Intramolecular interactions in ortho-methoxyalkylphenylboronic acids and their catechol esters

Article abstract of DOI:10.1016/j.saa.2013.07.091

(Graph Presented) Catechol esters of ortho-methoxyalkylphenylboronic acids have been synthesized and characterized by ¹⁷O NMR spectroscopy. The results were compared with the data for the parent acids. The influence of intramolecular and intermolecular hydrogen bonds on the properties of the boronic acids has been discussed. The ¹⁷O NMR data for the boronic esters proved that there are no O → B interactions in the investigated compounds. This fact is connected with weak Lewis acidity of the parent acids and their low sugars' receptors activity. Crystal structure of ortho -methoxyphenylboronic acid catechol ester was determined.

Full text of DOI:10.1016/j.saa.2013.07.091

Accepted Manuscript
Intramolecular interactions in ortho-methoxyalkylphenylboronic acids and their
catechol esters
Agnieszka Adamczyk-Woźniak, Krzysztof M. Borys, Karolina Czerwińska,
Błażej Gierczyk, Michał Jakubczyk, Izabela D. Madura, Andrzej Sporzyński,
Ewelina Tomecka
PII:
S1386-1425(13)00839-1
http://dx.doi.org/10.1016/j.saa.2013.07.091
SAA 10835
DOI:
Reference:
To appear in:
Spectrochimica Acta Part A: Molecular and Biomo‐
lecular Spectroscopy
Received Date:
Revised Date:
Accepted Date:
23 May 2013
18 July 2013
28 July 2013
Please cite this article as: A. Adamczyk-Woźniak, K.M. Borys, K. Czerwińska, B. Gierczyk, M. Jakubczyk, I.D.
Madura, A. Sporzyński, E. Tomecka, Intramolecular interactions in ortho-methoxyalkylphenylboronic acids and
their catechol esters, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2013), doi: http://
dx.doi.org/10.1016/j.saa.2013.07.091
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Intramolecular interactions in ortho-methoxyalkylphenylboronic acids and their
catechol esters
Agnieszka Adamczyk-Woźniaka1, Krzysztof M. Borysa, Karolina Czerwińskaa, Błażej
Gierczykb, Michał Jakubczyka, Izabela D. Maduraa, Andrzej Sporzyńskia, Ewelina Tomeckaa
a Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw,
Poland
b
Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89B, 61-614 Poznań,
Poland
Keywords: boronic acids; boronic esters; 17O NMR; hydrogen bond
Highlights:
 Synthesis of ortho-methoxyalkylphenylboronic acids catechol esters.

17O NMR characterization of the esters and parent acids.
 Influence of hydrogen bond on the properties of the acids.
 No O→B interactions in the investigated compounds.
 Diminished acidity compared with the unsubstituted phenylboronic acid.
Abstract
Catechol esters of ortho-methoxyalkylphenylboronic acids have been synthesized and
characterized by 17O NMR spectroscopy. The results were compared with the data for the
parent acids. The influence of intramolecular and intermolecular hydrogen bonds on the
17
properties of the boronic acids has been discussed. The O NMR data for the boronic esters
proved that there are no O→B interactions in the investigated compounds. This fact is
connected with weak Lewis acidity of the parent acids and their low sugars' receptors activity.
Crystal structure of ortho-methoxyphenylboronic acid catechol ester was determined.
Introduction
Arylboronic acids are systems that attract an increasing scientific interest due to their
new applications in organic synthesis, catalysis, supramolecular chemistry, biology, medicine
1 Corresponding author. Tel.: +4822-2346147; fax: +4822-6282741; E-mail address: agnieszka@ch.pw.edu.pl
(A. Adamczyk-Woźniak).
1

and material engineering [1]. Recently, great interest has been paid to the supramolecular
systems which can be formed by both covalent [2] as well as hydrogen bonds [3,4].
Esters of phenylboronic acids are important group of derivatives due to their wide
applications. The formation of cyclic esters in the reaction of phenylboronic acids with diols
is the basis of their use in sensing of biologically important species, e.g. sugars [1]. The
esterification reaction is also applied in boronic group protection [5], dopamine detection [6],
affinity chromatography [7] and solid-state synthesis of saccharides [8]. Another interesting
application of that process is the formation of self-repairing polymers [9]. Phenylboronic
esters usually display higher stability as well as increased solubility in organic solvents in
comparison with the parent acids [10,11]. Lewis acid character of these compounds allows
their applications connected with binding of electron-rich molecules, e.g. in fluoride anion
sensing [12,13] or anion complexation, improving properties of polymer electrolytes [14-16].
The advantage of the use of phenylboronates over other anion complexing agents are low
cost, lack of reactive groups (like –OH), and low toxicity.
Ortho-substituted phenylboronic acids have been widely investigated due to possible
interactions between boronic group and the substituents, influencing the properties of these
compounds [1]. Substituents at ortho position of phenylboronic acids of Lewis base character
can interact with boronic group in several ways (Scheme 1).
H
O
HO
O
O
HO
OH
O
O
B
X
X
X
B
B
B
LB
X
a
b
c
d
Scheme 1. The possible interactions of ortho-substituent with the boronic moiety in case of
phenylboronic acids (a, b) and their esters (c, d).
If the substituent contains proton acceptor atom, intramolecular hydrogen bond is usually
formed (Scheme 1a). There are numerous examples of the structures with a strong
intramolecular hydrogen bond [17]. For the compounds possessing two alkoxy groups at the
ortho positions related to boronic group, first examples of monomeric units have been
recently reported [18]. Another interesting example is that of bifurcated hydrogen bond,
which was observed for phenylboronic acids with ortho polyoxaalkyl substituents [19]. Vastly
2

