Fluoro-substituted 2-formylphenylboronic acids: Structures, properties and tautomeric equilibria

Journal of Fluorine Chemistry 187 (2016) 1–8

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Journal of Fluorine Chemistry j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / fl u o r

Fluoro-substituted 2-formylphenylboronic acids: Structures, properties and tautomeric equilibria Kornelia Kowalskaa , Agnieszka Adamczyk-Wo
zniakb,* , Patrycja Gajowiecb , c b _ Gierczyk , Ewa Kaczorowska , Łukasz Popendad, Grzegorz Schroederc , Błazej
skib Artur Sikorskia , Andrzej Sporzyn
sk, Wita Stwosza 63, 80-308 Gdan
sk, Poland Faculty of Chemistry, University of Gdan Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland c
, Umultowska 89b, 61-614 Poznan
, Poland Faculty of Chemistry, Adam Mickiewicz University in Poznan d
, Umultowska 85, 61-614 Poznan
, Poland NanoBioMedical Centre, Adam Mickiewicz University in Poznan a

b

A R T I C L E I N F O

Article history: Received 16 March 2016 Received in revised form 27 April 2016 Accepted 1 May 2016 Available online 4 May 2016 Keywords: Boronic acid Benzoxaborole Fluorophenyl boronic acid Crystal structure Acidity Tautomerism

A B S T R A C T

Four isomeric fluoro-2-formylphenylboronic acids were synthesized and characterized by 1H, 13C, 19F and 17 O NMR. Molecular and crystal structure of two compounds was determined by single crystal XRD method. pKa values of all the isomers have been determined by spectrophotometric method and compared with the results for the corresponding benzoxaboroles as well as fluoro- and formylphenylboronic acids. Tautomeric equilibrium with cyclic benzoxaborole form was investigated. The influence of position of fluorine substituents on the properties of investigated compounds is discussed. ã 2016 Elsevier B.V. All rights reserved.

1. Introduction Arylboronic acids and their derivatives have attracted increasing interest because of their new applications in organic synthesis, catalysis, supramolecular chemistry, and material engineering, as well as in biology and medicine [1–4]. The presence of substituents in phenylboronic acid molecule has great influence on the molecular and crystal structure, and, consequently, on their properties [5]. Our recent research on the structures and properties of organoboron compounds was focused on the characterization of fluoro-substituted phenylboronic compounds. Generally, introduction of fluorine atoms increases the acidic character of the boronic center. Results of the systematic NMR studies of fluorinated phenylboronic acids revealed a close correlation between their structure and spectroscopic properties [6]. The influence of the position of fluorine atom on the structures, spectral characteristics and biological activity has been investigated for fluorobenzoxaboroles [7,8].

* Corresponding author. E-mail address: [email protected] (A. Adamczyk-Wo
zniak). http://dx.doi.org/10.1016/j.jfluchem.2016.05.001 0022-1139/ã 2016 Elsevier B.V. All rights reserved.

The affinity of boronic compounds towards polyols is crucial in the most important applications of these compounds, i.e. in medicine and materials chemistry. Recently, a review on boronate affinity materials for separation and molecular recognition was published [9]. The key problem is the preparation of materials that would be able to bind at a relatively low pH, which minimizes the risk of labile biomolecules’ degradation. Boronic ligands with electron withdrawing groups, benzoxaboroles as well as heterocyclic boronic acids have been found to be the most prospective receptors. Fluorine-substituted compounds exhibit higher acidity (lower pKa) compared with their non-fluorinated analogs. The compounds under investigation are four isomeric fluoro-2formylphenylboronic acids (1–4) with fluorine substituent at various positions. These compounds are of potential applications due to the presence of two functional groups: fluorine atom that enhances acidity of the compounds, and formyl group of a high synthetic versatility [10–13]. Three of the investigated isomers have been previously used in asymmetric Suzuki-Miyaura coupling with further transformation of the formyl group [12]. Two of them have been used to obtain axially chiral monophosphine oxides [14]. Some of them were also used for spectroscopic analysis of the enantiopurity of chiral diacids [15] and diols [16]. The 3-fluoroisomer (1) was used for the functionalization of protein amino

