Synthesis, characterization and electrochemical properties of 3-ferrocenylbenzoxaboroles

Journal Pre-proof Synthesis, characterization and electrochemical properties of 3ferrocenylbenzoxaboroles Krzysztof M. Borys, Maria B. Jaworska, Agata Kowalczyk, Anna M. Nowicka, Agnieszka Adamczyk-Woźniak PII:

S0022-328X(19)30459-0

DOI:

https://doi.org/10.1016/j.jorganchem.2019.121016

Reference:

JOM 121016

To appear in:

Journal of Organometallic Chemistry

Received Date: 18 September 2019 Revised Date:

29 October 2019

Accepted Date: 1 November 2019

Please cite this article as: K.M. Borys, M.B. Jaworska, A. Kowalczyk, A.M. Nowicka, A. AdamczykWoźniak, Synthesis, characterization and electrochemical properties of 3-ferrocenylbenzoxaboroles, Journal of Organometallic Chemistry (2019), doi: https://doi.org/10.1016/j.jorganchem.2019.121016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

1

Synthesis, characterization and electrochemical properties of 3-ferrocenylbenzoxaboroles

2 3

Krzysztof M. Borys,1,* Maria B. Jaworska,1 Agata Kowalczyk,2 Anna M. Nowicka,2 Agnieszka

4

Adamczyk-Woźniak1

5 6

1

Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland

7

2

Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland

8 9

* Corresponding author. E-mail address: [email protected] (K.M. Borys).

10 11

Abstract

12

3-Ferrocenylbenzoxaboroles are organoboron compounds combining the structural features of diol-

13

binding benzoxaborole with redox-active ferrocene. Herein, a two-step method for the preparation of

14

these hitherto unreported compounds is described. First, ferrocenecarboxaldehyde is transformed into

15

2-halo-1-ferrocenylbenzyl alcohols via halogen-selective transmetallation. Next, the obtained alcohols

16

are subjected to palladium-catalyzed borylation, affording the title benzoxaboroles. All compounds

17

have been characterized spectroscopically by means of NMR and FTIR, and their purity confirmed by

18

elemental analysis. Cyclic voltammetry studies have allowed for the determination of the redox

19

potentials, diffusion coefficients and electron-transfer rate constants of the studied electroactive

20

species.

21 22

Keywords

23

Benzoxaborole, ferrocene, boronic, organoboron, cyclic voltammetry

24 25

1

Introduction

26

1,3-Dihydro-1-hydroxy-2,1-benzoxaborole, often shortly referred to as benzoxaborole (1, Fig.

27

1), is an internal cyclic hemiester of 2-(hydroxymethyl)phenylboronic acid.[1,2] Similarly to

28

phenylboronic acids,[3] benzoxaboroles have gained considerable attention owing to their ability to

29

form esters with 1,2- and 1,3-diols in a reversible and pH-sensitive manner. Such diol-containing

30

analytes include monosaccharides, polysaccharides, glycopeptides, glycoproteins and catecholamine

31

neurotransmitters, making boronic compounds attractive molecular receptors for chemical sensing.

32

Importantly, benzoxaboroles were reported to be superior to the corresponding phenylboronic

33

acids in terms of receptor activity towards diols. Benzoxaboroles show enhanced stability and are

34

capable of binding diols effectively at physiological pH of 7.4.[4] This property gave rise to the

35

development of a range of diol-sensitive benzoxaborole-based sensors and materials.[2]

36

The same interaction with diol-containing biomolecules serves as the molecular basis for the

37

medicinal use of benzoxaboroles. Two benzoxaborole-based drugs – antifungal Tavaborole and anti-

38

inflammatory Crisaborole – have been recently approved by the FDA.[5,6]

39 40

Combining an oxaborole motif with an electroactive metallocene scaffold could expand these applications even further, resulting in novel redox-active molecular receptors.

41

Ferrocene (2, Fig. 1), or bis(η5-cyclopentadienyl)iron, was the first metallocene synthesized

42

and has served as the prototypical molecule for synthetic and structural studies of metallocenes ever

43

since.[7] Variously substituted derivatives of ferrocene have found applications as chiral ligands for

44

transition metal-catalyzed asymmetric synthesis.[8] Owing to its redox properties, ferrocenes have

45

been widely applied as electroactive probes in analytical, materials and supramolecular chemistry, e.g.

