Piperazine derivatives of boronic acids-potential bifunctional biologically active compounds

Article abstract of DOI:10.1039/c5nj00084j

The combination of a piperazine and boronic groups within one molecule can result in a totally novel biological activity. A series of benzyl piperazine derivatives of boronic acids have been obtained by the facile and effective method based on the aminati

Full text of DOI:10.1039/c5nj00084j

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Piperazine derivatives of boronic acids – potential
bifunctional biologically active compounds†
Cite this:DOI: 10.1039/c5nj00084j
Agnieszka Adamczyk-Wozniak,* Karolina Czerwinska, Izabela D. Madura,
´
´
Alicja Matuszewska, Andrzej Sporzynski and Anna Z˙ubrowska-Zembrzuska
´
The combination of a piperazine and boronic groups within one molecule can result in a totally novel
biological activity. A series of benzyl piperazine derivatives of boronic acids have been obtained by the
facile and effective method based on the amination-reduction reaction of 2-formylphenylboronic acid
with N-substituted piperazines. The molecular and crystal structures of six novel derivatives have been
investigated, along with Hirshfeld surface analysis and hydrogen bond energy estimation. The studied
compounds display several structural features that make them promising candidates as biologically
active compounds.
Received (in Montpellier, France)
12th January 2015,
Accepted 16th March 2015
DOI: 10.1039/c5nj00084j
www.rsc.org/njc
Introduction
Piperazine scaffolds are frequently found in biologically active
compounds probably due to their affinity to various receptors.1–3
Many phenyl and benzyl piperazine derivatives are notably
successful drugs, including antianginals (e.g. trimetazidine),4
antidepressants (e.g. trazodone),5 antihistamines (e.g. cyclizine
and cetirizine,6 buclizine,7 cinnarizine8) as well as antipsychotics
(e.g. aripiprazole).9 Some more arylpiperazines are currently under-
going clinical trials.10 There are also many so-called recreational
drugs having the piperazine structure, e.g. 1-benzylpiperazine
(BZP),11 4-methyl-1-benzylpiperazine (MBZP), 4-fluorophenyl-
piperazine (pFPP) and 2,3-dichlorophenylpiperazine (DCPP),
some of them have been made illegal.12 Further, Imatinib,
the piperazine containing potent anticancer drug, is the first
one that specifically acts by inhibiting a certain enzyme rather
than by killing all the rapidly dividing cells.13 A similar action is
displayed by the recently developed boronic anticancer drug
called Bortezomib, which inhibits the proteasome 26S receptor14
(Fig. 1). It should be noted that the boronic acid moiety, due to its
ability to reversibly form complexes with hydroxyl compounds,
can be responsible for binding to specific bio-molecules.15,16
Therefore, the combination of a piperazine and boronic groups
within one molecule can result in a totally novel biological activity
Fig. 1 Some of the benzyl or phenylpiperazine drugs and Bortezomib.
(Fig. 2). Moreover, the proximity of the nitrogen atom usually compounds, enabling their binding at physiological pH.17 The
increases the affinity of the boronic acid towards hydroxyl structure of the amine substituent can also influence the selectivity
of the complexation.18 Additionally, the ester formation with cis-
Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw,
Noakowskiego 3, Poland. E-mail: agnieszka@ch.pw.edu.pl
diols can considerably change the physicochemical properties of
the molecule, e.g. its solubility in lipids and altering the crossing of
the blood–brain barrier. The esterification of the boronic unit also
enables alternative drug formulation as in the case of Bortezomib,
which is actually used as its mannitol ester.19 The considered
compounds can also act as useful building-blocks, the Suzuki
† Electronic supplementary information (ESI) available: Details on X-ray diffrac-
tion studies, selected geometrical parameters for studied compounds, parameters
of weak intermolecular interactions, packing diagrams. CCDC 1040156–1040161.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c5nj00084j
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Fig. 2 Proposed mode of action of studied novel bifunctional piperazine
derivatives of boronic acids.
coupling of which should result in novel biphenyl piperazine
derivatives,20 which display the acetylcholine receptor antagonists’
activity21 as well as selective, and reversible inhibition of the
cathepsin K enzyme.22
The investigation of potential biologically active compounds/
drugs very often starts from the design, based on the crystal
structure analysis.23,24 Detailed structural studies can point out
stable conformations25 or preferred intermolecular interactions,26
which are the parameters being important for molecular recogni-
tion or binding with protein active sites.16,27 Therefore, we have
undertaken studies on selected new piperazine-boronic acid
bifunctional molecules (Fig. 2). Both the facile and effective
synthetic method and valuable information obtained from
crystal structure investigations supported by Hirshfeld surface
analysis28 and hydrogen bond energy estimation29 are presented.