investigated were also phenylboronic acids with an aminomethyl group at the ortho position.
They have wide applications as molecular receptors of sugars. The interaction between
boronic group and nitrogen atom plays the key role in fluorescent method of detection [20]. In
the solid state, formation of the intramolecular B-O-H...N hydrogen bond was observed in
many cases (Scheme 1a) [21-28]. Moreover, the recent calculations for model compounds in
the gas phase proved that the most stable form of the acid is that with intramolecular
hydrogen bond, while the form with dative bond (Scheme 1b) is less favored [29]. Very scant
representation of boronic acids with four coordinated boron atom has been described in the
solid state [30-32]. However, formation of the dative N→B [33-42] or O→B [43-50] bond
with ortho substituent is a very common motif for the esters of these compounds (Scheme 1c).
Further, the crystal structures of esters molecules with coordinated solvent molecule are also
observed (Scheme 1d) [21, 25, 34, 35, 51, 52].
Present paper deals with phenylboronic acids (1 - 3) and their catechol esters (1a - 3a)
possessing methoxyalkyl group at the ortho position. The ethers (1b - 3b) as well as
compounds 4, 5, 4a, and 5a have been investigated as reference compounds (Scheme 2).
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
B
B
B
B
B
O
O
O
1
2
3
4
5
O
O
O
O
O
O
O
O
O
O
B
B
B
B
B
O
O
O
1a
1b
2a
2b
3a
3b
4a
5a
O
O
O
Scheme 2. Investigated phenylboronic acids with methoxyalkyl group at the ortho position (1
- 3) and their catechol esters (1a - 3a). Reference ethers are numbered 1b - 3b and reference
boronic compounds 4, 4a, 5, 5a.
The aim of this work is to investigate the molecular structures of these compounds, in order to
analyze the possibility of the intramolecular O→B interaction.
Experimental
Materials
3

2-Methoxyphenylboronic acid, catechol, anisole (Sigma-Aldrich), benzyl methyl ether (Alfa
Aesar), phenylboronic acid and 2-ethylphenylboronic acid (Combi-Blocks) were used as
received. All solvents and auxiliary materials were purchased from POCH and used as
received.
Syntheses
of
2-methoxyethylphenylboronic
acid
and
2-
methoxymethylphenylboronic acid were described in the previous paper [17].
Synthesis
2-(2-Methoxyphenyl)-1,3,2-benzodioxaborole (1a)
The reaction was conducted in the solid phase. 2-Methoxyphenylboronic acid (2.00 g, 13.2
mmol) and catechol (1.45 g, 13.2 mmol) were ground manually for about an hour in an
ordinary mortar heated to ca. 60°C. The crude product was purified by sublimation. Colorless
crystals were obtained. Yield: 74%. Elemental anal.: Found: C, 69.23; H, 4.97. Calc. for
C13H11BO3: C, 69.08; H, 4.91%. HR EI-MS: Found: m/z 226.08025. Calc. for C13H11BO3:
m/z 226.08012. 1H NMR (CDCl3, 400 MHz): δ 3.98 (s, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.06-
7.09 (m, 1H), 7.11-7.12 (m, 2H), 7.33-7.34 (m, 2H), 7.55 (ddd, J = 8.4, 7.3, 1.8 Hz, 1H), 8.0
(dd, J = 7.3, 1.8 Hz, 1H) ppm, 11B NMR (CDCl3, 64 MHz): δ 31.7 ppm.
2-[2-(Methoxymethyl)phenyl]-1,3,2-benzodioxaborole (2a)
2-Methoxymethylphenylboronic acid (0.97 g, 5.8 mmol) and catechol (0.63 g, 5.8 mmol)
were dissolved in 150 ml of chloroform and placed in a vessel fitted with a reversed Dean-
Stark apparatus for azeotropic water removal. The solution was refluxed for 3 h. The crude
product was recrystallized from ethyl acetate to give a white solid. Yield: 55%. Elemental
1
anal.: Found: C, 69.27; H, 5.56. Calc. for C14H13BO3: C, 70.04; H, 5.46%. H NMR (CDCl3,
400 MHz): δ 3.45 (s, 3H), 4.87 (s, 2H), 7.11-7.14 (m, 2H), 7.29-7.31 (m, 2H), 7.37-7.40 (m,
1H) 7.48-7.55 (m, 2H), 8.05 (d, J = 7.3 Hz, 1H) ppm, 11B NMR (CDCl3, 64 MHz): 31.5 ppm.
2-[2-(2-Methoxyethyl)phenyl]-1,3,2-benzodioxaborole (3a)
2-Methoxyethylphenylboronic acid (1.10 g, 6.1 mmol) and catechol (0.67 g, 6.1 mmol) were
dissolved in 150 ml of chloroform and placed in a vessel fitted with a reversed Dean-Stark
apparatus for azeotropic water removal. The solution was refluxed for 3 h and the solvent was
removed by evaporation to give a yellow oil. The product was purified on silica gel. The oil
was dissolved in 100 mL of dichloromethane and shaken with about 15 g of silica gel (230-
400 mesh ASTM). Then the gel was filtered off and shaken again with 100 mL of ethyl
acetate. The solution was filtered and the solvent was removed under vacuum to give 3a as a
yellow oil. Yield: 43%. HR EI-MS: Found: m/z 254.11104. Calc. for C15H15BO3: m/z
254.11142. 1H NMR (CDCl3, 400 MHz): δ 3.35 (s, 3H), 3.37 (t, J = 7.0 Hz, 2H), 3.68 (t, J =
4