46

in conducting materials, thermotropic liquid crystals and electroactive macrocycles.[9,10]

47

Interestingly, ferrocene have also drawn attention in medicinal chemistry, contributing to the briskly

48

advancing field of organometallic therapeutics.[11,12]

49

Ferroceneboronic acid (3, Fig. 1) has been a well-established electroactive molecular receptor

50

for the construction of numerous electrochemical biosensors.[13] Conjugates of ferrocene and

51

phenylboronic acid[14] or heteroarylboronic acids like 3-thienylboronic acid[15] have also been

52

studied to this end. However, only two molecules combining ferrocene with an oxaborole motif have

53

been reported so far. The ferrocene benzoxaborole derivatives 4 and 5 (Fig. 1) were investigated as

54

potential components of an electrochemical displacement sensors for the detection of Escherichia coli

55

cells.[16]

56

From the structural point of view, both 4 and 5 are the amide derivatives of 6-

57

aminobenzoxaborole. To date, no benzoxaborole with a ferrocenyl substituent on either benzene or

58

oxaborole ring of the benzoxaborole system has been reported.

59 60 61

Figure 1. Structures of benzoxaborole (1), ferrocene (2), boronic derivatives of ferrocene 3-5 and

62

3-ferrocenylbenzoxaborole (6).

63

The objective of this work was to develop an efficient method for the synthesis of

64

3-ferrocenylbenzoxaborole (6, Fig. 1) and to carry out its spectroscopic and electrochemical

65

characterization. Once synthesized and characterized, 3-ferrocenylbenzoxaboroles could then be

66

introduced as molecular receptors of low molecular weight, diol-binding properties and the ability to

67

give electrochemical response upon analyte binding.

68 69

2

Results and discussion

70

2.1

Synthesis of 3-Ferrocenylbenzoxaboroles

71

A two-step pathway was proposed to access 3-ferrocenylbenzoxaborole (4). We envisaged

72

that compound 4 could be obtained by borylation of 2-bromo-1-ferrocenylbenzyl alcohol (5, Scheme

73

1). This, in turn, we planned to obtain from the commercially available ferrocenecarboxaldehyde.

74

75 76 77

Scheme 1. Retrosynthetic approach to 3-ferrocenylbenzoxaborole (4).

78 79

The literature method for the preparation of alcohol 7 started from ferrocene (2).[17] The

80

three-step synthesis featured: (i) the preparation of an acyl chloride from 2-bromobenzoic acid, (ii)

81

Friedel-Crafts acylation of ferrocene with the obtained benzoyl chloride, followed by (iii) the

82

reduction of the resulting ketone to the desired secondary alcohol. The procedure was relatively

83

laborious, time-consuming, and involved the use of corrosive SOCl2 and AlCl3.

84 85

For an easier access to 2-halo-1-ferrocenylbenzyl alcohols, a one-pot method was proposed (Scheme 2).

86

87 88 89 90

Scheme 2. Preparation of 2-bromo-1-ferrocenylbenzyl alcohol (7) starting from 2-bromoiodobenzene.

91

The key reagent for this synthesis was an organomagnesium compound called Turbo

92

Grignard,

which

is

the

lithium

93

(i-PrMgCl⋅LiCl).

94

halogen/magnesium exchange compared to i-PrMgCl itself. Moreover, it was found to work better for

95

demanding substrates like aryl bromides with electron withdrawing groups. It is also compatible with

96

a wider scope of functional groups as well as provides excellent regioselectivity of

97

halogen/magnesium exchange in oligohalogenated aromatic systems. Contrary to i-PrMgCl, the THF

98

solutions of i-PrMgCl⋅LiCl are stable at room temperature, making them much more convenient to

99

handle.

