Influence of the ortho-methoxyalkyl substituent on the properties of phenylboronic acids

Article abstract of DOI:10.1016/j.molstruc.2012.09.049

Novel phenylboronic acids with methoxyalkyl groups at ortho position were synthesized. Molecular and crystal structures for two compounds were determined by single crystal X-ray diffraction. In both cases the O-H?O hydrogen-bonded dimers are the primary s

Full text of DOI:10.1016/j.molstruc.2012.09.049

Journal of Molecular Structure 1035 (2013) 190–197
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Influence of the ortho-methoxyalkyl substituent on the properties
of phenylboronic acids
´
Agnieszka Adamczyk-Wozniak, Zbigniew Brzózka, Marek Da˛browski, Izabela D. Madura,
⇑
_
´
Roy Scheidsbach, Ewelina Tomecka, Kamil Zukowski, Andrzej Sporzynski
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
h i g h l i g h t s
"
"
"
"
Novel phenylboronic acids with methoxyalkyl groups at ortho position: synthesis, crystal structure.
Hirshfeld surface analysis.
Comparison with other ortho-substituted phenylboronic acids.
Sugar receptor activity.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2012
Accepted 19 September 2012
Available online 27 September 2012
Novel phenylboronic acids with methoxyalkyl groups at ortho position were synthesized. Molecular and
crystal structures for two compounds were determined by single crystal X-ray diffraction. In both cases
the O–Hꢀ ꢀ ꢀO hydrogen-bonded dimers are the primary supramolecular motives in which the relatively
short intramolecular B–O–Hꢀ ꢀ ꢀO hydrogen bonds are observed between boronic group and oxygen atom
of the ortho-substituent. Based on the CSD data for ortho-substitued boronic acids, the relation between
the twist of the boronic moiety towards phenyl ring and the intramolecular H-bond angle is discussed.
The intermolecular interactions between dimeric motives were investigated with the aid of Hirshfeld sur-
Keywords:
Boronic acids
Hydrogen bond
Hirshfeld surface analysis
Sugar receptor activity
Weak interactions
face analysis. The weak C–Hꢀ ꢀ ꢀO and C–Hꢀ ꢀ ꢀ
ones. Sugar-binding ability of the methoxyalkyl compounds was evaluated for
-galactose by the competition assay with Alizarin Red S.
p
interactions were detected together with the agostic Bꢀ ꢀ ꢀH
D
-glucose, -fructose and
D
D
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
examples of weaker inter- and intramolecular bonds formation,
determining the crystal architecture [11].
Arylboronic acids are systems that attract an increasing scien-
tific interest due to their new applications in organic synthesis,
catalysis, supramolecular chemistry, biology, medicine and mate-
rial engineering [1]. Recently, a great interest has been paid to
the supramolecular systems which can be formed by both covalent
[2] as well as hydrogen bonds [3,4]. The flexibility of the boronic
acid molecule plays the important role in the diversity of the sys-
tems. The presence of two hydroxyl groups in different conforma-
tions (syn:syn, syn:anti or anti:anti) [5,6] enables the formation of a
variety of hydrogen bonded assemblies in one-component systems
(only boronic acids) or multi-component ones [7–9]. In addition to
strong intermolecular hydrogen bonds in typical dimeric units and
lateral hydrogen bonds connecting them [10], there are many
Substituents at ortho position of phenylboronic acids can inter-
act with boronic group in several ways. If the substituent contains
strong proton acceptor atom, intramolecular hydrogen bond can be
formed. It is observed for example in case of alkoxy [12–19], and
aryloxy [20] substituents. For the ortho-formyl group, intramolec-
ular hydrogen bond is also observed, and the formed seven-mem-
bered ring is essentially coplanar with the phenyl ring [21,22]. But
while the bulky substituent at 3 position is present the tautomeric
equilibrium with the formation of 3-hydroxybenzoxaboroles can
occur [22]. In the case of the fluorine [23,24], bromine [25], or
iodine [26] atoms at ortho position the formation of very weak
intramolecular interactions may also be assumed.
Phenylboronic acids with aminomethyl groups at the ortho
position 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 [27]. In the solid
state, the formation of intramolecular B–O–Hꢀ ꢀ ꢀN hydrogen bond
⇑
Corresponding author. Tel.: +48 222345737; fax: +48 226282741.