Scheme 1 Synthetic strategy for benzyl piperazine derivatives of phenyl-
boronic acids.
recently optimized amination-reduction methodology for the
2-aminomethylphenylboronic acids (Scheme 1).36
Results and discussion
General remarks
Crystal structures
Despite the potential importance of the molecules combining
piperazine and boronic scaffolds (Fig. 2), only few boronic The products were recrystallized to yield crystals suitable for single
derivatives of piperazines have been obtained and studied to crystal X-ray diffraction experiments. The results confirmed pure
date.30,31 The boronic derivatives that have been structurally crystals of 1, 3, 4 and solvates of 5, 6. In the case of 2, high residual
characterized are the ortho CH2–piperazine substituted bis- electron density was observed during structure refinement,
boronic acids and hemiesters, including benzoxaboroles,31 indicating the presence of a severely disordered or diffused
as well as monoboronic acid pinacol esters.30 In all the studied solvent (see ESI†).
structures no N-B dative bond was observed and this was
The intramolecular O–HÁ Á ÁN hydrogen bonds are denoted by
attributed to the lack of their activity against thrombin.30a dashed lines. Only hydrogen atoms of hydroxyl groups are shown.
However, the boronic acid esters do not form strong hydrogen In the case of 6, only the molecule A is presented.
bonds,32 while H-bonds were found to be competing with the
The studied molecules crystallize in centrosymmetric space
dative bond in the case of ortho substituted boronic acids.33 groups except for molecules 5 which crystallizes in non-
Moreover, the role of a hydrogen bond donor group for the centrosymmetric Pna21 space group of the orthorhombic system
affinity and selectivity towards the a1B-adrenoceptors, postulated (Table 2). In the case of 6, there are two crystallographically
by Bremner’s pharmacophore model1a was confirmed by func- independent molecules in the asymmetric part of the unit
tional and molecular modeling studies.2 There is also evidence cell. Only the minor differences in the torsion angles between
from protein crystallography that boronic acids are H-bonded these two molecules were detected (Table S1, ESI†). Generally,
active species during binding processes.16,34 Therefore, we decided the geometries of all the investigated molecules are similar
to synthesize and study ortho substituted phenylboronic monoacids (Table S1, ESI†). The boron atom shows a trigonal coordination,
with selected piperazines, including the analogues of already while OH groups adopt syn–anti conformation (Fig. 3). The B(OH)2
known drugs (Scheme 1). Compounds 1 and 5 can be treated as moiety is substantially twisted with respect to the phenyl ring
models to show the differences introduced by aromatic (1–4) or and the twist angle varies from 16.76(5)1 for 1 to 26.68(1)1 in 5
aliphatic (5–6) substituents in the piperazine scaffold on mole- (Table S1, ESI†).
cular geometry,35 as well as the types of possible intermolecular
As recently shown,38 the differences in this parameter may
interactions. Additionally, the relatively long substituents in 4 and 6 be due to intermolecular interactions, but the intramolecular
were chosen to study the role of spatial requirements in molecular interactions should also be taken into consideration.39 Further,
packing. Compounds 1–6 have been obtained according to the in all the cases, the piperazine fragment adopts a chair conformation
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Table 1 Geometrical parameters of the H-bonds in crystals of 1–6. The
bond lengths are given in Å, and bond angles in 1. The estimated energy is
given in kcal molÀ1
Compound
HÁ Á ÁA
DÁ Á ÁA
D–HÁ Á ÁA
Energy
1
O1–H1Á Á ÁN1
1.77(2)
1.89(2)
2.666(1)
2.756(1)
167(2)
177(2)
6.1
3.3
O2–H2Á Á ÁO1i a
2
O1–H1Á Á ÁN1
1.78
1.94
2.614(2)
2.768(2)
170
168
8.2
2.9
O2–H2Á Á ÁO1ii
3
O1–H1Á Á ÁN1
1.79(3)
2.03(3)
2.615(2)
2.824(2)
164(3)
170(3)
7.3
2.2
O2–H2Á Á ÁO1iii
4
O1–H1Á Á ÁN1
1.75(2)
2.11(2)
2.659(1)
2.9465(13)
168(2)
165(2)
6.4
1.1
O2–H2Á Á ÁO3iv
Fig. 3 Ortep drawing37 with atoms numbering scheme of studied mole-
cules. The ellipsoids are shown at 50% probability.
