH
Scheme 1. The equilibria for boronate ester formation coupled with the equilibria for acid
dissociation of the reaction components (water as the reaction component omitted)
The stability of boronate esters in neutral aqueous solutions is generally modest with
observed formation constants (Kobs) rarely surpassing 103 M-1 for most often employed
phenylboronic acid and common polyols such as sugars or sugar alcohols.7,8 However the high
stability under “physiological” conditions is very important especially for bioconjugation
applications. Earlier the improved binding with Kobs above 104 M-1 was found with
salicylhydroxamic acid as a ligand,6b,9 and recently unprecedentedly high stability constants
reaching the range 105-106 M-1 for boronate esters of pinanediol derivatives like 1 with ortho-
substituted phenylboronic acids were reported. 10
2

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OH
OH
OH
OH
OH
OH
O
(
)
O
CH
3
2
NaO3S
SO3Na
1
(−)-Pinanediol
Chromotropic acid
A traditional anionic tetrahedral hydroxyboronate ester structure was assigned to the
complexes, but at the same time the stability of pinanediol esters decreased for boronic acids with
electron acceptor substituents 10 in a contradiction with a large positive Hammett  constant
reported for stability constants of hydroxyboronate esters with different diols.8 This prompted us
to undertake a deeper study of the thermodynamics of pinanediol – boronic acid interaction
involving determination of equilibrium constants by three different techniques (potentiometric,
UV-Vis and NMR titrations) in a wide range of pH together with X-Ray structural
characterization of the esters isolated from the same reaction medium. The interaction with 2-
fluorophenylboronic acid was studied in most details because it combined the high affinity with
fast equilibration time.
It appeared that although the postulated tetrahedral boronate ester of pinanediol did exist
in basic solutions, it was surprisingly less stable than the trigonal boronic acid ester (Ktet < Ktrig)
breaking seemingly universal tendency of higher stability of tetrahedral boronate esters usually
attributed to the release of strain induced in the O-B-O angle of the trigonal five-membered cyclic
ester.1 However, the X-ray structures of two isolated pinanediol esters showed the existence of a
usual strain, which in this case did not provide the expected large Ktet/Ktrig ratio. It is worth noting
that large reported Ktet/Ktrig ratios 7,11,12 are obtained with polyols rather than with diols because
only polyols give esters of sufficient stability allowing determination of both Ktrig and Ktet.
However polyols tend to form tridentate tetrahedral complexes 1,13 impossible for trigonal esters.
This extra chelation evidently gives an extra stability to tetrahedral complexes in comparison
with trigonal esters and contributes to high Ktet/Ktrig ratios. In this respect pinanediol provides a
unique example of an aliphatic diol which allows one a quantitative estimate of the Ktet/Ktrig ratio
free of the extra chelation effect.
To further discuss the role of strain in relative stabilities of trigonal and tetrahedral esters
we measured also Ktet/Ktrig ratios for a series of strain-free six-membered esters of chromotropic
acid. A comparison of results obtained in this study with relevant literature data shows that the
3

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electronic effects manifested in the diol acidity are more important for the relative stability of
trigonal and tetrahedral esters than the strain release effect.
An often discussed related phenomenon is the difference in acidities of a free boronic acid
and its trigonal ester. It follows from the Scheme 1 that the ratio Ktet/Ktrig must be equal to the
ratio of the acidity constants KaE/KaB. This relationship is manifested in a shift in the observed
pKa of a boronic acid in the presence of added diol, which has been proved on many occasions
experimentally.1,7,11,12 At the molecular level the origin of both effects is the same because the
same species are involved and throughout this paper only the interpretation of Ktet/Ktrig ratio is
discussed.
The relative stability of tetrahedral hydroxyboronate complexes and the respective
trigonal cyclic boronic acid esters (Ktet/Ktrig or KaE/KaB ratio) is one of the key aspects of
thermodynamics of boronate ester formation. In a comprehensive review of different approaches
to interpretation of this ratio it is concluded that analysis based on O-B-O angle contraction “is
somewhat of a simplification”, but it still plays the central role.1a In this paper we turn attention
to the importance of diol acidity as a predominant factor.
Results and Discussion
Reactions of pinanediol with boronic acids were studied under conditions similar to those
employed in ref.10, namely in aqueous solutions containing 40% vol. MeCN at room temperature
in the presence of 0.05 M appropriate buffer. Initially we attempted to study the interaction with
2-methyl-4-methoxyphenylboronic acid (MMPBA) which was reported as the most efficient
reagent (Kobs = 3.3105 M-1 for binding to 1)10, but the equilibration was very slow and therefore
the most of the work was performed with 2-fluorophenylboronic acid (FPBA) possessing lower,
but still a very large affinity (Kobs = 2.7104 M-1 for binding to 1)10 and equilibrating within ca. 5
min.