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K. Kowalska et al. / Journal of Fluorine Chemistry 187 (2016) 1–8

groups to investigate the interactions with sugars [17]. Only one compound, namely 3-fluoro-2-formylphenylboronic acid (1), was previously characterized in crystal state and in solution. It was found, that it exists in equilibrium with its cyclic tautomer: hydroxybenzoxaborole [18]. The aim of this work is to investigate how the position of fluorine atom in 2-formylphenylboronic acids (1–4) influences their structures, spectral properties as well as acidity. 2. Results and discussion The compounds investigated in the present paper are shown in Chart 1. 2.1. Synthesis The compounds 1–4 were synthesized from the corresponding bromobenzaldehydes in two-step reactions with overall yield of over 78% according to Scheme 1. 2.2. Molecular and crystal structures The present paper describes molecular and crystal structures of the compounds 2 (Fig. 1a) and 4 (Fig. 1b). Molecular structure of the

HO

OH

B

HO 7

1 6

3 4

OH

HO

O

2

5

B

B

O

F

HO

OH O

B

OH

F

O

F F

1

2

3

4

Chart 1. Boronic acids under investigation with numbering of carbon atoms.

Br O F

Br

HC(OMe)3 , MeOH

HC(OMe)2 F

1. BuLi OH HO B 2. B(OEt)3 3. aq. HCl

O

F

Scheme 1. Synthesis of fluorinated 2-formylphenylboronic acids.

Fig. 1. Molecular structures of compounds 2 (a) and 4 (b) showing the atomlabeling scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radius (hydrogen bonds and B  O interactions are represented by dashed lines).

compounds with the atomic numbering and ring labeling schemes are presented in Fig. 1. The crystal data and refinement parameters are summarized in Table 1. Single-crystal X-ray diffraction measurements show that compounds 2 and 4 crystallize in the monoclinic C2/c (2) and P21/c (4) space groups with one molecule in the asymmetric unit (Fig. 1, Table 1). The bond lengths and valence angles characterizing the geometry of the phenylboronic acid moiety in compounds 2 and 4 are consistent with the geometric parameters observed for formylphenylboronic acids [19]. The comparison of the crystal structure of compounds 2 and 4 with the known crystal structure of 3-fluoro-2-formylphenylboronic acid (1) (triclinic P-1 space group) [18], shows that in all cases the boronic moiety (B(OH)2) has syn-anti conformation and makes angle of 10.3(1)
, 44.6(1), and 74.7(2)
with the mean plane of the phenyl ring, in compounds 1, 2, and 4, respectively. As a consequence, differences in the crystals packing of mono fluoro substituted 2-formylphenylboronic acids are observed. In the crystals of compound 2, the intermolecular C10–H10  O9 hydrogen bond is observed and molecules are linked into inversion R22(8) dimers by pairs of O9–H9  O8 hydrogen bonds which is typical of many phenylboronic acids (Table 2 and Fig. 2a). Centrosymmetric R22(8) dimers are also observed in the crystals of compound 1, however one of the hydroxyl group is engaged in intramolecular O H  O hydrogen bond with the formyl group. In the crystal packing of 2, the neighbouring dimers are linked by O8–H8  O11 hydrogen bond to produce 2D-layers along the c-axis (Table 2 and Fig. 3a). Adjacent layers are interwoven and interact by C6–H6  O11 hydrogen bond and p–p interactions (CgCg = 3.754(1) Å; Cg is the centroid of the benzene ring C1–C6; interplanar distances = 3.489(2) Å; slippage 1.385(2) Å), to form a double layers along the b-axis (Table 2, Fig. 3b). The neighbouring layers are linked by CH  F (C3– H3  F12 and C5–H5  F12) hydrogen bonds to form a threedimensional framework structure (Table 2, Fig. 3b). Similar crystal packing is observed in the crystals of 3-formylboronic acid [19]. In the crystal packing of 1, centrosymmetric dimers are linked via weak C H  O hydrogen bonds and p–p interactions into columns along the c-axis.