5
O1–H1Á Á ÁN1
O2–H2Á Á ÁN2v
O3–H3BÁ Á ÁO2vi
O3–H3AÁ Á ÁO1vii
1.85
1.95
1.98
2.05
2.682(2)
2.712(2)
2.802(2)
2.887(2)
169
150
163
167
5.8
3.0
2.2
1.5
with comparable geometrical parameters except for the pyramida-
lization of N2 atom (Table S1, ESI†). This results from the different
nature of the piperazine substituents. In the case of compounds 1–4,
the aromatic fragment tends to conjugate with the nitrogen atom,
causing the decrease in both the pyramidalization as well as N2–C12
bond length (Table S1, ESI†). For compound 5 and 6, the N2 bond
with aliphatic C12 carbon atom is by B0.06 Å longer, while the
N2 atom deviates from plane defined by the three bonded atoms
by more than 0.5 Å.
6
O1–H1Á Á ÁN1
O3–H3Á Á ÁN3
O2–H2Á Á ÁO3
O3–H4Á Á ÁO1
1.75
1.81
1.90
1.86
2.587(1)
2.633(1)
2.7426(13)
2.696(1)
173
168
175
174
9.8
7.2
3.5
4.5
a
Symmetry codes: (i) 1 À x, 1 À y, 1 À z; (ii) 1/2 À x, 1/2 À y, 3/2 À z;
(iii) Àx, Ày, 1 À z; (iv) À1/2 + x, 1/2 À y, À1/2 + z; (v) 1/2 À x, 1/2 + y, À1/2 + z;
(vi) 1/2 À x, À1/2 + y, 1/2 + z; (vii) 1 À x, 1 À y, 1/2 + z.
In the entire analyzed series, the formation of intramolecular
O1–H1Á Á ÁN1 hydrogen bond with S(7) graph designator40 was
detected. The values of OÁ Á ÁN distance range from 2.587(1) to
2.682(2) Å, whereas the O–HÁ Á ÁN angle oscillates around 1701
(Table 1). These values agree perfectly with those found for
the entire range of S(7) rings in the case of variously ortho-
substituted phenylboronic acids.39 To better compare the result-
ing interactions, an energy estimation based on Lippincott and
Schroeder one-dimensional H-bond model was performed.29
The values range from 6 to 10 kcal molÀ1, placing these inter-
actions among strong hydrogen bonds.41 Therefore, it can be
assumed that this O1–H1Á Á ÁN1 hydrogen bond induces the syn–
anti conformation of the boronic moiety. However, the difference
in the nature of piperazine substituent seems unlikely to influence
this intramolecular H-bond (Table 1) as both the weakest and the
strongest H-bonds are found in aliphatic analogues. Furthermore,
the difference in the H-bond energy in molecules A and B of 6
being over 2.5 kcal molÀ1 may suggest that the intermolecular
interactions are decisive for the twist, and simultaneously influ-
ence the intramolecular hydrogen bond strength. Nevertheless,
the formation of a strong intramolecular H-bond can cause these
boronic acid derivatives to further assemble via one strong
hydrogen bond donor only, which is similar to the usually more
active benzoxaborole derivatives.31,42
To investigate the most probable interacting sites of the
studied potentially active compounds, derivatives 1 and 5 were
chosen as the models. Fig. 4a presents the overall shape of these
Fig. 4 Side view of model molecules of 1 and 5 (a). Hirshfeld surfaces for 1
and 5 in form of di (b) and de (c). Red and blue arrows indicate donors and
molecules in crystals. The boronic and piperazine fragments acceptors in intermolecular hydrogen bonds, respectively.