HO
OH
B
HO
HO
OH
HO
OH
B
O
B
B
F
O
PBA
MMPBA
FPBA
benzoxaborole
4

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The signals in 1H spectrum of both free pinanediol and its PBA (phenylboronic acid) ester
were assigned by using the standard 2D technique (ESI, Figs. S1, S2). Figure 1 shows
superposition of spectra of free components, pinanediol and FPBA (Fig.1a, b), and their 1:1
mixture, which is converted almost quantitatively into the ester (Fig.1c). Large complexation
induced downfield shifts are observed for protons of pinanediol in positions 2 and 10 closest to
the hydroxyl groups apparently due to the electron acceptor effect of the boronic acid. Also
significant both upfield and downfield shifts are observed for distant protons in positions 5’ and
3’. All signals of aromatic protons of FPBA move slightly upfield. Noticeable shifts of sharp
intense signals of methyl groups provide the most convenient way for the calculation of the
observed association constant by integration of the signals of free and bound diol. From results
shown in Fig. 1 we estimated Kobs = 1.5×104 M-1 in a close agreement with the reported stability
constant of FPBA ester of 1 under similar conditions (Ref. 10, see above). Similar spectral
changes were observed in DMSO, where the disappearance of OH groups of both components is
clearly seen (ESI, Fig.S3), and with other arylboronic acids in MeCN/water (ESI, Fig.S4).
Figure 1. 1H NMR spectra for free pinanediol (a), free FPBA (b), the equimolar mixture of 5 mM
FPBA-pinanediol (c), FPBA in the presence of 1 equivalent of NaOH (d), the equimolar mixture
of 5 mM FPBA-pinanediol in presence of 1 equivalent of NaOH (e) in 40% v/v MeCN-d3/D2O.
Asterisks mark the signals of free pinanediol in spectra of FPBA-pinanediol mixtures.
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If the ester obtained under conditions of Fig. 1c would be the tetrahedral
hydroxocomplex, the addition of base would not induce further changes in its NMR spectrum.
However, as shown in Fig.1e, the addition of NaOH induces strong changes in the spectrum of
the system. Signals of protons of free pinanediol become relatively more intense, signals which
belong to the trigonal ester disappear completely and new signals apparently belonging to the
tetrahedral hydroxocomplex are observed. Signals of aromatic protons move up-field and become
close to those of the FPBA anion (Fig.1d). There are more signals than expected for a single
reaction product indicating formation of a mixture of isomeric hydroxocomplexes. Since
pinanediol is chiral and the formation of the tetrahedral boron by addition of hydroxide creates a
new chiral center, a mixture of diastereomeric complexes can be produced. An estimate of Ktet by
integration of signals in this spectrum was impossible due to the uncertainty in signal assignment,
but a quantitative analysis of the ester formation in a basic solution turned out to be possible by
using 11B NMR results.
Figure 2a shows the 11B NMR spectrum of free FPBA in a neutral solution with the signal
at 27.95 ppm. In the presence of 1 molar equivalent of pinanediol two poorly resolved signals are
observed attributable to the mixture of the trigonal ester with maximum at 29.28 ppm and a small
amount of the free acid (Fig.2b). Addition of 1 molar equivalent of hydroxide to this mixture
transforms the spectrum in that shown in Figure 2d with well resolved signals at 1.57 and 5.88
ppm. The signal at 1.57 ppm belongs to the free anion of FPBA (Fig. 2c). Integration of these
signals gives Ktet = 4000 M-1, approximately 4 times smaller than the given above Kobs in a
neutral solution, which corresponds to Ktrig.
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Figure 2. 11B NMR spectra of free 5 mM FPBA (a), the equimolar mixture of FPBA-pinanediol
without added base (b), FPBA in presence of 1 equivalent of NaOH (c), equimolar mixture of
FPBA-pinanediol in the presence of 1 equivalent of NaOH (d) obtained in 40% v/v MeCN-
d3/D2O.
In addition, monitoring the FPBA – pinanediol interaction by 19F NMR, which showed
well resolved peaks for free boronic acid and the respective ester both in neutral and basic
solutions (ESI, Fig. S5), allowed us to estimate Ktrig = 1.8×104 M-1 and Ktet = 4500 M-1 values in
agreement with above results.