Table 1 Crystal data and structure refinement for the compounds 2 and 4. Compound Chemical formula FW/g mol1 Crystal system Space group a/Å b/Å c/Å b/
V/Å3 Z T/K lCu/Å rcalc/g cm3 m/mm1 F(000) 2u range for data collection/
Completeness 2u/% Reflections collected Reflections unique Data/restraints/parameters Goodness-of-fit on F2 Final R1 value (I > 2s (I)) Final wR2 value (I > 2s (I)) Final R1 value (all data) Final wR2 value (all data) CCDC number

2 C7H6BFO3 167.93 monoclinic C2/c 30.045(6) 3.754(6) 13.516(9) 90.39(1) 1524.2(2) 8 295(2) 1.54184 1.464 1.094 688 5.89–67.50 99.0 7101 1371[Rint = 0.0484] 1371/0/115 1.056 0.0463 0.1347 0.0571 0.1493 1439278

4 C7H6BFO3H2O 185.94 monoclinic P21/c 7.540(9) 8.180(9) 14.096(9) 99.16(1) 858.3(2) 4 295(2) 1.54184 1.439 1.114 384 5.94–67.39 99.0 4172 1534[Rint = 0.0331] 1534/15/186 1.102 0.0842 0.2136 0.0974 0.2259 1439279

K. Kowalska et al. / Journal of Fluorine Chemistry 187 (2016) 1–8

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Table 2 Hydrogen bond geometry for the compounds 2 and 4. Compound

D–H  A

d(D–H) (Å)

d(H  A) (Å)

d(D  A) (Å)

O8–H8  O11i 0.88(3) 1.86(3) 2.734(2) O9–H9  O8ii 0.94(3) 1.83(3) 2.773(2) C10–H10  O9 0.93 2.48 3.080(2) iii C3–H3  F12 0.93 2.69 3.458(2) iv C5–H5  F12 0.93 2.68 3.355(2) i C6–H6  O11 0.93 2.82 3.312(2) Symmetry code: (i) x,1y,1/2 + z; (ii) 1x,y,1z; (iii) 1/2x,1/2 + y,3/2z; (iv) 1/2x,1/2y,1z O8–H8  O1W 0.80(5) 2.01(6) 2.771(5) 4 O9–H9  O9vi 0.81(8) 2.50(8) 3.263(8) O1W–H1W  O8i 0.88(4) 1.94(4) 2.800(6) ii O1W–H2W  O9 0.89(3) 1.94(3) 2.762(5) iii C3–H3A  F12 0.93 2.55 3.458(9) iv C4–H4A  O11 0.93 2.70 3.308(9) C4–H4A  O1Wv 0.93 2.69 3.432(9) Symmetry code: (i) x,1/2 + y,3/2z; (ii) x,1/2y,1/2 + z; (iii) 1 + x,y,z; (iv) x,1 + y,z; (v) 1x, 1/2 + y, 3/2z; (vi) x,1y,1z 2


lowering electron density at the phenyl ring, which results in decreasing pKa values compared to that of the parent unsubstituted phenylboronic acid (Chart 2). The inductive effect is expected to be stronger in case of the fluorine group than that of the formyl group. The mesomeric effect of the formyl group is also negative, whereas it is positive in case of the fluorine group. The influence of each of the substituents separately on the dissociation constant of the phenyl boronic acids can be analyzed on the basis of the values reported previously for the unsubstituted phenylboronic acid and its isomeric monosubstituted fluorine or formyl derivatives. In case of the ortho and para formyl phenylboronic acids it is possible to

Fig. 2. The centrosymmetric dimers formed by OH  O hydrogen bonds in the crystals of compound 2 (a) and hydrogen-bonded network of water and acid molecules in 4 (b).

In the crystals of compound 4, close O11  B7 intermolecular interactions (2.770(9) Å) occur and molecules are linked into inversion D dimers by O9-H9  O8 hydrogen bond (Table 2). The neighboring dimers interact through weak C4H4A  O11 hydrogen bond and with water molecules by O-H  O (O1W-H1W  O8 and O1W-H2W  O9) hydrogen bonds to produce columns along the b-axis (Table 2 and Fig. 4a and b). The adjacent columns are linked via C3–H3A  F12 and C4–H4A  O1W hydrogen bonds, C10–O11p interactions and O11  O1W contact to produce a three-dimensional framework structure (Tables 2 and 3, Fig. 4b). Similar crystal packing is observed in the crystals of (2,3difluoro-1,4-phenylene)diboronic acid [20]. 2.3. pKa values The results of pKa measurements are collected in Table 4. The observed values of dissociation constants for the investigated compounds (1–4) are governed by the simultaneous influence of the fluoro and formyl substituents on the boronic group. Both substituents display negative inductive effect,

Fig. 3. Crystal packing of compound 2 viewed along the c-axis (a) and b-axis (b) (hydrogen bonds are represented by dashed lines).