E-mail address: spor@ch.pw.edu.pl (A. Sporzyn´ ski).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.09.049

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A. Adamczyk-Wozniak et al. / Journal of Molecular Structure 1035 (2013) 190–197
191
cooling to 0 °C, the reaction was quenched with water and
extracted with diethyl ether (20 mL). The water layer was
separated and washed with diethyl ether (3 ꢁ 20 mL). The
collected organic layer was washed with brine, dried over Na2SO4,
followed by solvent removal by a rotary vacuum evaporator to
obtain the product as an yellow oil, 14.32 g (85.0%), which was
used without further purification. 1H NMR (400 MHz, CDCl3): d:
3.48 (s, 3H), 4.54 (s, 2H), 7.13–7.17 (m, 1H), 7.30–7.34 (m, 1H),
7.46–7.49 (m, 1H), 7.54–7.56 ppm (d, 1H).
HO
OH
HO
OH
HO
OH
B
B
B
O
O
O
1
2
3
Chart 1. The investigated compounds.
was observed in many cases [28–35]. Similar bond is formed for
iminomethyl group [21]. Recently, calculations for model com-
pounds in the gas phase proved that the most stable form is that
with intramolecular hydrogen bond, while the form with dative
N ? B bond is less favoured [36].
As ortho-monosubstituted phenylboronic acids usually form
typical dimers in the crystal lattice, presence of two hydrogen
acceptor groups at ortho positions reveal much bigger variety of
possible interactions. The first examples of monomeric boronic
acid molecules with two intramolecular hydrogen bonds have been
recently reported for 2,6-dialkoxyphenylboronic acids [37].
In addition to the systems with intramolecular hydrogen bonds,
there are some boronic acids in which such a bond is not formed,
although hydrogen acceptor atoms are present in the group at
ortho position. The examples are compounds with acetyl [38],
methoxycarbonyl [39] and nitro [40] groups.
2.1.2. [2-(Methoxymethyl)phenyl]boronic acid (2)
The reaction was carried out under argon protection. Diethyl
ether (200 mL) was placed in a three-necked round-bottomed
flask, equipped with a CO2/acetone bath and magnetic stirrer was
cooled down to ꢂ70 °C. n-Butyllithium (2.5 M in hexanes,
29.9 mL, 74.8 mmol) was slowly added to the stirred solvent. 1-
Bromo-2-(methoxymethyl)benzene (2a) (14.32 g, 71.2 mmol) was
dropped-in for 10 min while keeping the temperature below
ꢂ65 °C. After 1 h of stirring at that temperature, triethyl borate
(12.71 mL, 74.8 mmol) was dropped-in while keeping the temper-
ature below ꢂ65 °C. The stirring was continued for an additional
hour at this temperature. After that time the CO2/acetone bath
was removed and aq. HCl (3 M, 50 mL) was quickly added while
intense stirring. The temperature rose until about 10 °C. The
resulting phases were separated and the aqueous phase was
extracted twice with diethyl ether (30 mL). The organic phases
were combined and about 3/4 of the volume of the solvent
removed under reduced pressure. Water (100 mL) was added to
the remaining liquid and evaporation was continued for an
additional half an hour. The aqueous phase was removed by decan-
tation. The slurry was kept at 4 °C for 10 days. After that time a
white solid was filtered off. and dried on air to give the crystalline
product (3.85 g, 32.5% yield). Anal.: Calcd for C8H11BO3: C 57.89%,
H 6.68%; Found: C 57.04%, H 6.56%. 11B NMR (128.3 MHz, CDCl3):
d: 29.6 ppm. 1H NMR (400 MHz, acetone-d6): d: 3.34 (s, 3H), 4.58
(s, 2H), 7.28–7.38 (m, 3H), 7.46 (s, 2BOH), 7.79–7.81 ppm (m,
1H). 13C NMR (100 MHz, CDCl3): d 57.0, 76.3, 128.1, 130.0, 130.2,
136.3, 140.3, 183.8 ppm.
The aim of the present work is the analysis of the influence of
the spacer between methoxy group and phenyl ring at the ortho
position of phenylboronic acid on the structure and the properties
of these compounds. The investigated compounds are shown in
Chart 1.
2. Experimental
2.1. Synthesis
Compound 1 was commercially available. Compounds 2 and 3
were prepared according to the Scheme 1.
2.1.1. 1-Bromo-2-(methoxymethyl)benzene (2a)
2.1.3. 1-Bromo-2-(2-methoxyethyl)benzene (3a) [41]
4.36 g (181.7 mmol) of sodium hydride (60% in mineral oil) was
washed twice with hexanes and placed in 100 mL of THF in a three-
necked flask fitted with dropping funnel, magnetic stirrer and
thermometer under argon flow. A solution of 15.73 g (84.1 mmol)
of 2-bromobenzyl alcohol in 50 mL of THF was dropped in at 0 °C.