Additional useful information was obtained with benzoxaborole as a boronic acid. In this
case formation of a trigonal ester seems impossible because this requires opening of a highly
stable oxaborole ring,14 Scheme 2.
HO
OH
OH
R'
OH
OH
R'
OH
OH
B
B
-
Ka
O
H2O
H+
O
+
+
+
+
R''
R''
Ktet
Ktrig
R''
R'
R''
O
O
B
O
2 H2O
2 H2O
H+
R'
+
+
+
O
B
-
O
OH
Scheme 2. The equilibria for boronate ester formation with benzoxaborole.
Results shown in Figure 3a,b demonstrate that addition of benzoxaborole to pinanediol
induces shifts of pinanediol proton signals resembling those observed with FPBA (cf. Fig.1a-c)
indicating the ester formation. However, the integration of methyl signals gives in this case a
small Ktrig = 300 M-1 evidently due to unfavorable opening of the oxaborole ring manifested in
the appearance of the signal at 4.7 ppm corresponding to ortho-CH2OH group. 15 Formation of a
trigonal nopoldiol (a pinanediol derivative) complex with benzoxaborol was reported recently by
Di Wu et al. 16 Addition of hydroxide in this case leads to formation of the tetrahedral ester with a
simple spectrum (Fig. 3c) and Ktet=1.4×104 M-1. Studies by 11B NMR confirm results obtained by
1H NMR (ESI, Fig.S6).
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Figure 3. 1H NMR spectra for free 5 mM benzoxaborole (a), the equimolar mixture of
benzoxaborole-pinanediol without added base (b) and in presence of 1 equivalent of NaOH (c) in
40% v/v MeCN-d3/D2O. Asterisks mark the signals of free pinanediol and free benzoxaborole in
spectra of benzoxaborole-pinanediol mixtures.
The predominant formation of the trigonal ester with FPBA was confirmed by the
potentiometric titration. The interaction of a polyol with a boronic acid typically shifts the
titration curve of the acid to lower pH values as a result of consumption of hydroxide ions for the
formation of the tetrahedral hydroxocomplex. As one can see from Figure 4, the addition of
pinanediol shifts the titration profile of FPBA in the opposite direction, to higher pH values,
which reflects a higher stability of the neutral trigonal ester. To be sure that this was not an effect
of a high content of organic co-solvent, the titration of FPBA in the same conditions was
performed also with mannitol and a “normal” behavior was observed (Figure 4). Fitting of
titration curves with Hyperquad program allowed us to calculate pKa = 9.3 for FPBA, logKtet =
3.93 for mannitol (lit.17 logKtet = 3.36 in water with PBA), Ktrig = 2.0104 M-1 and Ktet = 6.2103
M-1 for pinanediol in agreement with NMR results. It is worth noting that an increased apparent
pKa 9.7 for the FPBA in the presence of pinanediol is observed in line with Ktrig/Ktet > 1.
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12
11
10
9
FPBA+Pinanediol
FPBA
8
FPBA+Mannitol
7
6
0.0
0.5
1.0
1.5
a
Figure 4. Potentiometric titration of FPBA (open squares) and 1:1 mixtures of FPBA with
pinanediol (solid circles) or mannitol (solid squares) in 40% vol MeCN; a is the number of mole
equivalents of NaOH. Solid lines are the fitting curves generated by HYPERQUAD.
Interaction of FPBA with pinanediol is accompanied by a noticeable change in the UV-
Vis spectrum of the boronic acid, which allows one a fast and simple determination of the
equilibrium constant under variable conditions. Figure 5 illustrates the course of the
spectrophotometric titration of FPBA with pinanediol characterized by an increase in the
absorbance in the range 260-290 nm. The results fit very well to the respective theoretical
equation 1 (see Experimental Section), as shown in the inset in the Figure 5, with Kobs
(1.90.1)104 M-1.
=
0.7
0.45
0.6
0.40
0.35
0.5
0.30
0.4
0.25
0.20
0.3
0.0000
0.0002
0.0004
0.0006
0.0008
[Pinanediol], M
0.2
0.1
0.0
240
260
280
300
320
340
360
Wavelength (nm)
Figure 5. Spectrophotometric titration of 0.4 mM FPBA by pinanediol in 40% vol MeCN at pH
7. Arrow shows the direction of spectral changes induced by increased pinanediol concentrations.
Inset shows the titration profile at a single wavelength and its fitting to the equation (1).
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Spectrophotometric titrations at variable pH showed that Kobs remained constant in the
range of pH 5-8 and started to decrease at pH above 9 in agreement with lower stability of the
tetrahedral anionic ester.