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locate almost perpendicularly, with the distance between fore-
most fragments being around 11 and 6 Å in the case of 1 and 5,
respectively. The calculated molecular Hirshfeld surfaces (HS)
with mapped di and de properties are presented in Fig. 4b and c;
they reflect the donor and acceptor properties of the molecules
in terms of intermolecular interactions in the crystal, respec-
tively. It is noteworthy that such surfaces can also serve as
starting points to model interactions with proteins.26,27 It was
also recently found that the benzylpiperazine scaffold can dock
either via hydrogen bonds or edge-to-face interactions.43 In turn,
the phenylboronic fragment may interact via hydrogen bonds,
aromatic or electron donor–acceptor interactions.16 The mapped
di on the HS surface suggests that the best H-bond donors are
the syn oriented OH group and CH groups of the phenyl ring
from boronic fragment. Additionally, in 1, the phenyl substituent
of piperazine fragment serves as a donor site for weak hydrogen
bonds, while the lack of the aromatic counterpart in the case of 5
causes the activation of CH donors of the piperazine ring
(Table S2, ESI†). Both the oxygen atoms and aromatic ring/rings
can act as the H-bond acceptors (Fig. 4c, Table S2, ESI†). Noteworthy
are the enhanced acceptor properties of N2 atom in case of 5,
resulting from its better availability (i.e. small, not conjugating
substituent) compared to other studied compounds.
The dual role of boronic OH group in the hydrogen bonds is
observed in the case of 1, 2, 3 and 6 in which the O–HÁ Á ÁO
hydrogen bonded dimers are formed (Fig. 5a). The estimated
energy of these interactions is substantially lower than that
of the intramolecular O–HÁ Á ÁN bonds and range from 2.2 to
4.5 kcal molÀ1 (Table 1). In 4, the O–HÁ Á ÁO hydrogen bond is
also formed, but in this case the NO2 group acts as the acceptor.
The resulting chain motif can be described with C(16) graph.40
This H-bond is nearly twice weaker than that leading to dimeric
motives and amounts to 1 kcal molÀ1 only. The different arrange-
ment in 4 might result from steric factors, i.e. long piperazine
fragment. Nevertheless, the packing index44 of all the studied
molecules is relatively high and exceed 70% of the crystal lattice
despite the formation of the O–HÁ Á ÁO bonded primary motives
(Fig. 5a).
A noteworthy feature is the different packing of dimers in
the case of 2 (Fig. 5c). The residual electron density was found
at the final step of the structure refinement but the attempts to
ascribe it to any solvent molecule/molecules were not successful.
However, the diffusion of the solvent cannot be excluded and
this might explain the differences in the packing of the dimers in
2. The solvent molecules are found in both aliphatic derivatives.
In 5 it is a water molecule while in 6, two independent molecules
Fig. 5 (a) Primary motives with their mutual arrangement. The hydrogen
bonds are given with dash lines; (b) simplified model of the primary motif
derived by connection (in line with H-bonds) of nodes (center of gravity of
phenyl rings). Red and blue colours of nodes represent the boronic and
piperazine fragments, respectively. (c) Packing diagrams of primary
motives in simplified representations (see Fig. S2 in ESI† for full packing
diagrams). The solvent molecules in 5 and 6 are omitted.
molecules of 5, while the water molecule serves as linker through
the O–HÁ Á ÁO bonds with boronic moiety, acting as a H-bond
acceptor. The energies of these interchain H-bonds are substan-
tially lower than those in the main O–HÁ Á ÁN chain (Table 1). This
may suggest that the found active binding sites of this molecule
might be effective in bringing about interactions with bio-
molecules even though water molecules are present.