After stirring for 1 h at that temperature, 6.95 mL (15.85 g,
111.7 mmol) of iodomethane was added via syringe. The reaction
mixture was stirred at 0 °C for 1 h and at RT for 45 min. After
17.6 g (0.314 mol) KOH in 100 mL DMSO was placed in a flask
fitted with dropping funnel and magnetic stirrer placed in water
bath at ca. 7 °C. A solution of 9.9 mL (22.57 g, 0.159 mol) of iodo-
methane and 13.94 g (0.0742 mol) of 2-(2-bromophenyl)ethanol
in 80 mL DMSO was dropped-in while keeping the temperature
21–22 °C. Water bath was removed and the reaction mixture was
stirred for 2 h while the temperature raised to 27 °C. After cooling
to RT reaction mixture was poured into 600 mL of water, than
1. BuLi
HO
OH
Br
Br
B
2. (EtO)3B
3. aq. HCl
CH3I, NaH
THF
OH
O
O
Et2O
2
2a
HO
OH
1. BuLi
Br
Br
B
2. (EtO)3B
CH3I, KOH
DMSO
O
OH
O
3. aq. HCl
Et2O
3a
3
Scheme 1. Synthesis of the investigated compounds.

´
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Table 1
extracted with diethyl ether (300 mL and 2 ꢁ 100 mL). Ether ex-
tract was washed with water (2 ꢁ 150 mL) and volatiles were dis-
tilled off to give 14.6 g of 2-bromo-(2-methoxyethyl)benzene
(0.0679 mol, 91.5%), which was used without further purification.
1H NMR (400 MHz, CDCl3): d: 3.08 (t, 2H), 3.42 (s, 3H), 3.66 (t,
2H), 7.10–7.14 (m, 1H), 7.26–7.33 (m, 2H), 7.57–7.59 ppm (m, 1H).
Crystal data for the compounds 2 and 3.
Compound
2
3
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
Unit cell dimensions
a (Å)
C8H11BO3
165.98
100.0(4)
Orthorhombic
Pca21
C9H13BO3
180.00
10.0(4)
Monoclinic
P21/n
2.1.4. [2-(2-Methoxyethyl)phenyl]boronic acid (3)
20.0922(3)
6.46665(10)
13.2401(2)
90
90
90
1720.27(5)
8
1.282
0.781
704.0
8.08451(10)
12.22010(14)
10.59340(14)
90
104.0973(13)
90
1015.04(2)
4
1.178
0.698
384.0
32540
1618
[Rint = 0.0607]
–
1618/0/128
1.060
R1 = 0.0320
wR2 = 0.0837
R1 = 0.0323
wR2 = 0.0839
0.28 and ꢂ0.15
The reaction was carried out under argon protection. THF
(60 mL) placed in a three-necked round-bottomed flask, equipped
with a CO2/acetone bath and magnetic stirrer was cooled down
to ꢂ70 °C. n-Butyllithium (2.5 M in hexanes, 27.2 mL,
0.0679 mol) was slowly added to the stirred solvent. 1-Bromo-2-
(2-methoxyethyl)benzene (3a) (14.6 g, 0.0679 mol) in 30 mL THF
was dropped-in for 10 min while keeping the temperature below
ꢂ60 °C. After 5 min of stirring temperature decreased to ꢂ70 °C.
Trimethyl borate (9.2 mL, 0.0825 mol) was dropped-in for
10 min. while keeping the temperature below ꢂ57 °C. The stirring
was continued for an additional 5 min. After that time the CO2/ace-
tone bath was removed and the temperature raised to ꢂ18 °C dur-
ing 30 min. Aq. HCl (2 M, 50 mL) was added while intense stirring.
The resulting phases were separated and the aqueous phase was
extracted twice with diethyl ether (30 mL). The organic phases
were combined and about 3/4 of the volume of the solvent
removed under reduced pressure. Water (100 mL) was added to
the remaining liquid and evaporation was continued for an addi-
tional half an hour. 25 mL of pentane was added, the solid was
filtered off and dried under vacuum (RT, 8 h). The solid was mixed
with 25 mL of pentane, filtered off, washed with 10 mL of pentane
and vacuum dried (RT, 2 h) to give the crystalline product (7.12 g,
32.5% yield). Anal.: Calcd for C9H13BO3: C 60.05%, H 7.28%; Found:
C 60.33%, H 7.27%. 11B NMR (128.3 MHz, CDCl3): d: 30,0 ppm. 1H
NMR (400 MHz, acetone-d6): d: 2.99 (t, 2H), 3.27 (s, 3H), 3.66
(t, 2H), 7.10–7.40 (m, 3H), 7.30 (s, 2BOH), 7.55–7.60 ppm (s, 1H).