All values of Ktrig and Ktet for pinanediol determined by different techniques in 40% vol
MeCN are collected in Table 1.
Table 1. Stability constants (M-1) of boronic acid esters of pinanediol in 40% vol aqueous
MeCN; relative errors less or equal ±20%. Entries 5 through 13 show substituents in PBA.
Boronic acid Ktrig
FPBA
Ktet
Method
Pot
UV
2.0104 6.2103
1.9104
1
2
3
4
5
6
7
8
9
FPBA
FPBA
benzoxaborole
4-MeO
4-Cl
3-NO2
H (PBA)
2-Me-4-MeO
1.5×104
3.0102
4.6103
1.5103
2.4103
1.0104
2.1105
6.5103
1.3104
2.8104
3.3104
NMR
4.0103
1.4×104 NMR
NMR
NMR
NMR
NMR
NMR
NMR
UV
10 3-CF3
11 2-Formyl
12 2-F-5-MeO
13 2-CN
UV
UV
Results with meta- and para-substituted phenylboronic acids are shown as a plot of logKtrig vs.
the Hammett substituent constant in Fig. 6. It gives a small negative slope  = -0.30.5 not
distinguishable from zero in limits of uncertainty. This observation qualitatively agrees with
reported18 results on stability of trigonal esters of substituted phenylboronic acids with 4-tert-
butylcatechol in chloroform also shown in Fig.6 in Hammett coordinates with  = -0.90.3.
Small values of  indicate a minor contribution of electronic effects in stability of trigonal esters.
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4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Pinanediol
4-tert-Butylcatechol
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8

Figure 6. Hammett correlations of stability constants for trigonal esters of meta- and para-
substituted phenylboronic acids with pinanediol in 40% aqueous MaCN (solid squares, this
paper) and with 4-tert-butylcatechol in CDCl3 (open squares, Ref. [18]).
Another conclusion which follows from inspection of Table 1 is a significant stabilizing
effect of ortho-substituents in phenylboronic acid. Thus the incorporation of ortho- CHO, -F and
–CN groups in PBA increases Ktrig by factors 1.3, 1.5-2 and 3.3 respectively (cf. entries 8, 11, 1-3
and 13). Particularly strong effect is observed with ortho-Me group, which improves binding by
the factor of 45 (entries 5 and 9). This stabilizing ortho-effect reported also in Ref. 10 is opposite
to usually observed steric hindrance effects 19 and its origin is unclear. In a hope to observe a
structural manifestation of this effect we prepared and characterized by single crystal X-ray
diffraction the pinanediol esters with FPBA and MMPBA.
The esters were isolated from 40% vol aqueous MeCN under the same conditions which
were used in equilibrium studies employing high concentrations of both components. Their
crystal structures (Fig. 7, see also ESI, Figs. S15 and S16) confirm formation of neutral trigonal
esters and closely resemble reported earlier crystal structure of the pinanediol ester of
unsubstituted PBA.20 In the FPBA ester 2 O-B-O angle is 114.72°, sum of the bond angles
around B is 360.0°, the phenyl ring is practically coplanar to the dioxaborolane ring with the
interplanar tilt angle 2.57° (the respective values for the PBA ester are 114.25°, 360° and 1.96°).
In the MMPBA ester 3 the O-B-O angle is 113.07°, the sum of the bond angles around B is
360.0° and the tilt angle between the rings 8.85°. Structures of the dioxaborolane ring and the
pinanediol moiety in all three esters are practically identical. So the structures of esters by
themselves do not demonstrate any unusual features due to the presence of an ortho-substituent,
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in particular 2-Me group. On the other hand, the presence of ortho-substituents in phenylboronic
acids typically creates a large distortion in coplanarity between the aryl ring and the BO2 plane
inducing tilt angles up to 75°.21 For instance, the presence of 2-Me group in 2-methyl-4-
methoxycarbonylphenylboronic acid induces the tilt angle of 42.92°. 22 (ESI, Fig. S17). However
in the ester 3 the tilt angle is only 8.85° and a plausible reason for this is the contraction of the O-
B-O angle during formation of the ester, which moves the O3 atom further from the 2-Me group
reducing the steric repulsion. We suppose therefore that the stabilizing effect of the 2-Me group
is observed because the strain created in the cyclic ester is compensated by the release of the
strain initially created by the ortho-methyl group in the free boronic acid.
2
3
4
Figure 7. Crystal structures of pinanediol esters of FPBA (2) and MMPBA (3) and the simulated
structure of the hydroxocomplex of FPBA ester (4). In structures 2 and 3 non-H atoms are
represented by 50% probability ellipsoids and H atoms are shown as small circles of arbitrary
size.