Conclusions
of acetone can be distinguished. In this case a minor influence We have synthesized and structurally characterized six novel
of the acetone molecules on the packing of dimers in 6 is bifunctional compounds composed of phenylboronic acid frag-
observed comparing to structures of 1 and 3 (Fig. 5c). On the ment and selected piperazine derivatives with promising features
contrary, the water molecule is strongly interacting with 5 to enhance their binding properties. The molecules were found
serving as a hydrogen bond donor, thus competing with boronic not to be affected by piperazine N2 substituents except the
hydroxyl groups. The observed intermolecular interactions are N2–C12 bond length depended on the degree of conjugation
far different here than in the other studied analogues. First, the with the substituent. In all the cases the boron atom exhibited
N2 atom is engaged in the hydrogen bond with boronic moiety trigonal coordination with OH groups in syn–anti conforma-
and this interaction is of similar strength as those found for tion. The conformation seemed to be induced here by the
dimers. The C(10) chain motif is formed by joining the relatively strong intramolecular O–HÁ Á ÁN hydrogen bonds with
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estimated energy range of 6–10 kcal molÀ1. The molecular at À10 1C, followed by addition of NaBH4 (1 eq.) and 20 min of
Hirshfeld surface analysis was used to show the probable active subsequent vigorous stirring. Resulting mixtures were acidified
sites of the aromatic and aliphatic derivatives. The results with a 3 M HClaq. Benzoxaborole side-product was removed by
revealed that the lack of an aromatic or bulky substituent near extraction with three portions of Et2O, according to the pre-
N2 atom causes its activation as the effective H-bond acceptor. viously reported method.36 The remaining aqueous phase was
Otherwise the dimeric motif with boronic hydroxyl groups neutralized with NH3aq (pH ca. 7). The desired boronic acids
acting as donors and acceptors are found. The only exception were extracted with ethyl acetate. The organic phase was dried
is a 4-NO2 phenyl substituted piperazine derivative in which the over anhydrous Na2SO4 and evaporated under reduced pressure
long tail favors chain arrangement over the dimer. The phenyl resulting in solid products.
rings of both the boronic and piperazine fragment take part in
2-((4-(2-Methoxyphenyl)piperazin-1-yl)methyl)phenylboronic
acid (2)
weak aromatic interactions, mostly of C–HÁ Á ÁO and C–HÁ Á Áp
type. For aliphatic analogues the CH donors also come from the
piperazine ring. The investigated boronic acid analogue of the (4.77 g, 57%), mp 163–165 1C (from ethyl acetate). Found: C,
MBZPZ drug (5) appeared to be the most effective dual molecule 66.1; H, 6.9; N, 8.4. Calc. for C18H23BN2O3: C, 66.3; H, 7.0; N,
in terms of intermolecular interactions observed in crystal; hence, 8.6. dH(400 MHz; CDCl3) 2.74 (4H, s, br, 2 Â CH2), 3.14 (4H, s,
in our opinion, it is worth further biological evaluation tests.
br, 2 Â CH2), 3.71 (2H, s, CH2), 3.86 (3H, s, CH3), 6.85–7.02
(3H, m, Ar), 7.19–7.21 (1H, m, Ar), 7.32–7.37 (1H, m, Ar), 7.92–
7.95 (2H, m, Ar), 8.57 (2H, s, br, B(OH)2). dC(100 MHz; CDCl3)
50.0, 52.1, 55.2, 64.2, 111.1, 118.4, 120.9, 123.3, 127.5, 130.1,
130.5, 136.3, 140.6, 140.8, 152.0. dB(64.1 MHz; (CD3)2CO) 33.
Crystals suitable for X-ray measurements were obtained by
crystallization from acetonitrile.
Experimental
1H and 13C NMR spectra were recorded on Varian Mercury 400
or Varian Inova 500 spectrometers. The 11B NMR spectra were
recorded on Varian Unity Plus 200 operating at 64 MHz,
chemical shifts were determined using inserts with BF3ÁEt2O
in benzene (d = 0.0 ppm). A drop of D2O was added to some of
the samples to avoid additional signals corresponding to boroxines.
Elemental analyses for C, H and N were obtained using Perkin
Elmer CHNS/O II Model 240 analyser.