According

to

chloride

Knochel

et

complex al.,[18]

of

isopropylmagnesium

i-PrMgCl⋅LiCl

allows

for

bromide faster

100

Exploiting the fact that bromine/magnesium exchange is known to be much slower than

101

iodine/magnesium exchange,[18] 2-bromoiodobenzene was anticipated to be selectively converted

102

into the intermediate 8, which could then be reacted with ferrocenecarboxaldehyde to afford alcohol 7.

103

To our delight, product 7 was obtained in 60% yield at first attempt. To extend the scope of the

104

installed halogens and provide more substrates for further transformation into benzoxaboroles, two

105

more alcohols were prepared. 2-Bromo-1-ferrocenyl-4-fluorobenzyl alcohol (9, Table 1) was afforded

106

in 84%, while 2-iodo-1-ferrocenylbenzyl alcohol (10, Table 1) in 66% yield.

107 108

Table 1. Preparation of 2-halo-1-ferrocenylbenzyl alcohols 7, 9 and 10.

109 Entry Compound

R1

R2

Isolated yield

1

7

Br

H

60%

2

9

Br

F

84%

3

10

I

H

66%

110 111

With alcohols 7, 9 and 10 at hand, we started to search for the right conditions to transform

112

them into the corresponding 3-ferrocenylbenzoxaboroles. The main substrate for the optimization was

113

2-bromo-1-ferrocenyl-4-fluorobenzyl alcohol (9), as its synthesis had the highest yield out of three

114

haloalcohols obtained and it could be easily prepared on a several gram scale. The optimization steps

115

are given in Table 2.

116 117

Table 2. Optimization of the synthesis of 3-ferrocenylbenzoxaboroles 7 and 11.

118 Isolated yield

Entry

R1

R2

1

Br

F

1) nBuLi, hexane, Et2O; 2) B(OiPr)3; 3) HCl/H2O

0%

2

Br

F

1) iPrMgCl⋅LiCl, THF; 2) B(OMe)3; 3) HCl/H2O

0%

3

Br

F

1) iPrMgCl⋅LiCl, THF, 1,4-dioxane; 2) B(OMe)3

0%

4

I

H

1) iPrMgCl, THF; 2) B(OMe)3

0%

5

Br

F

B2pin2, PdCl2(PPh3)2, AcONa, DMSO

0%

6

Br

H

B2pin2, PdCl2(PPh3)2, AcONa, DMSO

0%

7

Br

H

B2(OH)4, XPhos Pd G2, XPhos, AcONa, EtOH

74%

8

Br

F

B2(OH)4, XPhos Pd G2, XPhos, AcONa, EtOH

94%

9

Br

H

B2(OH)4, SiliaCat DPP-Pd, AcOK, MeCN

47%

Reagents

of benzoxaborole

119 120

All the optimization steps were based on the reagents already reported in the literature to

121

convert 2-halobenzylic alcohols into benzoxaboroles. In all cases, the reaction mixtures were resolved

122

by column chromatography on silica gel, and the products analyzed by 1H NMR.

123

The first four attempts (Entries 1-4, Table 2) were based on the most common strategy for

124

benzoxaborole synthesis, which is the halogen/metal exchange followed by the reaction with a

125

trialkoxyborane.

126

First, alcohol 9 was treated with n-butyllithium, followed by triisopropoxyborane and

127

hydrolysis with hydrochloric acid (Entry 1, Table 2). The reagents and conditions were the same as in

128

the literature procedure for preparation of 5-fluorobenzoxaborole.[19] In case of ferrocenylated

129

substrate, however, the reaction did not lead to the formation of benzoxaborole.

130

The second attempt (Entry 2) was made with Turbo Grignard as the metallating agent and

131

trimethoxyborane as the boron source. The bromine/lithium exchange did not work in this instance, as

132

the starting alcohol was almost fully recovered.

133

The next reaction (Entry 3) again made use of Turbo Grignard, yet with an additive of 1,4-

134

dioxane. According to Knochel et al.,[20] 1,4-dioxane shifts the Schlenk equilibrium of

135

alkylmagnesium

136

i-Pr2Mg⋅LiCl was found to convert aryl bromides into the corresponding Grignard reagents more

137

effectively than i-PrMgCl⋅LiCl.[20] Unfortunately, the applied modification did not result in the

halides

to

dialkylmagnesium

species.