The very high stability of the trigonal esters of pinanediol can be attributed to well
preorganized rigid structure of the diol. However, such preorganization must be equally favorable
for stability of the respective tetrahedral complex and therefore cannot explain the “inverted”
order Ktet < Ktrig. The “normal” relationship Ktet > Ktrig is usually explained by the release of strain
in the O-B-O angle of trigonal esters, too small for still sp2 boron atom and more appropriate for
sp3 boron in tetrahedral esters. This concept fails in the case of pinanediol. Figure 7 shows the
minimized structure of the hydroxo complex of FPBA 4 generated by adding OH- anion to the
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respective neutral ester 2. It has the O-B-O angle 104.81° within the range 102-105° found in
crystal structures of many tetrahedral anionic esters, 23 while the O-B-O angle in 2 is close to the
typical for trigonal esters value of 113°.24 So the strain release occurs in pinanediol esters to the
same degree as in esters of other diols. No intramolecular short contacts potentially producing
repulsive interactions and reducing stability were identified in the calculated structure 4. The
closest to the boronic acid aromatic ring proton of a CH bond in the pinane backbone is at 3.48 Å
from the ring centroid. Incidentally, one may note that reported O-B-O angles in tetrahedral
complexes (102-105°)23 are smaller than the tetrahedral angle 109.5° to the same extent as O-B-O
angles of trigonal esters (112-114o)24 are smaller than the trigonal angle 120° and this
additionally makes questionable whether the strain release really contributes to higher stability of
tetrahedral esters.
An indirect evidence in favor of the strain release hypothesis comes from studies of
complexation with 1,3-diols. In six-membered cyclic esters formed with 1,3-diols the difference
in stabilities between trigonal and tetrahedral esters should be small or even absent because they
are expected to have unstrained O-B-O angles 120° and 109° respectively.25a The relevant
experimental results are scarce, however. For 1,3-propanediol in water only tetrahedral
hydroxocomplexes were reported with PBA and boric acid,17 although an increase in pKa of PBA
in the presence of 1,3-propanediol indicative of greater stability of the trigonal ester was
reported.7 A very low stability of these esters may create some uncertainty in experimental
measurements. For more stable esters of substituted aliphatic 1,3-diols such as 2,4-pentanediol
indeed both trigonal and tetrahedral complexes of boric acid were detected with Ktrig only 3-5
times smaller than Ktet and with inverted relationship Ktrig > Ktet for 2-methyl-2,4-pentanediol.26
In case of aromatic 1,3-diols formation of both trigonal and tetrahedral complexes was
reported for chromotropic acid.27 To get more details on this system we measured Ktrig and Ktet
for chromotropic acid and a series of substituted phenylboronic acids by spectrophotometric
titrations as illustrated in Figures S7 and S8 (ESI). Chromotropic acid with pKaD = 5.33 is more
acidic than PBA with pKaB = 8.8 and therefore the experimentally measured association constant
(Kobs) at pH 7 corresponds to interaction of the deprotonated diol with neutral boronic acid i.e.
Kobs = K’tet (Scheme 1). At pH 1 both boronic acid and diol are neutral species and Kobs = Ktrig.
The values of Kobs determined spectrophotometrically at pH 7 and pH 1 for several substituted
phenylboronic acids are shown in Fig. 8 in coordinates of the Hammett equation.
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5.5
5.0
4.5
3-CF3
4-Cl
pH 7
H
4-MeO
2.5
2.0
1.5
pH 1
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5

Figure 8. Hammett plots for formation constants of substituted phenylboronic acid esters with
chromotropic acid at pH 7 (squares) and pH 1 (triangles).
The large positive slope  = 1.7±0.1 of the plot at pH 7 agrees with the formation of an
anionic ester and a small slope  = 0.4±0.3 at pH 1 agrees with results for pinanediol confirming
week electronic effects in the formation of the trigonal ester. For PBA logK’tet = 4.80 and logKtrig
=1.63. As follows from Scheme 1, log Ktet = log K’tet + pKaB – pKaD = 8.2. Evidently, the stability
of anionic tetrahedral complex with chromotropic acid is by several orders of magnitude higher
than that of neutral trigonal ester, but this cannot be attributed to the strain effect because O-B-O
angles in each ester (5 and 6, Fig. 9) allow the formation of unstrained cycles. Therefore the
relationship Ktet >> Ktrig in this case should be attributed to the stabilization of the negatively
charged tetrahedral ester by the electron acceptor effect of the acidic aromatic 1,3-diol. Such
acceptor effect is absent for aliphatic 1,3-diols and they form trigonal and tetrahedral esters of
similar stability.26
5
6
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Figure 9. Simulated structures of PBA trigonal ester (5) and tetrahedral hydroxocomplex (6) with
chromotropic acid.