2-((4-Methylpiperazin-1-yl)methyl)phenylboronic acid (5)
(0.36 g, 23%), mp 201–201 1C (from ethyl acetate). Found: C,
61.7; H, 8.0; N, 11.9. Calc. for C12H19BN2O2: C, 61.6; H, 8.1; N,
11.9. dH(400 MHz; (CD3)2CO + D2O) 2.17 (3H, s, Me), 2.47 (8H, s,
br, 4 Â CH2), 3.58 (2H, s, CH2), 7.19–7.22 (1H, m, Ar), 7.25–7.28
(1H, m, Ar), 7.29–7.34 (1H, m, Ar). dC(100 MHz; (CD3)2CO +
D2O) 45.8, 52.4, 55.2, 64.42, 127.8, 130.4, 131.4, 136.9, 142.1,
163.8. dB(64.1 MHz; (CD3)2CO + D2O) 29.8, 20.5. Crystals suitable
for X-ray measurements were obtained by crystallization from
acetonitrile.
2-Formylphenylboronic acid was obtained by a standard pro-
1
cedure and its purity was confirmed on the basis of H NMR
spectrum. All the starting piperazines were purchased from
Sigma-Aldrich and used without further purification.
Synthesis of 2-((4-phenylpiperazin-1-yl)methyl)phenylboronic
acid (1)
2-((4-Benzhydrylpiperazin-1-yl)methyl)phenylboronic acid (6)
Solution of equimolar amounts of 2-formylphenylboronic (1 g,
6.6 Â 10À3 mol) acid and N-phenylpiperazine (1.07 g, 6.6 Â
10À3 mol) in methanol (20 ml) was mixed at room temperature
for 24 hours. NaBH4 (1.96 g, 6.6 Â 10À3 mol) was added portion-
wise to the resulting yellow solution with vigorous stirring. After 2 h
of stirring a white solid precipitated that was filtered off and
recrystallized from a mixture of methylene chloride and acetonitrile
(1.06 g, 54%), mp 257–259 1C (from acetonitrile and methylene
chloride mixture). Found: C, 68.7; H, 7.0; N, 9.3. Calc. for
C17H21BN2O2: C, 68.8; H, 7.2; N, 9.5. dH(400 MHz; (CD3)2SO)
2.55 (4H, s, br, 2 Â CH2), 3.11 (4H, s, br, 2 Â CH2), 3.61 (2H, s,
CH2), 6.77 (1H, m, Ar), 6.90–6.92 (2H, m, Ar), 7.17–7.34 (5H, Ar),
7.66–7.67 (1H, m, Ar), 9.23 (2H, s, B(OH)2). dC(100 MHz;
(CD3)2SO) 47.9, 51.4, 62.9, 115.7, 119.2, 127.0, 129.1, 129.4,
130.2, 135.3, 141.3, 150.9. dB(64.1 MHz; (CD3)2SO) 30. Crystals
suitable for X-ray measurements were obtained by crystallization
from acetonitrile and methylene chloride mixture.
(2.06 g, 80%), mp 182–184 1C, partial melting at 98 and 158 1C
(from acetone). Found: C, 72.9; H, 7.5; N, 6.2. Calc. for
C
24H27BN2O2* (CH3)2CO: C, 72.9; H, 7.5; N, 6.4. dH(400 MHz;
(CD3)2CO + drop of D2O) 2.51 (8H, s, br, 4 Â CH2), 3.61 (2H, s,
CH2), 4.28 (1H, s, CH), 7.12–7.18 (2H, m, Ar), 7.19–7.31 (7H, m,
Ar), 7.43–7.47 (2H, m, Ar), 7.83–7.85 (1H, m, Ar), 9.15 (2H, s,
B(OH)2, minor intensity). dC(100 MHz; (CD3)2CO + drop of D2O)
51.1, 51.8, 63.5, 75.5, 126.8, 126.7, 127.6, 128.4, 129.5, 130.5,
136.0, 141.3, 142.9. dB(64.1 MHz; (CD3)2CO + drop of D2O) 30.
Crystals suitable for X-ray measurements were obtained by
crystallization from acetone and contained acetone molecule
within the crystal.