The

in-situ

formed

138

formation of the desired benzoxaborole. Interestingly though, an additive of 1,4-dioxane did trigger

139

the bromine/lithium exchange. Column chromatography afforded a product which differed from the

140

substrate only in the number of aromatic protons in the 1H NMR spectrum (4H instead of 3H by

141

relative integration). The product was identified as 3-fluoro-1-ferrocenylbenzyl alcohol (12, Scheme

142

3), meaning that the Br/Mg exchange occurred to a certain extent, but the generated organometallic

143

intermediate did not react with trimethoxyborane. Instead, it got hydrolysed with the formation of a

144

debrominated product 12.

145

146 147 148

Scheme 3. Plausible way of the formation of debromination product 12.

149 150

The fourth attempt (Entry 4) featured a recently published method for benzoxaboroles

151

preparation starting from 2-iodobenzyl alcohols.[21] Iodine/magnesium exchange of such systems

152

with i-PrMgCl, followed by the reaction with trimethoxyborane, was reported to afford

153

benzoxaboroles in good yields. To check this route, the reaction was carried out starting from 2-iodo-

154

1-ferrocenylbenzyl alcohol (10). Most of the substrate was recovered, indicating that the

155

iodine/magnesium exchange did not work.

156 157

Since neither of the halogen/metal exchange methods worked, they were given up in favor of palladium-catalyzed borylations.

158

According to a literature example,[22] Miyaura borylation of 2-bromobenzyl alcohol with

159

bis(pinacolato)diboron as a boron source, bis(triphenylphosphine)palladium(II) dichloride as a catalyst

160

and potassium acetate as a base resulted in the formation of unsubstituted benzoxaborole (1) in 55%

161

yield. The same reagents and conditions were used for the reaction with the fluorinated alcohol 9

162

(Entry 5). The complex reaction mixture was resolved chromatographically. The 1H NMR analysis of

163

one out of six series of combined fractions revealed signals that could be attributed to the benzylic

164

proton of a benzoxaborole system. However, the compound was apparently impure judging by the 1H

165

NMR spectrum and TLC analysis. The efforts to isolate the product were unsuccessful as the sample

166

degraded upon further purification.

167

Spurred on by this finding, the same reaction was run for the alcohol 7 as the starting material

168

(Entry 6). The reaction mixture was again found to be complex and particularly hard to resolve

169

chromatographically. Although the 1H NMR analysis of one series of combined fractions indicated the

170

formation of benzoxaborole, the product was inseparable from the impurities.

171

Carrying on with palladium-catalyzed borylations, a change in the reagents was proposed

172

(Entry 7). Bis(pinacolato)diboron was replaced with tetrahydroxydiboron, which is not only more

173

atom-economical than B2pin2, but also eliminates the need for problematic removal of the co-formed

174

pinacol from the reaction mixture. Palladium(II) chloride complex was replaced with an XPhos Pd

175

G2/XPhos catalytic system, recently reported to efficiently promote the conversion of 2-bromobenzyl

176

alcohols into benzoxaboroles.[23,24] Following the same reports, ethanol was used instead of DMSO.

177

Importantly, the solvent was thoroughly degassed directly before use in order to limit any side

178

reactions that could result from the presence of oxygen dissolved in the solvent.

179

Encouragingly, the TLC analysis of the reaction mixture showed complete consumption of the

180

starting material after 2 hours. The mixture was worked-up and resolved chromatographically as in the

181

original work.[24] However, the product remained impure. Chromatographical resolutions with

182

neither gradient nor isocratic gradient elution allowed for the efficient purification. Judging by TLC,

183

the impurities could be either the catalyst or the phosphine ligand used. This hypothesis was supported

184

by a recent paper,[25] reporting problems with isolating the product from XPhos Pd G2 or XPhos,

185

which persistently remained in the product despite repeated attempts at their removal. After numerous

186

adjustments, the purification challenges were finally overcome by switching the eluent from

187

AcOEt/hexane to MeOH/DCM. This modification resulted in a visible narrowing of the ferrocene-

188

containing bands on the column, limiting the so-called "tailing" of the product, and most importantly

189

allowing to resolve the product from the impurities. This way, the hitherto unreported 3-

190

ferrocenylbenzoxaborole (6) was isolated in 74% yield.