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
Volume (Å3)
Z
Dcalculated (Mg/m3)
Absorption coefficient (mmꢂ1
F(000)
)
Reflections collected
Independent reflections
60801
3068
[Rint = 0.0500]
0.00(18)
3068/1/236
1.045
R1 = 0.0361
wR2 = 0.0933
R1 = 0.0365
wR2 = 0.0940
0.24 and ꢂ0.19
Flack parameter
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I 2
r(I)]
R indices (all data)
Largest diff. peak and hole (e/Åꢂ3
)
Table 2
Selected geometrical parameters for the compounds 2 and 3.
2 (Molecule 1)
2 (Molecule 2)
3
Bond length, Å
O1–B1
O2–B1
C1–B1
O3–C7
O3–C8
O3–C9
C2–C7
1.369(2)
1.350(2)
1.586(2)
1.437(2)
1.426(2)
–
1.370(2)
1.352(2)
1.585(2)
1.439(2)
1.436(2)
–
1.365(2)
1.355(2)
1.580(2)
–
1.425(2)
1.422(2)
1.514(2)
2.2. X-ray diffraction
1.508(2)
1.506(2)
Bond angles, °
O1–B1–O2
O1–B1–C1
O2–B1–C1
C2–C1–B1
C6–C1–B1
C6–C1–C2
C7–O3–C8
C8–O3–C9
C1–C2–C7
C3–C2–C7
O3–C7–C2
O3–C8–C7
Single crystal data for 2 and 3 were collected on Gemini A
119.6(1)
122.7(1)
117.6(1)
125.0(1)
117.3(1)
117.7(1)
110.4(1)
–
119.2(1)
122.6(1)
118.2(1)
124.7(1)
117.3(1)
118.0(1)
110.7(1)
–
122.3(1)
117.7(1)
110.4(1)
–
118.8(1)
124.1(1)
117.1(1)
124.6(1)
117.3(1)
118.1(1)
–
112.4(1)
123.3(1)
117.5(1)
–
Ultra Diffractometer (Agilent Technologies). Cu/K
a radiation
(k = 1.5418 Å) monochromated by an Oxford Diffraction Enhance
Ultra assembly was used for cell parameters determination and
data collection to a resolution of 0.87 Å. The CrysAlisPro [42] pro-
gram was used for data collection, cell refinement, data reduction
and the empirical absorption corrections using spherical harmon-
ics, implemented in mutli-scan scaling algorithm. The structures
were solved using direct methods, and refined with the full-matrix
least-squares technique using the SHELXS97 and SHELXL97 pro-
grams respectively [43], both implemented in OLEX2 suite [44].
All non-hydrogen atoms were refined with anisotropic tempera-
ture factors. The hydrogen atoms bonded to oxygen atoms were
refined freely while those connected to carbons were placed in cal-
culated positions with fixed isotropic thermal parameters. In case
of 2 the values of the Flack x parameter [45,46] at the end of the
refinement converged 0.00(18) indicating the correct assignment
of the absolute configurations. Relevant crystallographic data are
given in Table 1. Molecular and packing diagrams were generated
using ORTEP-3 for Windows [47] while the geometric calculations
were done by PLATON package [48]. Values involving hydrogen
atoms in the calculated positions are given without estimated
standard deviations.
122.1(1)
117.7(1)
110.4(1)
109.5(1)
Torsion angles, °
C2–C1–B1–O1
C2–C1–B1–O2
C1–C2–C7–O3
C1–C2–C7–C8
C2–C7–O3–C8
C2–C7–C8–O3
C7–C8–O3–C9
–28.6(2)
153.9(1)
69.3(2)
–
177.2(1)
–
–
–27.2(2)
153.6(1)
68.5(2)
–
176.8(1)
–
–
–39.5(2)
140.5(1)
–
93.3(1)
–
–68.6(1)
–175.3(1)
2.3. CSD data search
CCDC-893689 (for 2) and ꢂ893690 (for 3) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
The Cambridge Structural Databse [49] (CSD version 5.33 with
the May 2012 updates) with the implemented program ConQuest
v. 1.14 was used to retrieve the crystal data. The search fragment
comprised the phenylboronic moiety with the introduced X atom

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193
(a)
(b)
Fig. 1. Basic dimeric motives formed between two independent molecules in crystals of 2 (a) and between molecules related by inversion center in 3 (b). In both cases the
atom numbering scheme is given and thermal ellipsoids are drawn with 50% probability level [47]. The intra- and intermolecular O–Hꢀ ꢀ ꢀO hydrogen bonds are denoted with
dotted and dashed lines, respectively.