2-((4-(2,3-Dichlorophenyl)piperazin-1-yl)methyl)phenylboronic
acid (3)
A solution of equimolar quantities of 2-formylphenylboronic
acid and 2,3-dichlorophenylpiperazine in 50 ml of methanol
was prepared at À12 1C, followed by the addition of NaBH4
(1 eq.) and 20 min of subsequent vigorous stirring. 3 M HClaq
Synthesis of 2, 5 and 6
Solutions of equimolar quantities of 2-formylphenylboronic acid was added till pH of the mixture was B1, followed by 10 min
and the corresponding piperazine in methanol were prepared of stirring. The post-reaction mixture was extracted with Et2O
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(1 Â 60 ml, 2 Â 30 ml). The remaining aqueous phase was 8.03–8.05 (2H, m, Ar). dC((CD3)2CO + drop of D2O) 46.7, 51.7,
neutralized with NH3aq (pH ca. 7). The desired boronic acid was 63.5, 113.7, 126.3, 127.9, 130.4, 130.9, 136.2, 138.5, 141.5, 155.6.
extracted with Et2O (3 Â 30 ml). The organic phase was dried dB((CD3)2CO + drop of D2O): 32, 23.
over anhydrous Na2SO4 and evaporated under reduced pressure,
X-ray diffraction
resulting in solid product (yield 22%). The crude product
was washed with acetone resulting in pure 3. Crystals suitable
for X-ray measurements were obtained by crystallization from
acetone. dH(500 MHz; DMSO) 2.60 (4H, s, br, 2 Â CH2), 2.99
(4H, s, br, 2 Â CH2), 3.65 (2H, s, CH2), 7.13–7.34 (6H, m, Ar),
7.68–7.70 (1H, m, Ar), 9.14 (2H, s, B(OH)2). dC(126 MHz, DMSO)
150.8, 141.0, 135.2, 132.5, 130.1, 129.2, 128.5, 126.7, 126.0, 124.4,
119.6, 62.8, 51.5, 50.3. dB(CD3OD) 14.
Single crystal X-ray diffraction experiments were conducted on
a Gemini A Ultra Diffractometer (Agilent Technologies). Data
collection and data reduction were performed in the CrysAlisPro
program.45 To solve and refine the structures OLEX-2 suite46
with implemented SHELX program47 was used. Further details
of structural studies are given in ESI.† The crystallographic data
are summarized in Table 2. CCDC 1040156–1040161.
2-((4-(4-Nitrophenyl)piperazin-1-yl)methyl)phenylboronic acid (4) Calculations
A solution of 2-formylphenylboronic acid (2 eq.) and p-nitro- Estimation of O–HÁ Á ÁO hydrogen bonds energy was based on the
phenylpiperazine (1 eq.) in methanol (45 ml) was prepared at Lippincott and Schroeder one dimensional H-bond model.29 It is
À10 1C, followed by the addition of NaBH4 (1 eq.) and 20 min of a semi-empirical method for calculating binding energies of the
subsequent vigorous stirring. 3 M HClaq (15 ml) was added and H-bond starting from its geometry. Therefore, the O–H bond
mixture was stirred for another 10 min, followed by extraction lengths were normalized to be consistent with those obtained
with Et2O (1 Â 30 ml, 2 Â 40 ml). The remaining aqueous phase from neutron diffraction studies and are equal to 0.93 Å.48
was neutralized with NH3aq (pH ca. 7). The desired boronic acid The algorithm and parameterization was implemented in the
was extracted with Et2O (3 Â 30 ml). The organic phase was LSHB program available as a courtesy from Professors Paola
dried over anhydrous Na2SO4 and evaporated under reduced and Gastone Gilli.49
pressure, resulting in a solid product (yield 10%). dH(500 MHz;