191

Applying the same reaction conditions and the optimized purification method to the

192

fluorinated alcohol 9 (Entry 8), 5-fluoro-3-ferrocenylbenzoxaborole (11) was prepared in an excellent

193

94% isolated yield. Importantly for potential future studies in terms of structure-bioactivity

194

relationships, compound 11 constitutes an unreported ferrocenyl analogue of 5-fluorobenzoxaborole –

195

Tavaborole.

196

As the last optimization step (Entry 9), the application of a solid-supported catalyst was

197

attempted in order to limit the contamination of the product with the catalyst or ligand.

198

A recently developed method for benzoxaboroles synthesis made use of a commercially available

199

catalyst named SiliaCat DPP-Pd.[25] SiliaCat DPP-Pd is a heterogenous catalyst containing

200

diphenylphosphine palladium(II) complex (palladium loading ≥0.20 mmol/g) immobilized in a leach-

201

resistant organosilica matrix. It has been successfully employed in a wide range of palladium-

202

catalyzed reactions, including Suzuki-Miyaura, Mizoroki-Heck and Sonogashira cross-couplings.[26]

203

Following a slightly modified literature procedure,[25] 2-bromo-1-ferrocenylbenzyl alcohol (7) was

204

treated with tetrahydroxydiboron B2(OH)4, SiliaCat DPP-Pd and AcOK in acetonitrile. Judging by

205

TLC, the starting material was completely consumed after 15 minutes, whereas the product formation

206

started after 1 hour. Extractive work-up of the overnight reaction, followed by chromatographical

207

resolution with a MeOH/DCM mixture as an eluent, afforded 3-ferrocenylbenzoxaborole (6) in an

208

isolated yield of 47%. Although the yield was almost 30% lower than in case of the reaction with the

209

XPhos Pd G2/XPhos catalytic system, the use of SiliaCat contributed to a much easier isolation of the

210

product by means of column chromatography.

211 212

2.2

Spectroscopic characterization

213

Among the obtained 2-halo-1-ferrocenylbenzyl alcohols 7, 9, 10 and 3-ferrocenyl-

214

benzoxaboroles 6 and 11, only 2-bromo-1-ferrocenylbenzyl alcohol (7) has been reported in the

215

literature before.[17] Hence, the unreported compounds were characterized by means of 1H NMR, 13C

216

NMR, FTIR as well as 11B NMR and 19F NMR where applicable. The obtained spectra unequivocally

217

confirmed the structures of the products. High purity of the samples was indicated by TLC analyses

218

and then confirmed by means of the elemental analyses.

219

Interestingly, the 1H NMR analyses of 3-ferrocenylbenzoxaboroles 6 and 11 suggested that the

220

compounds exist in more than one form in the acetone-d6 solutions. Aromatic, benzylic and ferrocenyl

221

protons emerged as pairs of signals, having an integration ratio of ca. 0.65:0.35 in each pair. When a

222

drop of D2O was added to each sample and the NMR spectra retaken, certain signals disappeared

223

while others slightly shifted (Fig. S1 in Supplementary Data).

224

According to literature precedents,[27,28] the addition of D2O to a boronic acid-containing

225

sample may result in the simplification of spectrum, with a reduction in the number of signals. In case

226

of phenylboronic acids, this phenomenon is explained by a D2O-induced shift in the equilibrium

227

between the mixture of a boronic acid and its boroxine (a cyclic, trimeric anhydride of boronic acid

228

formed under water-free conditions) and the boronic acid alone (as a consequence of the hydrolysis of

229

boroxine by D2O). In case of the systems described herein, a hydrolytic opening of the "closed"

230

benzoxaborole form, leading to the formation of an "open" 2-(hydroxymethyl)phenylboronic acid, was

231

hypothesized (Scheme 4).