7.0 Hz, 2H), 7.11-7.16 (m, 2H), 7.31-7.32 (m, 2H), 7.31-7.36 (m, 2H), 7.46-7.51 (m, 1H),
8.08 (dd, J = 1.5, 7.7 Hz, 1H) ppm, 11B NMR (CDCl3, 64 MHz): 31.8 ppm.
(2-Methoxyethyl)benzene (3b)
To a stirred heterogenous mixture of KOH (3.29 g, 58.7 mmol) and DMSO (20 mL), a
solution of 2-phenylethanol (1.69 g, 13.8 mmol) and methyl iodide (3.91 g, 27.6 mmol) in
DMSO (15 mL) was added dropwise at room temperature over 20 min. The reaction mixture
was stirred for 2 h, then poured into water (100 mL). The resulting mixture was extracted with
diethyl ether (1x50mL, then 3x25mL). Combined ether extracts were washed with water
(3x25mL, then 1x10mL). Volatiles were distilled off using a rotary evaporator. Purification
by column chromatography (silica gel, hexane:AcOEt,10:1) afforded the product as a slightly
1
yellowish liquid (1.22 g, 8.97 mmol, 65% yield). H NMR (CDCl3, 400 MHz): δ 2.92 (t, J =
7.2 Hz, 2H), 3.38 (s, 3H), 3.63 (t, J = 7.2 Hz, 2H), 7.26-7.22 (m, 3H), 7.34-7.30 (m, 2H) ppm.
The spectrum is in accordance with the one previously reported [53].
Esters of model compounds (4a and 5a) were synthesized by reaction of the
corresponding acids with catechol in boiling benzene and purified by flash chromatography
(SiO2/dichloromethane).
17O NMR spectroscopy
The 17O NMR spectra have been recorded on Bruker Avance DRX 600 spectrometer,
17
operating at frequency 81.339 MHz, equipped with 5 mm probehead (BB/1H; 90° O pulse
width: 5 µs) with aring2 sequence from Bruker pulse library. The acquisition parameters were
as follows: spectral width 52 kHz, acquisition time 0.2 s, 90° flip angle. Depending on the
concentration, 100 000 – 4 000 000 transients were recorded to obtain satisfactory signal-to-
noise ratio. Line broadening factor of 50 Hz was used. The spectra were recorded at 298 K in
anhydrous [2H]-chloroform and referenced to external doubly distilled water (0.00 ppm). The
measured chemical shifts were corrected for magnetic susceptibility of the solvent.
11B NMR spectroscopy
11B NMR spectra were recorded on a Varian Unity Plus 200 operating at 64 MHz.
pKa determination
The analyzed compounds were dissolved in a 0.1 M phosphate buffer to the final
concentration of 1.0 x 10-3 M. The pH of the solution was adjusted with sodium hydroxide to
an appropriately high value, usually 12. The pH measurements were performed using a
5

Mettler Toledo pH meter. Spectrophotometric measurements for the determination of the
boronic acid dissociation constants were carried out using an Analytik Jena SPECORD S600
spectrophotometer. Solutions having the proper pH were placed in quartz cuvettes, and UV-
Vis absorption scans were performed. The spectra were analyzed by calculating the spectral
difference between the acid spectra and the spectra obtained at other pH. The wavelengths of
maximum positive and negative deviations were determined graphically, and the absolute
values of the absorbance difference were then plotted vs. pH. The data was fit to the
Henderson–Hasselbalch equation [54] to obtain the pKa value.
X-ray diffraction
The single crystal X-ray experiment was conducted at 100 K on the Gemini A Ultra
Diffractometer (Agilent Technologies) using mirror monochromated Cu/Kα radiation (λ =
1.5418 Å) (Table S1, Supplementary Data). Data collection and data reduction were
performed in the CrysAlisPro program [55]. The empirical absorption corrections using
spherical harmonics, implemented in multi-scan scaling algorithm were also applied. To solve
and refine the structure OLEX-2 suite [56] with implemented SHELXS97 (direct methods)
and SHELXL97 (the full-matrix least-squares technique) programs were used [57]. All non-
hydrogen atoms were refined with anisotropic temperature factors. The hydrogen atoms were
placed in calculated positions with fixed isotropic thermal parameters (Uiso(H) = 1.2 x
[Ueq(C)] for aromatic hydrogens and Uiso(H) = 1.5 x [Ueq(C)] in case of methyl group) and
were included in the structure factor calculations in the final stage of the refinement. The final
refinement indices converged to R1 = 3.81% and wR2 = 9.48% for the observed data (see
Table S1 in Supplementary Information). Selected geometrical parameters are collected in
Table S2 in Supplementary Information file.
Results and discussion
The recently published paper [17] described the crystal structures of phenylboronic
acids 1 – 3. They form dimers with two intermolecular hydrogen bonds, as well as
intramolecular hydrogen bond between B-OH and ether groups. Geometric parameters of
hydrogen bonds in these acids and in the unsubstituted analogue (4) are collected in Table 1.
6