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K. Kowalska et al. / Journal of Fluorine Chemistry 187 (2016) 1–8 Table 3 C O  p geometry for compound 4. Y–X  A C10–O11Cg

d(X  A) (Å) 3.283(7)

d(Y  A) (Å) 3.787(8)


Symmetry code: 1x,1/2 + y,3/2z; Cg is the centroid of the aromatic ring C1–C6.

Table 4 pKa values for the investigated compounds. Compound

1

2

3

4

pKa

5.74  0.02

6.42  0.03

6.72  0.03

6.05  0.03

para fluorine isomers display partially negative charge at the nextto-boron carbon atom resulting in increased pKa. Consequently, the most acidic within the series of monosubstituted derivatives are the 3-fluoro (pKa = 7.50) and the 2-formyl phenylboronic acids (pKa = 7.26). Similar influence of the fluorine substituents on the acidity can be observed within the series of benzoxaboroles [7]. Structures with partial negative charge at the next-to-boron carbon atom result in higher pKas within the series of fluorobenzoxaboroles. Introducing fluorine substituent at various position of the 2-formylphenylboronic acid in compounds 1–4 results in lowering pKas of about a unit, which is first of all the effect of the presence of two electron-withdrawing groups within the molecules (negative inductive effect of both the fluorine and the formyl group). The differences in the corresponding pKa values of 1–4 arise from the subtle interplay of mesomeric and inductive effects of the fluorine and formyl groups. The effects influence the

Fig. 4. Crystal packing of compound 4 viewed along the a-axis (a) and b-axis (hydrogen bonds are represented by dashed lines and C O  p and O  O interactions by dotted lines).

draw resonance structures with a positive charge at the next-toboron carbon atom which results in considerably lower pKa in comparison with the meta isomer (Chart 2). Since the mesomeric effect of the fluorine atom is positive, the corresponding ortho and

HO

B(OH)2

B

O 7.39[22]

8.72[21] B(OH)2

B(OH)2

4

F

O

HO

B(OH)2 F

O

7.83[24]

7.26 7.31[23] B(OH)2

B(OH)2

B

O

F 7.42[7]

6.05 3

HO

B(OH)2

B

O

O

O 7.8[25] B(OH)2

F

F

7.50[24] B(OH)2

2

6.72 B(OH)2

F

6.57[7]

HO

B

O

O O

7.6[25]

F

F

8.66[24] 1

6.42 HO

B(OH)2

6.97[7]

F B

O

O F 5.74

F

6.36[7]

Chart 2. pKa values of formyl- and fluoro-substituted phenylboronic acids and benzoxaboroles (values in green are from ref’s [7,21–25].

K. Kowalska et al. / Journal of Fluorine Chemistry 187 (2016) 1–8

5

Table 5 NMR data (d/ppm, J/Hz) for the investigated compounds (in [2H]6-acetone; 298 K). Compound

1

BOH

HCO

COH

H3/F3

H4/F4

H5/F5

H6/F6

1 (aldehyde)

7.4 bs

10.38 s

–

122.39 dd 3 JF3H4 = 11.1 4 JF3H5 = 5.3

8.4 bs

6.46 s

6.18 bs

120.81 ddd 3 JF3H4 = 9.5 4 JF3H5 = 4.4 5 JF3H6 = 1.0

2 (aldehyde)

7.7 bs

10.34 d 5 JH7F4 = 1.9

–

7.67 dd 3 JH3F4 = 9.5 4 JH3H5 = 2.7

2 (cyclic)

8.2 bs

6.27 s

6.11 bs

7.21 dt 3 JH3F4 = 9.6 4 JH3H5 = 2.3

112.75 dddd 3 JH3F4 = 9.5 3 JH5F4 = 8.2 4 JH6F4 = 6.0 5 JH7F4 = 1.9 111.21 td 3 JH3F4 =3JH5F4 = 9.6 4 JH6F4 = 5.7