It follows from the whole set of results that Ktrig can be much smaller than Ktet in the
absence of strain, but with a sufficiently acidic diol, and that the presence of strain does not make
Ktet larger than Ktrig with a low acidic diol incapable of formation of tridentate tetrahedral
complexes. The role of tridentate binding can be seen e. g. from comparison of log(Ktet/Ktrig) =
5.2 for PBA and fructose, with predominantly tridentate binding, and log(Ktet/Ktrig) = 2.6 for PBA
and glucose,12 with predominantly bidentate binding. On the other hand, it is well known that
stability of tetrahedral boronate hydroxocomplexes increases when both the boronic acid and diol
become more acidic.8,28 In quantitative terms logKtet was found to correlate with pKa of diol
linearly with the slope -0.7 for PBA.8 There are no quantitative data of this sort for trigonal
esters, but semi-quantitative results of Roy and Brown 29 show that the increased acidity of diols
is not favorable for Ktrig. Thus comparing an aliphatic 1,2-diol with pKa about 15 and a sugar with
pKa about 12 one should expect for the latter an increased by ca. 2 orders of magnitude Ktet but
unchanged or even decreased Ktrig and therefore a significantly increased Ktet/Ktrig not related to
the strain releasing effect. Further increase in diol acidity for catechol leads to even much higher
Ktet value with no indication of detectable trigonal ester formation,17 meaning very large Ktet/Ktrig
ratio.
Conclusions
Pinanediol forms highly stable trigonal boronic acid esters, but less stable tetrahedral
hydroxocomplexes with arylboronic acids in aqueous media. Stability constants of trigonal esters
with meta and para-substituted phenylboronic acids demonstrate the Hammett plot with small
negative slope, not distinguishable from zero in limits of uncertainty. This indicates that the
electronic effects of substituents in the boronic acid are insignificant for stability of trigonal
esters.
An unusual feature of pinanediol complexation is a strongly enhanced stability with
phenylboronic acids bearing the ortho-substituents particularly the methyl group. Comparison of
crystal structures of the esters 2 and 3 of such acids with that of the ester of unsubstituted
phenylboronic acid does not reveal any structural differences which might be responsible for this
effect, but a possible explanation is that the strain induced by O-B-O angle contraction is
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compensated by the relieve of strain created by the ortho-methyl group in the free boronic acid.
Inspection of crystal structures 2 and 3 together with the simulated structure 4 of the
hydroxocomplex of 2 reveals typical for 5-membered cyclic trigonal esters strain in O-B-O angle,
which can be relieved by the addition of hydroxide anion to boron atom to the same degree as is
characteristic for other five-membered boronate esters, but this does not lead to the “normal”
relationship Ktet > Ktrig. On the other hand, the relationship Ktet >> Ktrig is observed for strain free
six-membered boronic acid esters with an aromatic 1,3-diol chromotropic acid due to
stabilization of the anionic tetrahedral complex by the electron accepting diol. In general, results
of this study and relevant literature data show that the stability of trigonal esters is essentially
independent of electronic effects, but the stability of tetrahedral hydroxocomplexes increases
significantly for more electron accepting diols. From this point of view the “inversion” in relative
stabilities of the trigonal ester and the tetrahedral hydroxocomplex of pinanediol, Ktet < Ktrig, is
observed because this diol lacks the electron acceptor power for an extra stabilization of the
tetrahedral hydroxocomplex.
Experimental section
General Experimental Methods. Commercially available pinanediol, substituted
phenylboronic acids and components of buffer solutions (CHES, MOPS, MES) were used as
supplied. All titration experiments were performed at 25°C and ionic strength 0.05 M created
either by buffer or NaCl. All spectroscopic and potentiometric titrations were performed with
completely equilibrated solutions incubated at 25oC for at least 1 h before starting the titration
experiment and making at least 5 min intervals between additions of a titrant aliquots to the
mixtures of pinanediol and the respective boronic acid.