Table 1.
Selected parameters of intra- and intermolecular hydrogen bonds in crystals of the compounds
1 – 4 (Å,º).
Intramolecular HB
D...A
Intermolecular HB
D...A
Compound
D-H...A
140(2)
D-H...A
177(2)
Ref.
18
2.654(2)
2.781(1)
1
2
3
4
2.654(1)/2.661(1)a 159(2)/161(3)a 2.775(1)/2.813(1)a 174(2)/177(1) 17
2.623(1)
-
175(2)
-
2.742(1)
176(2)
17
2.721(2)/2.734(2)a 175(3)/175(3)a 57
a Two independent molecules
The geometry of intramolecular hydrogen bonds formed in the compounds 1 and 2 is
somewhat worse than the parameters observed for 3. The difference is probably caused by the
rigidity of the 6- and 7-membered H-bonded ring formed in 1 and 2, while more flexible
structure with 8-membered ring is observed in 3. The consequence of this flexibility is also
reflected in the slight enhancement of the intermolecular interactions in the dimer of 3 (2.742
Ǻ) compared with 1 and 2 (2.775 and 2.813 Ǻ). The shorter intermolecular hydrogen bond is
also observed for unsubstituted compound 4. No O→B interactions have been observed in the
crystal structure of the acids 1 - 3, which is similar to the analogs with the aminomethyl
groups [29].
The influence of hydrogen bond formation on the 17O spectra of boronic acid solutions
was recently investigated [59]. In an inert solvent, i.e. not able to be an acceptor or a donor of
the proton, the concentration of the sample does not influence the intramolecular hydrogen
bond. On the contrary, the association of boronic acids by formation of the intermolecular
hydrogen bonds is dependent on the concentration. It was found that a significant increase in
chemical shift of B(OH)2 oxygen signals was observed (ca. 9 ppm) on changing concentration
from 0.001 to 0.7 M in CDCl3, which is the effect of hydrogen-bonded dimer formation [59].
On the other hand, the formation of the intramolecular hydrogen bond in boronic acids
between boronyl group (donor) and the substituent at ortho position causes smaller increase in
chemical shift of the B-O oxygen atom (3-5 ppm).
In order to estimate the effects of hydrogen bonds formation in solutions of the studied
compounds, their 17O NMR spectra have been recorded at two different concentrations (0.001
7

and 0.2 M). Measurements at higher concentrations were impossible due to limited solubility
of the investigated acids in CDCl3. The results are presented in Table 2.
Table 2. The 17O NMR chemical shifts (δ/ppm) of the B-O-X oxygen for the studied
compounds at two different concentrations (in CDCl3; 298 K).
Concentration
Compound
Difference
0.001 M 0.2 M
acids
1
82.4
86.3
87.2
71.0
80.1
83.9
87.0
92.7
76.5
86.0
1.5
0.7
5.5
5.5
5.9
2
3
4
5
esters
1a
2a
3a
4a
5a
155.4
157.5
163.7
150.1
156.9
155.4 0.0
157.2 -0.3
163.6 -0.1
150.2 0.1
157.3 0.4
As it was expected, the concentration change influences the chemical shift of boronic acids (1
– 5), but not of the esters (1a – 5a). It is interesting that relatively small change is observed
for two acids with ortho-alkoxy substituents (1 and 2), whereas the change for the third
compound of this class (3) is comparable with that for the compounds without alkoxy group
(4 and 5). On that basis, as well as the crystals data presented in Table 1 one can conclude,
that compounds 1 and 2 form weaker intermolecular hydrogen bonds than 3, both in the
solution as well as in the solid state. The previous observations [17, 18, 23] concerning the
rotation of the B(OH)2 moiety and its engagement in the intermolecular hydrogen bonds in
crystals show that the flexibility of boronyl group influences the ability of boronic acids
association. In case of 1 and 2 the formation of 6- and 7-membered H-bonded rings,
respectively, reduces to some extent the free rotation on the B-C bond. In case of 3 the more
flexible 8-membered ring as well as lack of the intramolecular hydrogen bond in 4 and 5
8