7.68 dddd 3 JH4H5 = 8.3 3 JH5H6 = 7.2 4 JF3H5 = 5.3 6 JH5H7 = 0.6 7.47 dddd 3 JH4H5 = 8.0 3 JH5H6 = 7.1 4 JF3H5 = 4.4 6 JH5H7 = 0.6 7.44 td 3 JH5F4 =3JH5H6 = 8.2 4 JH3H5 = 2.7

7.44 dq 3 JH5H6 = 7.2 4 JH4H6 = 5JH6H7 = 5JF3H6 = 0.7

1 (cyclic)

7.27 dddd 3 JF3H4 = 11.1 3 JH4H5 = 8.3 5 JH4H7 = 1.0 4 JH4H6 = 0.7 7.21 ddt 3 JF3H4 = 9.5 3 JH4H5 = 8.0 4 JH4H6 = 1.0

7.72 dd 3 JH5H6 = 8.2 4 JH6F4 = 5.7

3 (aldehyde)

7.6 bs

10.20 s

–

8.05 dd 3 JH3H4 = 8.5 4 JH3F5 = 5.5

7.34 td 3 JH3H4 =3JH4F5 = 8.5 4 JH4H6 = 2.9

3 (cyclic)

–1

6.30 s

–1

7.52 dd 3 JH3H4 = 8.2 4 JH3F5 = 5.0

7.26 ddd 3 JH4F5 = 9.4 3 JH3H4 = 8.2 4 JH4H6 = 2.4

4 (aldehyde)

7.5 bs

10.04 d 5 JF6H7 = 2.4

–

7.75 dt 3 JH3H4 = 7.5 4 JH3H5 = 5JH3F6 = 0.8

7.59 ddd 3 JH4H5 = 8.2 3 JH3H4 = 7.5 4 JH4F6 = 5.6

7.17 ddd 3 JH5F4 = 9.6 3 JH5H6 = 8.2 4 JH3H5 = 2.3 106.73 dddt 3 JH6F5 = 9.4 3 JH4F5 = 8.5 4 JH3F5 = 5.5 6 JH7F5 = 1.5 116.12 dddd 3 JH4F5 = 9.4 3 JH6F5 = 8.2 4 JH3F5 = 5.0 6 JH7F5 = 1.3 7.36 td 3 JH4H5 =3JH5F6 = 8.2 4 JH3H5 = 0.8

4 (cyclic)

–1

6.27 s

–1

7.31 ddt 3 JH3H4 = 7.4 5 JH3F6 = 1.5 4 JH3H5 = 4JH3H7 = 0.7

7.57 ddd 3 JH4H5 = 8.2 3 JH3H4 = 7.4 4 JH4F6 = 5.2

Compound

H and

13

19

F NMR parameters

COH

189.71 d 3 JCF = 7.5

1 (cyclic) 2 (aldehyde)

7.41 dd 3 JH6F5 = 8.2 4 JH4H6 = 2.4

106.03 dddd 3 JH5F6 = 8.2 4 JH4F6 = 5.6 5 JF6H7 = 2.4 5 JH3F6 = 0.8 105.52 ddd 3 JH5F6 = 8.2 4 JH4F6 = 5.2 5 JH3F6 = 1.5

C2

C3

C4

C5

C6

141.6 b

127.58 d 2 JCF = 13.6 140.81 d 2 JCF = 13.3 143.72 d 3 JCF = 5.6 159.00 d 3 JCF = 8.2 137.42 d 4 JCF = 2.3 151.56 d 4 JCF = 2.1 142.69 d 3 JCF = 9.0 159.51 d 3 JCF = 8.0

165.35 d 1 JCF = 257.6 158.82 d 1 JCF = 251.67 116.91 d 2 JCF = 20.9 110.55 d 2 JCF = 22.1 134.99 d 3 JCF = 9.4 125.60 d 3 JCF = 8.3 128.91 d 4 JCF = 2.4 120.67 d 4 JCF = 3.6

116.89 d 2 JCF = 20.9 118.61 d 2 JCF = 20.1 164.47 d 1 JCF = 248.7 165.95 d 1 JCF = 248.2 117.08 d 2 JCF = 22.3 118.99 d 2 JCF = 23.6 132.17 d 3 JCF = 8.1 135.69 d 3 JCF = 7.4