(where X = N, O, F, S, Cl, Br or I) forming the intramolecular
hydrogen bond with one of the boronic OH donors. The Hꢀ ꢀ ꢀX dis-
tance was restricted to be within the sum of van der Waals radii of
the interacting atoms. The following general search filters were
also chosen from the ConQuest search menu: 3D coordinates
determined, no errors, not powder data and R < 5%. The data for
diboronic acids were excluded manually. Subsequently, 32 struc-
tures retrieved from the Cambridge Structural Database were sup-
plemented with the crystal data of recently published structures
[37] resulting in the 42 structures. As in some of the crystals
Z0 > 1 and also diortho substituted molecules were analyzed, the
entire data set contained finally 61 fragments (i.e. data points).
Both MS Excell as well as VISTA (a part of CSD) programs were used
to analyze the data.
tion of de versus di, called a 2-D fingerprint plot, provides the sum-
mary of intermolecular contacts in the crystal [51]. The close
contacts between particular atom types can be highlighted in the
decomposed fingerprint plots [52]. This enables the separation of
contributions from different interaction types, which commonly
overlap in the full fingerprint. The decomposed 2-D fingerprint
plots presented in this paper in Fig. 3 were generated using Crystal
Explorer 3.0 program [53].
2.5. Determination of the apparent binding constants with ARS and
sugars
A Varian Cary Eclipse fluorimeter was used for the fluorescence
studies. All compounds were dissolved in the mixture: metha-
nol ꢂ 0.1 M aqueous phosphate buffer pH = 7.400 (1:1, v/v) + 1
vol% DMSO. Fluorescence spectra were collected for a solution with
constant concentration of ARS (10ꢂ4 M) and proper boronic recep-
tor. All the spectra were smoothed using Savitzky–Golay function
[54]. The maximum fluorescence intensity was then read from
2.4. Hirshfeld surface analysis
Molecular Hirshfeld surface in the crystal structure is con-
structed basing on the electron distribution calculated as the
sum of spherical atom electron densities [50] and it is defined by
points where the contribution to the electron density from the
molecule of interest is equal to the contribution from all the other
molecules. The point on the surface is described by two distances:
de and di being the distances from the point to the nearest nucleus
external and internal to the surface, respectively. The representa-
the spectra. The association constant of the ARS-boronic acid (KARS
)
was calculated using the modified Benesi–Hildebrand equation
[55]. Then a 1.0 ꢁ 10ꢂ4 M solution of ARS with an appropriate
boronic acid concentration was prepared, keeping ca. 20% of ARS
in its free form. The solution was transferred into a quartz cuvette
where fluorimetric titration was performed.

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A. Adamczyk-Wozniak et al. / Journal of Molecular Structure 1035 (2013) 190–197
194
Table 3
oxygen atom points towards boronic moiety. Such orientation
and the relatively large twist results in the formation of a short
and almost linear H-bond (Hꢀ ꢀ ꢀO = 1.76(2) Å, O–Hꢀ ꢀ ꢀO = 175(2)°)
described with the graph S(8) [56,57]. In case of 2 the formation
of 7-membered H-bond rings, S(7), is observed for both molecules,
and in both cases the Hꢀ ꢀ ꢀO distances are longer by ꢃ0.1 Å than
these observed for 3. Comparing the geometry of the intramolecu-
lar H-bonded ring in 1 it is important to notice that the formed S(6)
ring is essentially flat (the twist of boronic moiety is only 4.11(6)°)
[37]. The Oꢀ ꢀ ꢀO distance of 2.654(2) Å is akin to these found in 2
but the O–Hꢀ ꢀ ꢀO angle is by ꢃ20° smaller. This observation may
lead to conclusion that there is a relation between the boronic moi-
ety twist and the intramolecular H-bonded ring geometry.
The geometry of intra- and intermolecular hydrogen bonds in crystals of 2 and 3 (Å, °).
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D–Hꢀ ꢀ ꢀA
Motif with graph
descriptor
2 (Molecule 1)
O1–H1ꢀ ꢀ ꢀO3
1.85(3)
1.93(2)
2.654(1)
2.775(1)
159(2)
174(2)
Motif a S(7)
Motif c D(3)a
O2–H2ꢀ ꢀ ꢀO1Ai
2 (Molecule 2)
O1A–H1Aꢀ ꢀ ꢀO3A
O2A–H2Aꢀ ꢀ ꢀO1ii
3
1.84(3)
1.98(2)
2.661(1)
2.813(1)
161(3)
177(1)
Motif b S(7)
Motif d D(3)a
O(1)–H(1)ꢀ ꢀ ꢀO(3)
1.76(2)
1.90(2)
2.623(1)
2.742(1)
175(2)
176(2)
Motif a S(8)
O(2)–H(2)ꢀ ꢀ ꢀO(1)iii
Motif b R22ð8Þ
C(7)–H(7A)ꢀ ꢀ ꢀO(1)
2.58
3.145(1)
116
Motif c S(7)
Therefore, we performed the analysis of the crystal data for var-
ious ortho-substituted phenylboronic acids found in Cambridge
Structural Database (CSD) [49]. The decision to extend the study
to other ortho-substituded derivatives was made because the mol-
ecule of compound 3 is the first example with such an eight-mem-
bered H-bonded ring observed so far in crystals of boronic acids,
and there are only few examples of S(7) rings. The database search
was restricted to the molecules able to form the intramolecular H-
bond between at least one of the boronic O–H donor and any
acceptor coming from any substituent. The CSD search resulted
in 32 structures data set which has been supplemented with the
recently published data of 10 ortho-substituted boronic acids
[36,37]. The detailed description of the data retrieval is given in
the Experimental section as well as the appropriate reference
codes are given in the Supplementary data file.