enable the adjustment of the boronic moiety orientation towards formation of more favourable
intermolecular interactions.
17
Comparing the O NMR signals corresponding to equal and low concentration of 4
(71.0 ppm) and 5 (80.1 ppm) the steric effect of the ortho substituent is manifested (shift by 9
ppm). This effect can be predicted on the basis of the Charton scale steric effects [60]. It has
been shown previously [59], that for the ortho-substituted phenylboronic acids the steric
interactions determine the chemical shift of the B-O oxygen, while the inductive and
resonance effects do not affect these values significantly. According to that, the 17O NMR
shift, observed for ortho-methoxyphenylboronic acid (1) (82.4 ppm), 5 ppm higher than
predicted should be the effect of intramolecular hydrogen bond formation.
Catechol ester formation has significant influence on the shielding of the B-O oxygen
atoms. Ester formation causes a change of the chemical shift from ca. 70-90 ppm observed for
the acids (1 – 3) to ca. 150-160 ppm for the esters (1a – 3a). It is worth emphasizing, that
almost the same change of the chemical shift is observed for all the compounds (1 – 5) on
going from acid to the corresponding ester (70.2-72.7), which indicates that no O→B bond is
formed in the compounds 1a – 3a.
Formation of hydrogen bond has an influence on 17O NMR chemical shift of both
proton acceptor and proton donor atoms. For the carbonyl group, being proton acceptor in
intramolecular hydrogen bonds, relatively high decrease in chemical shift (by ca. 70 ppm) is
observed [61]. The sensitivity of the methoxy group to hydrogen bonding was found to be
much smaller than that of a carbonyl group. Small decrease (2-6 ppm) was observed for
ortho-anisic acid and ortho-anisamide compared with the analogous methyl ester and N,N-
17
dimethyl derivative [62]. The O NMR chemical shifts of the ether group oxygen (C-O-C)
for the investigated compound are presented in Table 3.
Table 3. The 17O NMR chemical shifts (δ/ppm) of the C-O-C oxygen for the studied
compounds at two different concentrations and for the reference compounds (in CDCl3; 298
K).
Concentration
0.001 M
39.5
Difference
Compound
0.2 M
40.3
1.1
0.8
0.9
-1.8
1
2
3
0.2
-20.8
-22.6
9

57.9
56.0
-5.4
-1.9
1a
2a
3a
1b
2b
3b
-5.3
-0.1
-8.2
-8.4
-0.2
-
-
-
46.2
-16.3
-18.3
-
-
-
For all the investigated compounds the effect of concentration on the C-O-C oxygen
chemical shift is small. In esters it is due to the fact that they do not associate through strong
hydrogen bonds while in acids the methoxy group is engaged only in intramolecular hydrogen
bond, which is less concentration-dependent than the intermolecular one. The differences
between boronic esters (1a - 3a) and corresponding ethers without boronic group (1b - 3b) are
ca. 10 ppm. Considerably higher values for boronic esters are caused by the steric effect of the
boronic group. The difference between boronic esters 1a, 2a and 3a is similar as for the
reference compounds 1b, 2b and 3b. As the intramolecular O→B bond can be taken into
consideration for 2a and 3a, but not for 1a, the observed tendency exclude this interaction for
all the investigated boronic esters (1a - 3a).
11
Similar conclusion can be drawn from B NMR spectra of 1 – 5 and 1a – 5a, which
display one signal at ca. 30 ppm, corresponding to the three-coordinate boron atom.
Formation of the O→B bond should significantly change the chemical shift towards lower
values (ca. 10 ppm), which is observed for the compounds with aminomethyl group [33].
10

Fig. 1. An ORTEP-3 [63] drawing with the atoms numbering scheme for 1a molecule. The
thermal ellipsoids are shown with 50% probability. Front (a) and side (b) views of the
molecule are presented.
The molecular structure of 1a determined in crystalline state is shown in Fig.1. The molecules
of 1a crystallize in I2/a space group symmetry of the monoclinic system with one molecule in
the asymmetric unit (see Table S1). The boron trigonal coordination is retained in crystal. The
formation of the 5-membered ring fused with catechol aromatic ring causes the narrowing of
the O(1)–B(1)–O(2) angle that equals to 111.13(13)°. The similar value of OBO angle was
also noticed in crystals of unsubstituted boronic catechol ester 4a [64], while in the parent
boronic acid 1 this angle is close to 120°. The remaining angles at boron atom in 1a are
differentiated due to the presence of only one ortho substituent. The broadening by 6° is
observed for the angle O(2)–B(1)–C(1) in proximity of the methoxy group. In case of the acid
1 the difference is smaller (ca. 3°) what may be attributed to the formation of intramolecular
O–H…O hydrogen bond. Lack of the substituent in 4a results in symmetrical position of
thefused rings towards the phenyl ring. Moreover in 4a both B–O bonds are the same and
equal to 1.394(1) Å. Whereas in 1a the B–O bonds differ by 0.011(1) Å and the O(2)–B(1)
bond is shorter. The B–C bond is a little bit longer in methoxy derivative 1a comparing to the
unsubstituted ester 4a while substantially shorter than in the acids 1 and 4. Furthermore, the
analysis has revealed a tendency of 1a molecule for being flat with the acute angle between
the plane comprising the phenyl ring and the fused ring fragment being only 3.66(5)° (in 4a
the twist is 1.37(3)°). The methoxy oxygen atom lies also in the molecule's plane with the
deviation of only 0.058(1) Å. The C(13) atom (methyl group) is only 0.329(2) Å out of the
molecule's plane. Although the distance between O(3) oxygen atom from methoxy group and
boron atom is only 2.89(2) Å, the fact that the whole moiety is flat precludes the dative O→B
bond formation.
It was found that substituents display an influence on the acidity of boronic acids,
especially in case of possible intramolecular interactions [32]. The pKa values of the
investigated acids are collected in Table 4.
Table 4. pKa values for the investigated boronic acids.
Compound
1
2
3
4
pKA
9.318 ± 0.025
9.776 ± 0.068
10.351 ± 0.029
8.8a
11