136.64 d 3 JCF = 9.0 132.21 d 3 JCF = 5.8 120.61 d 2 JCF = 20.2 116.84 d 2 JCF = 21.8 166.34 d 1 JCF = 254.8 164.02 d 1 JCF = 244.1 121.84 d 2 JCF = 25.5 116.39 d 2 JCF = 23.0

129.41 d 4 JCF = 3.6 126.78 d 4 JCF = 3.4 138.18 d 3 JCF = 7.4 133.02 d 3 JCF = 9.1 121.6 d 2 JCF = 20.5 116.49 d 2 JCF = 21.1 166.21 d 1 JCF = 241.2 165.11 d 1 JCF = 251.0

135.9 b

–

134.8 b 127.6 b 143.0 b 134.9 b

2 (cyclic) 3 (aldehyde)

194.48

97.87 d 4 JCF = 2.5 –

3 (cyclic)

–

98.09

4 (aldehyde)

193.87 d 3 JCF = 2.3

Compound

7.51 dd 3 JH6F5 = 9.4 4 JH4H6 = 2.9

C1

96.30 194.65 d 4 JCF = 2.2 –

4 (cyclic)

7.94 dd 3 JH5H6 = 8.2 4 JH6F4 = 6.0

C NMR parameters

CHO 1 (aldehyde)

7.07 tt 3 JH4H5 =3JH5F6 = 8.2 4 JH3H5 = 6JH5H7 = 0.7

7.51 dt 3 JH5H6 = 7.1 4 JH4H6 = 5JF3H6 = 1.0

126.6 b 98.87

118.8 b

17

O NMR chemical shifts

BOH

BOC

CHO

COH

97.4 93.7 88.6 85.7 98.5 –1 91.3 –1

– 159.9 – 156.0 – –1 – –1

582.0 – 564.2 – 557.7 – 571.9 –

– 69.9 – 67.0 – –1 – –1

1 1 2 2 3 3 4 4

(aldehyde) (cyclic) (aldehyde) (cyclic) (aldehyde) (cyclic) (aldehyde) (cyclic)

1

Not observed due to small concentration of this tautomer.

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K. Kowalska et al. / Journal of Fluorine Chemistry 187 (2016) 1–8

HO

B

OH

Kcycl O

HO

B

O OH

Scheme 2. Tautomeric equilibrium observed for 2-formylphenylboronic acids.

resultant charge at the next-to-boron carbon atom. The fluorine substituent at position “3” in 1 results in the lowest pKa value (5.74) since the mesomeric effect of the fluorine atom does not reduce the positive charge at the next-to-boron carbon atom cased by the adjacent formyl group. Single positive charge is also characteristic for structure 3, but in this case the inductive effect of fluorine group is lower than in 1 resulting in higher pKa (6.72). The strong inductive effect of the neighboring fluorine atom is responsible for a relatively low pKa of 4 (6.05). It is worth noting that the fluoro derivatives of 2-formylphenylboronic acid display generally higher acidity in comparison with the corresponding fluorobenzoxaboroles (except for compound 3). 2.4. NMR spectroscopy Chemical shifts and coupling constants for the investigated compounds are presented in Table 5. Numbering of carbon atoms is shown in Chart 1. For 2-formylphenylboronic acids in solution a tautomeric equilibrium with the formation of oxaborole ring by the formyl group was previously observed (Scheme 2) [10,18,26]. For all compounds studied signals assigned for both tautomers (aldehyde and cyclic benzoxaborole) have been observed in 1H, 19F and 13C NMR spectra (Fig. 5).