Pinanediol ester of FPBA (2); (4S,6R,7aS)-2-(2-fluorophenyl)-5,5,7a-
trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborole. (1R,2R,3S,5R)-(−)-Pinanediol (85
mg, 0.5 mmol) in 4 mL of acetonitrile was added to a solution of 2-fluorophenylboronic acid (70
mg, 0.50 mmol) in 6 mL of water, the mixture was stirred about 1 h at room temperature and the
white precipitate was collected by filtration and washed with water to give the ester 2 (92 mg) in
67% yield; 1H NMR (500 MHz, DMSO-d6) δ 7.69 – 7.65 (m, 1H), 7.56 (dddd, J = 9.3, 7.6, 5.7,
1.9 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.16 (dd, J = 13.3, 4.6 Hz, 1H), 4.53 (dd, J = 8.7, 1.8 Hz,
1H), 2.38 (ddt, J = 13.6, 8.7, 2.3 Hz, 1H), 2.25 – 2.20 (m, 1H), 2.08 (t, J = 5.5 Hz, 1H), 1.90 (tt, J
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= 5.9, 3.0 Hz, 1H), 1.82 (ddd, J = 14.5, 3.3, 1.9 Hz, 1H), 1.43 (s, 3H), 1.27 (s, 3H), 1.06 (d, J =
10.8 Hz, 1H), 0.86 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 166.8 (d, J = 249.5 Hz),
137.0 (d, J = 8.0 Hz), 134.4 (d, J = 8.7 Hz), 124.6 (d, J = 3.4 Hz), 115.8 (d, J = 23.4 Hz), 86.3,
77.6, 51.2, 38.2, 35.4, 28.7, 27.3, 26.5, 24.1; 11B NMR (160 MHz, DMSO- d6) δ 28.94; HRMS
(ESI-TOF) for C16H21BFO2 [M+H]+ calcd.: 275.1613; found: 275.1619; for C16H24BFNO2
[M+NH4]+ calc.: 292.1879; found: 292.1889; Anal. for C16H20BFO2 calcd.: C, 70.10; H, 7.35;
found: C, 70.49; H, 7.47.
Pinanediol ester of MeMPBA (3); (3aR,4R,6R,7aS)-2-(4-methoxy-2-methylphenyl)-
3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborole.
(1R,2R,3S,5R)-(−)-
Pinanediol (85 mg, 0.50 mmol) in 4 mL of acetonitrile was added to a solution of
4-methoxy-2-methylphenylboronic acid (83 mg, 0.50 mmol) in 6 mL of water, the mixture was
stirred about 1 h at room temperature and the white precipitate was collected by filtration and
washed with water to give the ester 3 (118 mg) in 79% yield; 1H NMR (500 MHz, DMSO- d6) δ
7.59 (d, J = 8.1 Hz, 1H), 6.74 (dd, J = 8.4, 5.4 Hz, 2H), 4.47 (dd, J = 8.7, 1.9 Hz, 1H), 3.75 (s,
3H), 2.43 (s, 3H), 2.41 – 2.35 (m, 1H), 2.23 – 2.18 (m, 1H), 2.06 (t, J = 5.5 Hz, 1H), 1.89 (tt, J =
5.8, 3.0 Hz, 1H), 1.81 (ddd, J = 14.5, 3.2, 2.0 Hz, 1H), 1.41 (s, 3H), 1.27 (s, 3H), 1.06 (d, J = 10.7
Hz, 1H), 0.86 (s, 3H); 13C{1H} NMR (75 MHz, DMSO- d6) δ 161.9, 146.8, 138.0, 115.8, 110.9,
85.6, 77.3, 55.3, 51.4, 38.2, 35.8, 28.9, 27.3, 26.5, 24.1, 22.6; 11B NMR (160 MHz, DMSO-d6) δ
30.00; HRMS (ESI-TOF) for C18H26BO3 [M+H]+ calcd.: 301.1970; found: 301.1938; Anal. for
C18H25BO3 calcd.: C, 72.02; H, 8.39; found: C, 72.61; H, 8.21.
Potentiometry. Potentiometric titrations were performed in a 25 mL thermostated cell
kept under nitrogen at 25.0 ± 0.1 °C with 0.05 M NaCl as background electrolyte; 2.0 mM
aqueous solutions (40% vol MeCN) of pinanediol in the presence of equimolar amount of FPBA
were employed. The pKa value of FPBA was determined independently by potentiometric
titrations in the same conditions and was used as a fixed parameter in the fitting of results for the
polyol−FPBA mixtures. Experimental details and procedure for the electrode calibration were the
same as in ref.30 The program Hyperquad 200831 was used to calculate all equilibrium constants.