a Ref. [65].
Introduction of the methoxyalkyl group at ortho position decreases the acidity of the
compounds in the order 1 – 3. The value for 1 is about 0.5 higher than for phenylboronic acid
-
4. It can be explained by the less favourable B(OH)3 formation for the species with
intramolecular hydrogen bonds of increased strength. This effect is opposite in comparison
with ortho-aminomethylphenylboronic acids. Introduction of –CH2NR2 group at the ortho
position of phenylboronic acids strongly increases the acidity. The pKa values for the
compounds with cyclic amino-substituents are between 4.8 – 6.3, which confirms the N→B
interaction and places those compounds amongst boronic acids of the lowest pKa [35]. These
results once again exclude the possibility of the O→B interaction in the investigated
compounds in solution. Further, the results described above are in good accordance with the
sugars’ receptor activity. Compounds 1 – 3 have the binding constants with glucose, fructose
and galactose about 10 times lower than phenylboronic acid 4 [17], while the compounds with
ortho-aminomethyl substituents display enhanced activity compared with 4 [23].
Conclusions
1. In ortho-methoxyalkylphenylboronic acids both intra- and intermolecular hydrogen bonds
are observed in the solid state. The evidence of their formation in solutions was investigated
17
by O NMR technique. The formation of intermolecular hydrogen bonds in studied boronic
acids influences the 17O NMR chemical shift of B-O oxygen signals: it is concentration
dependent.
2. Lack of strong intermolecular hydrogen bonds results in no significant difference of NMR
spectra upon concentration. Therefore, for esters the chemical shifts do not differ.
Nevertheless, ester formation has significant influence on the chemical shift of B-O oxygen
atoms increasing its value by 70-90 ppm comparing to acids.
3. The methoxy group is engaged only in intramolecular hydrogen bond, which is less
concentration-dependent than the intermolecular one. The sensitivity of methoxyl oxygen
atoms to hydrogen bond formation was found to be small (ca. 10 ppm).
4. On the basis of 17O NMR results the formation of O→B dative bond in solution is
precluded, which is in agreement with the 11B NMR data.
5. In the solid state the molecules of ortho-methoxyphenylboronic acid catechol ester are
almost planar.
12

6. Introduction of the methoxyalkyl group at ortho position decreases the acidity of the
compounds compared with the unsubstituted phenylboronic acid.
Acknowledgement
This work was supported by the National Science Centre of Poland, project number N204
135639.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.saa. Crystallographic data (excluding structure factors) for the
structure reported in this paper has been deposited with the Cambridge Crystallographic Data
Centre as deposit number CCDC 939286. Copies of the data can be obtained, free of charge,
on application to the CCDC, 12 Union Rd, Cambridge CB2IEZ UK (fax: +44 (1223) 336 033;
e-mail: deposit@ccdc.cam.ac.uk).
References
[1] Boronic Acids. Preparation and Applications in Organic Synthesis, Medicine and
Materials, D. G. Hall (Ed.), Wiley-VCH, Weinheim, 2011.
[2] K. Severin, Dalton Trans. (2009) 5254-5264.
[3] A. Sporzyński, Pol. J. Chem. 81 (2007) 757-766.
[4] P. Rodríguez-Cuamatzi, R. Luna-García, A. Torres-Huerta, M.I. Bernal-Uruchurtu, V.
Barba, H. Höpfl, Cryst. Growth Des. 9 (2009) 1575-1583.
[5] J. Yan, S. Jin, B. Wang, Tetrahedron Lett. 46 (2005) 8503-8505.
[6] S.M. Strawbridge, S.J. Green, J.H.R. Tucker, Chem. Commun. (2000) 2393-2394.
[7] L. Ren, Z. Liu, M. Dong, M. Ye, H. Zou, J. Chromatogr. A. 1216 (2009) 4768-4774.
[8] G. Belogi, T. Zhu, G. Boons, Tetrahedron Lett. 41 (2000) 6969-6972.
[9] W. Niu, C. O’Sullivan, B.M. Rambo, M.D. Smith, J.J. Lavigne, Chem. Commun. (2005)
4342-4344.
[10] Y. Kitamura, A. Sakurai, T. Udzu, T. Maegawa, Y. Monguchi, H. Sajiki, Tetrahedron 63
(2007) 10596-10602.
[11] H. Chaumeil, S. Signorella, C.L. Drian, Tetrahedron 56 (2000) 9655-9662.
[12] C. Bresner, J.K. Day, N.D. Coombs, I.A. Fallis, S. Aldridge, S.J. Coles, M.B.
Hursthouse, Dalton Trans. (2006) 3660-3667.
13