Fig. 2a presents the diagram of the relation between the twist
angle (the dihedral angle between phenyl ring and B(OH)2 moiety)
and the O–Hꢀ ꢀ ꢀX (X = N, O, F, S, Cl, Br, I) angle of the intramolecular
hydrogen bond. The points can be grouped in two distinct clusters
(circled in the diagram). The points in the upper-left corner (the
largest twist and the O–Hꢀ ꢀ ꢀX angle less than 120°) correspond
mostly to the ortho-halogen substituted compounds with relatively
long Hꢀ ꢀ ꢀX distances (Fig. 2b). Although it can be questionable if
these interactions are the hydrogen bonds they lead to the forma-
tion of the 6-membered ring with the intramolecular H-bridge
described with the graph S(6). The other compounds in the same
cluster also form the S(6) rings, but in these case the X is an oxygen
or nitrogen atom. The presence of stronger H-bond acceptors
shortens the Hꢀ ꢀ ꢀX and Oꢀ ꢀ ꢀX distances to lie in the ranges of
1.9–2.4 and 2.6–2.9 Å (Fig. 2b), respectively. According to Gilli
Symmetry codes: (i) ꢂ1/2 + x, ꢂy, z; (ii) 1/2 + x, ꢂy, z; (iii) 1 ꢂ x, 1 ꢂ y, 1 ꢂ z.
Second level graph descriptor Ncd = R22ð8Þ [61].
a
3. Results and discussion
3.1. Molecular and crystal structures
Molecular and crystal structure of the compound 1 was dis-
cussed in details in the recent paper [37] but some remarks to it
will also be given below. The molecules of 2 and 3 crystallize in
orthorhombic and monoclinic system, respectively. In case of 2
there are two crystallographically independent molecules in the
asymmetric unit (Table 1). These molecules show high resem-
blance (see Table 2) and they are related by quasi inversion center,
but the attempts to refine the structure in appropriate centrosym-
metric space group failed.
In both 2 and 3 molecules, the boronic moiety, B(OH)2, exhibits
syn and anti conformation of OH groups (Fig. 1). The whole group is
twisted with respect to the phenyl ring by 28.20(6) and 26.79(6)°
for two independent molecules in 2, while in 3 the twist is larger
and amounts to 38.00(5)°. The substantial twist and relative prox-
imity of oxygen atom of the flexible ortho substituents may lead to
the formation of dative O ? B bond in case of 2 and 3. Nonetheless,
the intramolecular O–Hꢀ ꢀ ꢀO hydrogen bond is present in both dis-
cussed crystals (Table 3). The Oꢀ ꢀ ꢀO distances are 2.654(1),
2.661(1) and 2.623(1) Å in two molecules of 2 and 3, respectively.
Moreover, the conformation of –CH2CH2OCH3 substituent in 3 is
such that all its four atoms lie on the plane which is close to per-
pendicular to the phenyl ring (dihedral angle = 68.6(5)°) and the
(a)
(b)
Fig. 2. The scattergrams based on CSD data search for various boronic acids with least one B–OH donor engaged in the intramolecular hydrogen bond show the relations
between O–Hꢀ ꢀ ꢀX angle and the boronic moiety twist (a) or Oꢀ ꢀ ꢀX distances (b). The ovals denote clusters of points while the full circles the outliers discussed in the text.

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A. Adamczyk-Wozniak et al. / Journal of Molecular Structure 1035 (2013) 190–197
195
Fig. 3. Decomposed finger print plots [51] for dimeric units of compounds 1–3. The characteristic features for weak intermolecular C–Hꢀ ꢀ ꢀO (left column), C–Hꢀ ꢀ ꢀ
p
(middle
column) and agostic C–Hꢀ ꢀ ꢀB interactions are indicated with arrows. The oval denote the Bꢀ ꢀ ꢀ
p interactions found in 1.
et al. [58] they correspond to the medium-weak strength hydrogen
bonds. Further, in the S(6) cluster, the negative correlation
between the twist and the H-bond angle is observed (the correla-
tion coefficient equals to 0.88). These findings are in accordance
to the energy calculations performed for alkoxy derivatives [37].