11B NMR measurements. 11B NMR spectra were recorded in quartz tubes at 128.3 MHz
with Et2O·BF3 in CDCl3 as the external standard using the instrumental parameters similar to
those employed previously.8 Spectra were obtained using a 4.9 μs and 90° pulse, 50 ms FID
acquisition time, and 0 s acquisition delay. The sweep width was set to 87.2 ppm. Two thousand
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scans were taken for each sample. A solution of a boronic acid was prepared in D2O and mixed
with pinanediol solution in MeCN-d3 and buffer or base solution in D2O to obtain 5 – 10 mM
total boronic acid in final 40% v/v MeCN-d3/D2O solution.
Spectrophotometric Titrations. To a 0.40 mM aqueous solution (40% vol MeCN) of
FPBA in an appropriate 0.05 M buffer (MES, MOPS, or CHES in order of increasing pH from
5.5 to 9.5) portions of concentrated solution of pinanediol in the same buffer were added, and the
mixture was incubated for 8 min after each addition before recording the spectrum. In an
independent experiment, it was established that the system equilibrates completely during this
incubation period. The observed equilibrium constants of the ester formation (Kobs) were
calculated from the absorbance (A) vs concentration of pinanediol (L) profiles at several
wavelengths by nonlinear least squares fitting to the equation (1), and the results were averaged.
In equation (1), subscript T stands for total concentration, A0 is the initial absorbance of the
boronic acid B measured in the absence of L, and Δε is the difference in molar absorptivities
between the ester and free boronic acid.
A = A0+ 0.5{[L]T + [B]T+ 1/Kobs - (([L]T + [B]T+ 1/Kobs)2-4[L]T[B]T)0.5}
Calculation method. Structural optimization was performed at DFT level using a
(1)
dispersion corrected B3LYP-D3 functional 32 and 6-311+G(d,p)) basis set as is implemented in
Gaussian 09.33 At same time, frequency calculations were performed and no imaginary
frequencies were detected in all cases. The calculations were performed in water with the
Polarizable Continuum Model (PCM) method of solvation.34
X-ray Crystallography. Crystals of the boronate esters suitable for X-ray diffraction
were grown by slow evaporation from water-acetonitrile solution. Crystals 2 and 3 were studied
with Oxford Diffraction Gemini "A" diffractometer with a CCD area detector (MoK = 0.71073
Å, monochromator: graphite) source equipped with a sealed tube X-ray source. Unit cell
constants were determined with a set of 15/3 narrow frame/runs (1° in ) scans. A data sets
consisted of 417/5 and 168/4 frames/runs of intensity data collected for 2 and 3 respectively
with a frame width of 1° in , and a crystal-to-detector distance of 55.00 mm. The double pass
method of scanning was used to exclude any noise. The collected frames were integrated by
using an orientation matrix determined from the narrow frame scans.
CrysAlisPro and CrysAlis RED software packages35 were used for data collection and
data integration. Analysis of the integrated data did not reveal any decay. Final cell constants
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were determined by a global refinement of 3520 and 6510 reflections ( < 26 °) for 2 and 3
respectively. Collected data were corrected for absorbance by using Analytical numeric
absorption correction36 using a multifaceted crystal model based on expressions upon the Laue
symmetry using equivalent reflections.
Structure solution and refinement were carried out with the SHELXS-2014 and
SHELXL-2014 packages;37 WinGX v2014.1 software was used to prepare material for
publication.38
Full-matrix least-squares refinement was carried out by minimising (Fo2 – Fc2)2.
All non-hydrogen atoms were refined anisotropically.
The crystallographic data for 2 and 3 compounds reported in this paper has been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 1902042 and 1902043. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: (+44) 1223-336-
033, e-mail: deposit@ccdc.cam.ac.uk).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Mayte A. Martínez-Aguirre thanks CONACyT for the Doctoral fellowship (271108). The support
from Programa de Apoyo a la Investigación y el Posgrado (PAIP 5000-9042), Facultad de
Química de la UNAM is gratefully acknowledged.
Electronic supplementary information (ESI) available: COSY spectra of (-)-pinanediol and their
1:1 mixture with phenylboronic acid, 1H NMR spectra of pinanediol, 2-Fluorophenylboronic acid
and their 1:1 mixture in DMSO, 11B NMR spectra of mixtures of benzoxaborole and pinanediol,
spectrophotometric titrations of chromotropic acid by phenylboronic acid at selected pH values as
well as 1H, 13C and 11B NMR spectra, crystallographic data and CIF files of newly synthesized
compounds are presented.
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The “inverted” order of stabilities Ktrig > Ktet is observed for pinanediol boronate esters in spite of the
existence of a usual strain release effect in the O-B-O angle of the cyclic diol ester.