[13] M. Jańczyk, A. Adamczyk-Woźniak, A. Sporzyński, W. Wróblewski, Anal. Chim. Acta.
733 (2012) 71-77.
[14] H.S. Lee, X.Q. Yang, X. Sun, J. McBreen, J. Power Sources 97-98 (2001) 566-569.
[15] H.S. Lee, X.Q. Yang, X. Sun, J. McBreen, J. Electrochem. Soc. 149 (2002) A1460-
A1465.
[16] H.S. Lee, X.Q. Yang, X. Sun, J. McBreen, J. Electrochem. Soc. 151 (2004) A1429-
A1435.
[17] A. Adamczyk-Woźniak, Z. Brzózka, M. Dąbrowski, I.D. Madura, R. Scheidsbach, E.
Tomecka, K. Żukowski, A. Sporzyński, J. Mol. Struct. 1035 (2013) 190-197.
[18] M.K. Cyrański, P. Klimentowska, A. Rydzewska, J. Serwatowski, A. Sporzyński, D.K.
Stępień, CrystEngComm 14 (2012) 6282-6294.
[19] A. Adamczyk-Woźniak, M.K. Cyrański, A. Dąbrowska, B. Gierczyk, P. Klimentowska,
G. Schroeder, A. Żubrowska, A. Sporzyński, J. Mol. Struct. 920 (2009) 430-435.
[20] T.D. James, M.D. Phillips, S. Shinkai, Boronic Acids in Saccharide Recognition,
RSC Publishing: Cambridge, 2006.
[21] S.W. Coghlan, R.L. Giles, J.A.K. Howard, L.G.F. Patrick, M.R. Probert, G.E. Smith, A.
Whiting, J. Organomet. Chem. 690 (2005) 4784-4793.
[22] J. Zhao, M.G. Davidson, M.F. Mahon, G. Kociok- Köhn, T.D. James, J. Am. Chem. Soc.
126 (2004) 16179-16186.
[23] A. Adamczyk-Woźniak, Z. Brzózka, M.K. Cyrański, A. Filipowicz-Szymańska, P.
Klimentowska, A. Żubrowska, K. Żukowski, A. Sporzyński, Appl. Organometal. Chem. 22
(2008) 427-432.
[24] L. Zhang, J.A. Kerszulis, R.J. Clark, T. Ye, L. Zhu, Chem.Commun. (2009) 2151-2153.
[25] L. Zhu, S.H. Shabbir, M. Gray, V.M. Lynch, S. Sorey, E.V. Anslyn, J. Am. Chem. Soc.
128 (2006) 1222-1232.
[26] A. Adamczyk-Woźniak, R.M. Fratila, I.D. Madura, A. Pawełko, A. Sporzyński, M.
Tumanowicz, A.H. Velders, J. Żyła, Tetrahedron Lett. 52 (2011) 6639-6642.
[27] A. Sakakura, R. Yamashita, T. Ohkubo, M. Akakura, K. Ishihara, Aust. J. Chem. 64
(2011) 1458-1465.
[28] K. Arnold, A.S. Batsanov, B. Davies, A. Whiting, Green Chem. 10 (2008) 124-134.
[29] A. Adamczyk-Woźniak, M.K. Cyrański, B.T. Frączak, A. Lewandowska, I.D. Madura,
A. Sporzyński, Tetrahedron 68 (2012) 3761-3767.
[30] C.B. Aakeroy, J. Desper, B. Levin, CrystEngComm 7 (2005) 102-107.
14