In 17O NMR spectra of 3 and 4, the signals of cyclic forms do not occur, due to their small concentration. For three compounds (2, 3 and 4) the long-range coupling via 5 or 6 bonds between aldehyde proton and fluorine atom has been observed. Such couplings via six bonds has been also observed for cyclic tautomer of 3 (between F atom and CHO proton). These hydrogen atoms couple also with protons of the arene moiety. As in other arylboronic derivatives, the signal of carbon atom bonded to boron (C-1) is strongly broadened (Dn1/2 200–300 Hz), and thus, difficult to observe. This stems from two mechanisms: (i) fast relaxation caused by quadrupole mechanism and (ii) splitting of the signal due to the scalar coupling with both boron isotopes and fluorine nucleus. The characteristic chemical shift of C-2 (>140 ppm) is caused by deshielding via electronic effects of B atom at its ortho position. Moreover, in cyclic tautomer the strain effect of the formed fivemembered ring causes additional deshielding. The chemical shifts of oxygen atoms are strongly affected both by the electronic and steric effects. The value of d 17O for aldehyde group is the highest for 1, since the oxygen nucleus is deshielded by the interactions with two substituents. The observed value is ca. 30 ppm higher than that for 2-formylphenylboronic acid (582 vs. 556 ppm) [10]. The chemical shifts of other isomers are affected by the electronic influence of fluorine substituent. The value closest to that of parent compound has been observed for 3 (557 vs. 556 ppm) [10]. The low value of BO oxygen chemical shift is the result of the inductive effect of F substituent at para position. The values for meta isomers (1 & 3) are distinctly higher. For 4 the shielding caused by electronic effect of fluorine atom is masked by steric interaction causing opposite shift. The 17O NMR chemical shifts values for 1 measured in recent studies differ from reported previously [26]. The values given in the present paper should be considered correct. The reason of the error is the reaction of 1 isomer with acetone, resulting in the formation of the benzoxaborole

Fig. 5. 1H (a), 13C (b), 19F (c) and 17O (d) NMR spectra of compound 1 present in solution as two tautomeric forms: open: blue, cyclic: red; (reaction products with acetone-D6: black). For assignment of the signals: see Table 5. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

K. Kowalska et al. / Journal of Fluorine Chemistry 187 (2016) 1–8 Table 6 Equilibrium constants for cyclization of formylphenylboronic acids. Compound

1

2

3

4

Kcycl

0.69

0.14

0.05

0.08

derivative. To avoid the influence of this process, it is necessary to record the spectra for freshly prepared samples. Tautomeric equilibrium (Scheme 2) depends on substituents in phenylboronic acid [18]. Equilibrium constant for this reaction can be easily determined by NMR method on the basis of the integration of the corresponding signals in 1H NMR spectra [10]. The values of tautomeric equilibrium constant are collected in Table 6. The highest contribution of the cyclic tautomer (benzoxaborole) is observed for the compound 1, in which fluorine substituent is located at ortho position regarding the formyl group. It was previously observed for the compounds with other substituents in this position [18]. For the other isomers cyclization constant values are comparable with the value for 2-formylphenylboronic acid (Kcycl = 0.05) [10].

7

96.9%). 1H NMR (CDCl3, 500 MHz), d/ppm: 7.51 (m, 1H), 7.35 (m, 1H), 6.93 (m, 1H), 5.50 (s, 1H), 3.38 (s, 6H). 23.8 g (95.0 mmol) of the above compound was dissolved in 200 ml of dry Et2O and 40 ml THF under argon flow. The solution was cooled down to 75
C using dry ice/acetone bath. 2.5 M nbutyllithium in hexanes (42.0 ml, 110.0 mmol) was added dropwise to keep the temperature under 70
C. The solution was stirred for 1 h, then 16.1 g (110.0 mmol) of triethyl borate was added slowly, keeping the temperature under 70
C. Cooling bath was removed and the solution was brought to pH 3 with 3 M aq. HCl, while the temperature rose to 5
C. The aqueous layer was separated and extracted with Et2O (2  50 ml). The organic layers were combined and the solvent was partially removed under vacuum. Distillation was continued after addition of water. The solid precipitated after cooling was filtered and dried on air, giving 14.3 g of 4-fluoro-2formylphenylboronic acid (2) (yield 89.5%). 11B NMR (64 MHz, acetone-d6): d = 30.9 ppm. Compounds 1, 3 and 4 were synthesized in similar way from the appropriate fluoro-substituted 2-bromobenzaldehydes. Overall (two-steps) yields are as follows: 1: 85.4%, 3: 78.3%, 4: 92.1%. 4.2. X–ray diffraction