232

233 234 235

Scheme 4. Hypothesized hydrolytic opening of the "closed" form of benzoxaborole 6 into its "open"

236

form in acetone.

237 238 239

This

phenomenon

was

further 19

supported

by

the

19

F

NMR

studies

of

3-ferrocenyl-5-fluorobenzoxaborole (11). F NMR spectrum of 11 in acetone-d6 showed two signals

240

with very similar chemical shifts: 111.3 and 110.9 ppm. After the addition of D2O, only the signal of δ

241

111.3 ppm remained in the spectrum.

242

In acetone-water solutions, benzoxaboroles have been shown to exist predominantly in the

243

"closed" oxaborole form.[29] In case of 3-ferrocenylbenzoxaboroles, however, the tendency to

244

equilibrate into the "open" form might be attributed to the bulky ferrocene scaffold. The steric demand

245

of ferrocene might cause considerable strain in the oxaborole ring, so that the "closed" form is

246

energetically disfavoured and the "open" form prevented from closing back.

247

Since the electrochemical experiments (Section 2.3) were carried out in acetonitrile, the

248

reaction was also probed in acetonitrile-d3 for benzoxaborole 11 as a representative compound.

249

Contrary to the 1H NMR spectrum of 11 in acetone-d6 (Section 4.2.2), the aromatic, benzylic and

250

ferrocenyl protons did not emerge as pairs of signals in acetonitrile-d3. Upon addition of D2O, no

251

disappearance of signals that could be attributed to those protons was observed. Not only does this

252

demonstrate the reaction to be solvent-dependent, but also proves acetonitrile an appropriate solvent

253

for electrochemical studies.

254 255

2.3

Electrochemical Study

256

It is known that, during electrode process, ferrocene (2) and its derivatives exchange one

257

electron in a reversible manner in organic and aqueous media.[30-32] To investigate the mechanism of

258

oxidation and reduction process of the ferrocene derivatives studied, the cyclic voltammograms in

259

acetonitrile were recorded at different scan rate range from 0.002 to 1 V·s-1. The cyclic

260

voltammograms of the examined derivatives exhibited well-defined oxidation and reduction peaks

261

corresponding to the Fe2+/3+ redox pair of ferrocene in the whole studied scan rate range. The

262

representative cyclic voltammetry (CV) curves for one selected scan rate of all ferrocene derivatives

263

studied are shown in Fig. 2. The parameters values used for the characterization of cyclic

264

voltammogram of fast, reversible and one-electron process are: (i) the peak potential separation ∆Ep =

265

Epa - Epc = 0.059 at 298 K [33] and (ii) the peak current ratio = Ipa/Ipc = 1 at all scan rates. The

266

determined electrochemical parameters are given in Table 3.

267

268 269 270

Figure 2.

Normalized (versus peak current) cyclic voltammograms of the studied ferrocenes,

271

recorded in acetonitrile. Experimental conditions: CFc derivatives = 1 mM, CTBAHFP = 50 mM, v = 0.1 V·s-1,

272

T = 21 °C.

273 274

Table 3. Electrochemical parameters of the studied ferrocenes estimated from cyclic voltammograms

275

recorded at scan rate equal 0.1 V·s-1 in acetonitrile.

276

Compound

Ipa [µ µA]

Epa [V]

Ipc [µ µA]

Epc [V]

Ipa/Ipc

∆Ep [V]

Ef [V]

7

23.5 ± 1.5

0.513

-(25.2 ± 1.3)

0.386

0.93

0.127

0.450

9

23.9 ± 2.1

0.588

-(24.0 ± 1.1)

0.449

0.99

0.139

0.519

10

24.6 ± 0.9

0.552

-(26.9 ± 1.4)

0.439

0.91

0.113

0.496

6

23.1 ± 1.3

0.569

-(24.4 ± 1.2)

0.442

0.95

0.127

0.506

11

25.0 ± 1.7

0.530

-(25.1 ± 1.5)

0.430

0.99

0.100

0.480

2

29.1 ± 1.9

0.488

-(30.8 ± 1.7)

0.376

0.95

0.112

0.432

277

For all the investigated ferrocene derivatives, the peak current ratio was very close to one,