In the second cluster the H-bond angle ranges from to 150° to
170° and the twist exceeds 15°. No correlation is observed but all
the compounds form S(7) H-bonded rings with O or N acceptors.
The Dꢀ ꢀ ꢀA distances rage from 2.55 to 2.75 Å and thus can be
classified as strong-medium interactions.
It is worth noting that there are three outliers (denoted with full
circles on the chart). They are characterized with the large H-bond
angle and short Oꢀ ꢀ ꢀX distance. The two with the smaller twist, 7°
and 10°, correspond to molecules of 3-fluoro-2-formylphenylbo-
ronic acid [22] and 2-(phenyliminomethyl)phenylboronic acid
[36], respectively. The observed intramolecular H-bonded rings
are described with S(7) graphs but in both cases the rings are al-
most flat. The observed H-bond shortening might be explained
on the basis of resonance-assisted hydrogen bond theory [59],
but more data are needed to support this conclusion in case of
B–O–H donors [60]. Whereas the outlier with the substantial twist
corresponds to compound 3, i.e. the only data for 8-membered H-
bonded ring.
The above noticed relations for the intramolecular H-bonds in
molecules of boronic acids may be to some extent transferred to
the intermolecular H-bonds with the second boronic OH donor. In
most cases the primary supramolecular motif in form of 8-mem-
bered ring dimer with two O–Hꢀ ꢀ ꢀO intermolecular hydrogen bonds
is observed. Such dimers are either centrosymmetric with the graph
designator R22ð8Þ [55,56] or formed by two crystallographically
independent molecules, hence the ring motif appear at the second
level graph descriptor [61]. The first type of dimer is observed in
1 and 3 while the latter in 2. Further, in case of all the molecules
with the weakest intramolecular interactions (i.e. those with the
O–Hꢀ ꢀ ꢀX angle below 120°) the boronic group is simultaneously
engaged in two intermolecular H-bonds as a donor, leading to the
O–Hꢀ ꢀ ꢀO bonded ribbon or layer structures. Finally, no dimers are
observed in some di-ortho-substituted molecules [37,62].

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A. Adamczyk-Wozniak et al. / Journal of Molecular Structure 1035 (2013) 190–197
196
Table 4
on atoms. This effect was observed in the case of ortho-amino-
methyl substituents in phenylboronic acids [36]. The values of
binding constants in these cases are in the range of 50–450 Mꢂ1
for fructose, 5–100 Mꢂ1 for galactose, and 2–30 Mꢂ1 for glucose,
depending on the substituents in amino group [69,70]. Hence,
the investigated compounds are not interesting from the point of
view of potential sugar receptors.
Binding constants (Keq) of ARS and sugars with the compounds 1–3 and PhB(OH)2.
Diol
Keq/(Mꢂ1
)
1
2
3
PhB(OH)2
Alizarin Red S
1148 90
8.8 1.2
512 21
8.2 0.4
1390 250
7.7 3.5
1331 53
163 12
D-fructose
D-galactose
D-glucose
4.4 1.6
1.5 0.1
1.1 0.1
3.4 1.2
1.9 0.4
15 3.2
5.8 1.1
a
–
a
Evaluation was impossible due to insufficient binding.
5. Conclusions
The introduction of the spacer between methoxy group and
phenyl ring at the ortho position of phenylboronic acid in the stud-
ied series of compounds 1–3 revealed interesting relations in their
crystal structures. First of all the substantial twist of the boronic
moiety versus phenyl ring is observed in 2 and 3 comparing to
the methoxy derivative 1. Although the twist and relative proxim-
ity of oxygen atom of the flexible ortho substituents migth lead to
the formation of dative O?B bond in case of 2 and 3, the intramo-
lecular O–Hꢀ ꢀ ꢀO hydrogen bond is formed. Moreover, the analysis
of the geometry of H-bonded rings, starting from six-membered,
S(6), in 1 to S(8) in 3, pointed out the relation between the boronic
group twist and the widening of the O–Hꢀ ꢀ ꢀO angle. To support this
observation, the analysis was extended to all ortho substituted
boronic acids found in CSD database. The negative correlation
between the twist and the H-bond angle was observed in the case
of S(6) rings what is in accordance with the energy calculations
performed for alkoxy derivatives [37].