3. Conclusions 1. In the crystals of compounds 2 and 4, intramolecular hydrogen bonds between B O H group and formyl oxygen atom or fluorine atom are not formed. The formation of abovementioned bond was observed for 2-formylphenylboronic acid [19], 2,6diformylphenylboronic acid [10], and several fluorophenylboronic acids with fluorine atom at ortho position [27]. This is a subsequent proof that the molecular structure of phenylboronic acids and their derivatives are strongly influenced by weaker interactions in the crystal architecture [27,28] or by the presence of solvent molecules able to form hydrogen bonds [29,30]. Interestingly, intramolecular B OH  O¼C bond is observed in the crystals of 1 [18]. 2. Compound 4 does not form hydrogen-bonded dimeric unit which was observed for the compounds 1 [18] and 2, and which is a common structural unit for many boronic acids. Instead of this, a hydrogen-bonded tetrameric unit formed with water molecules is observed. 3. The chemical shifts of oxygen atoms are strongly affected both by the electronic and steric effects of the substituents. 4. pKa values of fluoro-substituted 2-formylphenylboronic acids are comparable and for compounds 1, 2 and 4 they are even lower than those of the corresponding benzoxaboroles. 5. The highest contribution of cyclic tautomer (benzoxaborole) is observed for the compound 1, while cyclization constant values for the other isomers are comparable with the value for 2formylphenylboronic acid [10].

4. Experimental 4.1. Synthesis 4.1.1. 4-fluoro-2-formylphenylboronic acid (2) 2-Bromo-5-fluorobenzaldehyde (20.0 g, 98.5 mmol) was dissolved in 40 ml of methanol. 0.5 ml of concentrated H2SO4 was added and 13.6 g (128 mmol) of trimethyl orthoformate was added dropwise. The solution was refluxed for 1 h and left to cool down. Then the solution was brought to pH 11 with a concentrated solution of NaOMe in methanol. After distillation of the volatiles the product was distilled under vacuum to give 23.8 g of 1-bromo2-(dimethoxymethyl)-4-fluorobenzene as a colorless liquid (yield

Single-crystal specimens of the title compounds were selected for the X-ray diffraction experiment at T = 295(2) K. Diffraction data were collected on an Oxford Diffraction Gemini R ULTRA Ruby CCD diffractometer with CuKa (l = 1.54184 Å) radiation (Table 1). The lattice parameters were obtained by least-squares fit to the optimized setting angles of the collected reflections by means of CrysAlis CCD [31]. The structural determination was carried out using the SHELX package. The structures were solved by direct methods, with refinements being carried out by full-matrix leastsquares on F2 using the SHELXL-97 program [32]. The molecule of 6-fluoro-2-formylphenylboronic acid in compound 4, has disordered orientations with refined site-occupancy factors of the disordered parts of 0.588 and 0.412 (the disordered benzene rings were refined as rigid ideal hexagons with C C = 1.39 Å and constrained with isotropic displacement parameters) (Fig. 1b). All H-atoms bound to C-atoms were placed geometrically and refined using a riding model with C-H = 0.93 Å and Uiso(H) = 1.2Ueq(C). Hatoms bound to O-atoms were located on a difference Fourier map and refined with restrains with Uiso(H) = 1.5Ueq(O). All the interactions demonstrated were found using the PLATON program [33]. The molecular graphics were prepared using the ORTEPII [34], PLUTO-78 [35] and Mercury [36] programs. 4.3. NMR measurements All spectra were recorded at 298 K. The samples concentration was 0.01 M. The 1H, 13C and 17O NMR measurements were performed on Agilent DD2 800 spectrometer, operating at frequencies 799.926, 201.162 and 108.442 MHz, respectively. 17O NMR spectra were recorded using a 5 mm probehead (BB/1H; 90
17 O pulse width 8 ms) using a simple one-pulse sequence (s2pul) with increased receiver gating time following pulse (rof2 = 30 ms) to reduce distortion of baseline. 1H and 13C spectra were acquired using 1H{13C/15N} triple resonance probe (90
pulse width: 1H – 13.6 ms; 13C – 6.9 ms) and standard one-pulse sequence (s2pul). The 13 C NMR spectra were recorded with broadband 1H decoupling. Line broadening factor of 10 Hz was used for 17O NMR spectra and 1 Hz for 13C spectra. The 19F NMR spectra were recorded on Bruker Avance II 400 equipped with ATM BBO BB(F)/1H 5 mm probehead, operating at frequency 376.498 MHz. Standard one-pulse sequence (zg30) and acquisition parameters were used. For measurements of coupling constants, increased digital resolution of 1H, 13C and 19F

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