The molecular Hirshfeld surfaces (HS)28 were generated using
(CD3)2CO + drop of D2O) 2.64 (4H, s, br, 2 Â CH2), 3.50 (4H, s, the Crystal Explorer 3.1 program.50 They were constructed based
br, 2 Â CH2), 3.67 (2H, s, CH2), 7.01–7.03 (2H, m, Ar), 7.20– on the electron distribution calculated as the sum of spherical
7.22 (1H, m, Ar), 7.26–7.33 (2H, m, Ar), 7.76–7.78 (1H, m, Ar), atom electron densities. The HS enclosing a molecule is defined
Table 2 Crystallographic data collection and refinement parameters for 1–6
Compound
1
2
3
4
5
6
Empirical formula
C17H21BN2O2
C18H23BN2O3
C17H19BClN2O2
C17H20BN3O4
C12H19BN2O2,
H2O
252.12
C
24H27BN2O2,
C3H6O
444.36
Mw [g molÀ1
]
296.17
326.19
365.05
341.17
Crystal size [mm]
T [K]
0.40 Â 0.60 Â 0.60 0.08 Â 0.24 Â 0.48 0.16 Â 0.21 Â 0.25 0.20 Â 0.50 Â 0.60 0.40 Â 0.50 Â 0.60 0.40 Â 0.45 Â 0.50
100(2)
100(2)
120(2)
100(2)
100(2)
100(2)
Radiation
Wave length [Å]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
Mo-Ka
0.7107
Cu-Ka
1.5418
Cu-Ka
Cu-Ka
1.5418
Cu-Ka
1.5418
Cu-Ka
1.5418
1.5418
Triclinic
%
P1
Monoclinic
P21/c
13.3088(2)
6.01200(10)
19.8330(2)
90
108.6467(14)
90
1503.59(4)
4
Monoclinic
I2/a
12.1978(3)
19.2053(5)
15.5424(4)
90
96.000(3)
90
3621.05(16)
8
Monoclinic
P21/n
10.32568(6)
9.10656(10)
18.03844(12)
90
90.7068(6)
90
1696.05(2)
4
Orthorhombic
Pna21
12.87751(17)
10.18562(12)
10.36536(14)
90
Monoclinic
P21/c
24.60371(16)
11.76829(7)
17.52165(11)
90
93.8287(6)
90
5061.96(6)
8
7.9155(4)
10.3130(4)
11.8333(7)
88.456(4)
72.897(5)
69.370(4)
860.88(8)
2
a [1]
b [1]
90
90
g [1]
V [Å3]
1359.58(3)
4
1.232
Z
rcalcd [Mg mÀ3
]
1.308
0.085
1.197
0.648
1.408
3.489
1.336
0.782
1.166
0.592
m [mmÀ1
]
0.704
Tmin, Tmax
F(000)
Reflections collected
0.838, 1.000
632
32 627
0.736, 1.000
1392
13 981
0.485, 1.000
380
7576
0.439, 1.000
720
77 017
0.704, 1.000
544
10 784
0.801, 1.000
1904
161 927
8915 [4.07%]
Independent reflection
3282 [2.47%]
3226 [3.11%]
3018 [4.14%]
3017 [6.7%]
2186 [2.54%]
[Rint
]
Reflections with I 4 2s(I) 3053
2777
2863
2922
2143
8238
y
min–ymax
3.23–27.00
1.043
À0.209/0.418
3.67–67.09
1.058
À0.169/0.256
R1 = 0.0392
wR2 = 0.1020
R1 = 0.0458
wR2 = 0.1059
3.92–66.49
1.034
À0.685/0.427
R1 = 0.0478
wR2 = 0.1262
R1 = 0.0493
wR2 = 0.1288
4.90–67.07
1.062
À0.193/0.253
R1 = 0.0364
wR2 = 0.0976
R1 = 0.0372
wR2 = 0.0984
5.54–67.21
1.089
À0.453/0.211
R1 = 0.0373
wR2 = 0.1052
R1 = 0.0381
wR2 = 0.1064
3.36–66.50
1.027
À0.298/0.429
R1 = 0.0357
wR2 = 0.0883
R1 = 0.0385
wR2 = 0.0905
GOF on F2
Drmin/max [e ÅÀ3
Final R indices (I 4 2s(I)) R1 = 0.0345
]
wR2 = 0.0919
R1 = 0.0365
wR2 = 0.0931
R indices (all data)
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Acknowledgements
Financial support by the Ministry of Science and Higher
Education (Grant NN204 135639) is kindly acknowledged.
K.C. acknowledges the support of the Faculty of Chemistry,
Warsaw University of Technology. This work has been supported
by the European Union in the framework of European Social Fund
through the Warsaw University of Technology Development
Program by the scholarship awarded by the Center of Advanced
Studies for Alicja Matuszewska.
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