[31] A.N. Cammidge, V.H.M. Goddard, H. Gopee, N.L. Harrison, D.L. Hughes, C.J.
Schubert, B.M. Sutton, G.L. Watts, A.J. Whitehead, Org. Lett. 8 (2006) 4071-4074.
[32] M. Reinholdt, J. Croissant, L. Di Carlo, D. Granier, P. Gaveau, S. Begu, J.-M.
Devoisselle, P.H. Mutin, M.E. Smith, C. Bonhomme, C. Gervais, A. van der Lee, D.
Laurencin, Inorg. Chem. 50 (2011) 7802-7810.
[33] L. Zhu, S.H. Shabbir, M. Gray, V.M. Lynch, S. Sorey, E.V. Anslyn, J. Am. Chem. Soc.
122 (2006) 1222-1232.
[34] B.E. Collins, S. Sorey, A.E. Hargrove, S.H. Shabbir, V.M. Lynch, E.V. Anslyn, J. Org.
Chem. 74 (2009) 4055-4060.
[35] A. Adamczyk-Woźniak, K.M. Borys, I.D. Madura, A. Pawełko, E. Tomecka, K.
Żukowski, New J. Chem. 37 (2013) 188-194.
[36] S.L. Wiskur, J.J. Lavigne, A. Metzger, S.L. Tobey, V. Lynch, Chem. Eur. J. 310 (2004)
3792-3804.
[37] S. Toyota, M. Oki, Bull. Chem. Soc. Jpn. 65 (1992) 1832-1840.
[38] S. Toyota, M. Asakura, T. Futawaka, M. Oki, Bull. Chem. Soc. Jpn. 72 (1999) 1879-
1885.
[39] S. Toyota, T. Futawaka, H. Ikeda, M. Oki, J. Chem. Soc., Chem. Commun. (1995) 2499-
2500.
[40] S. Toyota, T. Futawaka, M. Asakura, H. Ikeda, M. Oki, Organometallics 17 (1998) 4155-
4163.
[41] J.C. Norrild, I. Sotofte, J. Chem. Soc., Perkin Trans. 2 (2002) 303-311.
[42] X.-C. Liu, J.L. Hubbard, W.H. Scouten, J. Organomet. Chem. 493 (1995) 91-94.
[43] J. Nakatsuji, Y.Yamamoto, Bull. Chem. Soc. Jpn. 83 (2010) 767-776.
[44] J.W.J. Kennedy, D.G. Hall, Synlett (2002) 477-479.
[45] J.W.J. Kennedy, D.G. Hall, J. Organomet.Chem. 680 (2003) 263-270.
[46] M.G.D. Leed, N. Wolkow, D.M. Pham, C.L. Daniel, J.L. Dunaief, K.J. Franz, J. Inorg.
Biochem. 105 (2011) 1161-1172.
[47] T. Murafuji, K. Sugimoto, S. Yanagimoto, T. Moriya, Y. Sugihara, Y. Mikata, M. Kato,
S. Yano, Heterocycles 54 (2001) 929-942.
[48] O. Baslé, S. Porcel, S. Ladeira, G. Bouhadir, D. Bourissou, Chem.Commun. 48 (2012)
4495-4497.
[49] M. Gray, B.J. Chapell, J. Felding, N.J. Taylor, V. Snieckus, Synlett (1998) 422-424.
[50] X.-C. Liu, J.L. Hubbard, W.H. Scouten, J. Organomet. Chem. 493 (1995) 91-94.
[51] M.T. Reetz, C.M. Niemeyer, K. Harms, Angew. Chem. Int. Ed. 30 (1991) 1474-1476.
15

[52] L. Zhang, J.A. Kerszulis, R.J. Clark, T. Ye, L. Zhu, Chem. Commun. (2009) 2151-2153.
[53] S. Fornarini, V. Muraglia, J. Am. Chem. Soc. 111 (1989) 873-877.
[54] S. Soundararajan, M. Badawi, C.M. Kohlrust, J.H. Hageman, Anal. Biochem. 178 (1989)
125-134.
[55] CrysAlisPro, Agilent Technologies, Version 1.171.36.21 (release 14-08-2012
CrysAlis171 .NET).
[56] O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, J. Appl.
Crystallogr. 42 (2009) 339-341.
[57] G.M. Sheldrick, Acta Cryst. A 64 (2008) 112-122.
[58] M.K. Cyrański, A. Jezierska, P. Klimentowska, J.J. Panek, A. Sporzyński, J. Phys. Org.
Chem. 21 (2008) 472-482.
[59] B. Gierczyk, M. Kaźmierczak, G. Schroeder, A. Sporzyński, New J. Chem. 37 (2013)
1056-1072.
[60] M.H. Aslam, A.G. Burden, N.B. Chapman, J. Shorter, M. Charton, J. Chem. Soc., Perkin
Trans. 2 (1981) 500-508.
[61] 17O NMR Spectroscopy in Organic Chemistry, D.W. Boykin (Ed.), CRC Press, Boca
Raton, Chapter 5.
[62] G. Jaccard, P.-A. Carrupt, J. Lauterwein, Magn. Res. Chem. 26 (1988) 239-244.
[63] L.J. Farrugia, J. Appl. Crystallogr. 32 (1999) 837-838.
[64] H.D. Hausen, H. Hess, F. Zettler, Acta Cryst. B30 (1974) 1876-1878.
[65] J. Yan, G. Springsteen, S. Deeter, B. Wang, Tetrahedron 60 (2004) 11205-11209.
16

C(10)
C(9)
C(8)
(a)
(b)
C(11)
C(12)
C(7)
O(2)
C(12)
O(1)
B(1)
B(1)
O(1)
O(3)
C(6)
C(5)
C(13)
C(2)
C(3)
C(1)
C(4)
C(13)

Highlights:
 Synthesis of ortho-methoxyalkylphenylboronic acids catechol esters.
17O NMR characterization of the esters and parent acids.

 Influence of hydrogen bond on the properties of the acids.
 No O→B interactions in the investigated compounds.
 Diminished acidity compared with the unsubstituted phenylboronic acid.