278

which indicates the reversible character of the oxidation of ferrocene in the studied medium. The peak

279

potential separation was almost two times higher than for ideal reversible one electron process. It

280

should be noted that the metallocene redox potentials are strongly influenced by the nature of the

281

substituent(s) in the cyclopentadienyl ring as well as the type of solution. Metallocene-incorporating

282

electron-donating ligands exhibit more positive redox potentials compared to the complexes

283

containing the non-derivatized cyclopentadienyl rings. The discrepancy ∆Ep from the ideal value

284

(0.059 V) can be attributed to slow electron transfers and solution resistance.

285

The anodic and cathodic peak heights as function of the square root of the scan rate are shown

286

in Fig. S2 (see Supplementary Data). The ideal linear relationship of Ip versus (v)0.5 indicates clear

287

diffusion character of the electrode process of the studied compounds. The peak current of diffusion

288

controlled reversible or quasi-reversible electrochemical reaction is described by Randles–Sevcik

289

equation (Eq. 1): [33]

290

(1)

291

where: Ip is the peak current, n − the number of electron exchange during electrode process, A − the

292

surface area of the working electrode, D − the diffusion coefficient of the electroactive species, C0* −

293

the concentration of the electroactive species and v − the scan rate of voltammograms. Thus, the

294

diffusion coefficients for the studied ferrocene derivatives can be calculated from the slope of the plot

295

of anodic peak current versus square root of the scan rate, and are given in Table 4.

296

Table 4. Diffusion coefficients (DS) and regression coefficients: slope (a), intercept (b), correlation

297

coefficient (r) of linearized Ipa vs v0.5.

298

I p = 2.69 ⋅ 10 5 n 3 / 2 D 1 / 2 AC 0* v

DS·105

Compound

a ± s(a)

b ± s(b)

r

7

64.6 ± 0.9

2.37 ± 0.53

0.995

1.16 ± 0.01

9

66.9 ± 0.6

1.95 ± 0.33

0.998

1.24 ± 0.01

10

64.8 ± 1.0

3.24 ± 0.54

0.995

1.16 ± 0.01

6

64.8 ± 1.0

2.21 ± 0.52

0.995

1.16 ± 0.01

11

72.7 ± 0.6

1.62 ± 0.31

0.999

1.47 ± 0.01

2

83.0 ± 0.8

2.33 ± 0.40

0.998

1.91 ± 0.01

[cm2·s-1]

299

The value of diffusion coefficients strongly depends on the nature of the compound. The

300

presence of a large-volume substituent decreases the D value. Hence, the values of diffusion

301

coefficients for the studied ferrocene derivatives were smaller than the coefficient for unsubstituted

302

ferrocene determined under the same conditions.

303

To investigate the influence of the substituent on the constant rate of electron transfer, the

304

cyclic voltammograms were registered for sequentially increasing scan rate of polarization of the

305

electrode, so as to obtain a potential separation of the cathodic and anodic peaks more than 300 mV.

306

From the intercept of the dependences ln(Ipa) = f(Epa-Ef), the electron-transfer rate constants (k0, Table

307

5) were determined according to Eq. 2:

308

(2)

309

where: Ipa is the current intensity of the anodic peak, n − the number of electron exchange during

310

electrode process, F is Faraday constant, A − the electrode surface area, C0* − the concentration of the

311

electroactive species, Epa − the potential of the anodic peak, Ef − the formal potential, R is the gas

312

constant, T − temperature and α is the transition coefficient.