The dimeric units were found to be primary supramolecular
motives in studied compounds 1–3. The Hirshfeld surface calcula-
tions for dimeric units were performed and analyzed in form of the
decomposed 2-D plots. They revealed the presence of similar weak
interactions in case of 2 and 3. As none of the detected interactions
could be treated as the most important, the statement that they
work cooperatively seem to be appropriate in the case of 2 and
3. The secondary ribbon motif directed by weak C–Hꢀ ꢀ ꢀO hydrogen
bonds was confirmed in 1 [37].
The detected in 1–3 primary supramolecular dimeric motives
rise a question about other interactions leading to 3-D structure.
As both OH donors are satisfied with intra- or intermolecular O–
Hꢀ ꢀ ꢀO relatively short hydrogen bonds, the further interactions
have to belong to the weak ones. In case of 1 the ribbon structure
directed by C–Hꢀ ꢀ ꢀO hydrogen bonds was detected as a secondary
motif [37]. Further, several other weak interactions, also these with
p
-electrons, were found to build the crystal. To describe these
weak interactions in case of 2 and 3 the Hirshfeld surface analysis
was performed. It should be underlined that the surfaces have been
calculated for dimeric units to elucidated the secondary interac-
tions only. Therefore, the appropriate calculations were done for
dimmer of 1 as well. The 2-D representation of the Hirshfeld sur-
faces are shown in Fig. 3.
The first column in Fig. 3 presents the Oꢀ ꢀ ꢀH/Hꢀ ꢀ ꢀO contacts
only. The presence of weak C–Hꢀ ꢀ ꢀO interactions (see arrows at
the end of ‘‘whiskers’’) is evident in case of 1. Whereas in 2 and
3 the appearing ‘‘whiskers’’ are short and broadened, indicating
weak directionality as well as some cooperativity [63]. The charac-
teristic ‘‘wings’’ (middle column) corresponding to C–Hꢀ ꢀ ꢀ
p inter-
actions [64] are present in all cases. They occur between the
phenyl rings and the substituent’s –CH3 or –CH2 donors in 2 and
3, respectively (see Table S2 in the Supporting information for
the geometrical parameters for weak interactions). In case of 2
there are also C–Hꢀ ꢀ ꢀ
p interactions between phenyl rings coming
from different molecules. In 1 the shortest Cꢀ ꢀ ꢀH intermolecular
Further, the presence of weak intermolecular interactions with
contacts are rather associated with stacking interactions present
boron atom was found. In case of 1 the apparent Bꢀ ꢀ ꢀ
p stacking
in the crystal [37]. They may also come from the Bꢀ ꢀ ꢀ
p interactions
interactions are present while the presence of spacer in 2 and
3 enables the directional C–Hꢀ ꢀ ꢀB agostic interactions. These inter-
actions require an electron deficient atom (in this case three coor-
dinated boron) capable of accepting electron density from X–H
bonds (in this case C–H) belonging to another molecule. Nonethe-
less, these kind of interactions are rarely notified in literature [71]
and thus require further investigations [72].
which in turn are nicely reflected at the fingerprint plot for dimer
(top of the right column in Fig. 3). In case of 2 and 3 the fingerprint
plots investigation reveal the presence of other interesting interac-
tions with boron. The Bꢀ ꢀ ꢀH contacts which appear in plots as long
lines suggesting their directionality [52]. Although the C–Hꢀ ꢀ ꢀB
interactions can be described analogously to hydrogen bonds, they
rather should be classified as the agostic interactions similar to
these found in transition metal complexes [see for example Refs.
65–68].
All the investigated compounds have very low values of binding
constant with monosaccharides. There is no effect of ester stabil-
ization by the formation of dative bond between oxygen and boron
atoms.
4. Binding activity of boronic acids
Acknowledgements
The interaction of boronic acids 1–3 with monosaccharides was
investigated by a competition binding assay with Alizarin Red S
(ARS) as a reporter. The results are collected in Table 4. For all
the investigated compounds the determined sugar binding
Financial support by the Ministry of Science and Higher Educa-
tion (Grant No. N204 135639) is kindly acknowledged. Roy
Scheidsbach acknowledges financial support from ERASMUS-SOC-
RATES Program by HAN University of Applied Sciences, Nijmengen,
The Netherlands.
constant values are very low and range from about 1 to 8 Mꢂ1
.
The values are lower than for the unsubstituted phenylboronic
acid (Table 4). All the determined apparent binding constants
follow the well established order for monoboronic acids: KFru
>
KGal > KGlu. The interaction of 1 with glucose is so weak, that its
evaluation by the applied method was impossible. Introduction
of a spacer between phenyl ring and methoxy group has no signif-
icant influence on the binding of the investigated sugars.
The presented results show that there is no effect of stabilizing
the formation of ester by the dative bond between oxygen and bor-
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.molstruc.2012.
09.049.

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