 αnF  I pa = 0.227 nFAC 0* k 0 exp − ( E pa − Ef )   RT 

313 314

Table 5. Electron-transfer rate constants (k0) and regression coefficients: slope (a), intercept (b),

315

correlation coefficient (r) of linearized ln(Ipa) vs (Epa-Ef). k0·103

Compound

a ± s(a)

b ± s(b)

r

7

17.3 ± 1.4

-11.7 ± 0.1

0.924

5.36 ± 0.44

9

19.3 ± 0.9

-12.0 ± 0.1

0.966

3.97 ± 0.52

10

20.4 ± 0.8

-11.7 ± 0.1

0.980

5.36 ± 0.44

6

21.2 ± 1.3

-12.1 ± 0.1

0.948

3.60 ± 0.72

11

30.8 ± 1.6

-12.3 ± 0.1

0.963

2.94 ± 0.63

2

31.8 ± 1.1

-12.2 ± 0.1

0.980

3.25 ± 0.24

[cm·s-1]

316 317

3

Conclusions

318

The method for preparation of hitherto unreported ferrocene derivatives of benzoxaborole has

319

been developed. Two 3-ferrocenylbenzoxaboroles, including a ferrocene analogue of the marketed

320

oxaborole-based drug Tavaborole, have been obtained in a two-step procedure. In the first step,

321

the intermediate 2-halo-1-ferrocenylbenzyl alcohols were obtained from the commercially available

322

ferrocenecarboxaldehyde

323

haloiodobenzene derivatives with Turbo Grignard reagent. The second step – found to be considerably

324

more challenging than initially anticipated – involved an optimized palladium-catalyzed borylation

325

with subsequent spontaneous oxaborole ring closure. The procedure does not require the use of any

326

protecting groups. All the obtained ferrocene derivatives have been characterized spectroscopically,

327

indicating a hydrolytic opening of the "closed" benzoxaborole system in acetone. Preliminary

328

electrochemical study, based on cyclic voltammetry measurements in acetonitrile, demonstrated the

329

reversible character of the one-electron oxidation in case of all studied compounds. Comparison of the

330

voltammetric profiles of 2-halo-1-ferrocenyl-benzylic alcohols and their oxaborole counterparts

331

revealed that the presence of an oxaborole ring affects their voltammetric parameters to a minor

332

extent.

333

3-ferrocenylbenzoxaboroles as redox-active molecular receptors.

The

via

results

the

lay

halogen-selective

the

basis

iodine-magnesium

for

further

transmetallation

investigation

of

of

334 335

4

Materials and Methods

336

4.1

General Information

337

All starting materials, reagents and undeuterated solvents were obtained from commercial

338

sources (Sigma-Aldrich, Fluorochem, Acros Organics, POCH, or Chempur), were of minimum 95%

339

purity and used as received, without further purification. Deuterated solvents were purchased from

340

Armar Chemicals.

341 342

The inert atmosphere of argon was provided by a triple vacuum/argon backfill cycle of the oven-preheated glassware.

343

The temperature of the low-temperature (-40 °C to 0 °C) reaction mixtures was maintained

344

with the use of Lauda ECO RE 1050 cooling thermostat. The mixtures were concentrated under

345

reduced pressure using Heidolph Hei-VAP rotary evaporator with Welch Dry Vacuum System 2025.

346

TLC analyses were performed on Merck Silica gel 60 F254 aluminium sheets, visualized under

347

UV light (254 nm), or by treatment with a staining solution followed by heating. An alkaline solutions

348

of potassium permanganate was used as the staining solution. Flash column chromatography was

349

carried out using Fluorochem 60A silica gel.

350

1

H,

11

B,

13

C and

19

F NMR spectra were recorded using Varian VNMRS 500 MHz

351

spectrometer, equipped with a multinuclear z-gradient inverse probe head. In all experiments, the

352

probe temperature was maintained at 25 °C. Standard 5 mm glass NMR tubes were used, except for

353

some 11B NMR experiments for which the samples were prepared in quartz tubes. Chemical shifts are

354

reported relative to residual undeuterated solvent peak (1H NMR),[34] solvent signal (13C NMR),[34]

355

or external references (BF3⋅Et2O in CDCl3 for

356

signals are reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t =

357

triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets, tdd =

11

B NMR and CFCl3 in CDCl3 for

19

F NMR). The

358

triplet of doublets of doublets, m = multiplet, br = broad signal), coupling constant (J, Hz; where

359

applicable), integration.

360

FTIR spectra were recorded in transmission mode using Thermo Nicolet Avatar

361

370 spectrometer. The samples of the analyzed compounds were mixed with potassium bromide and

362

formed

363

into

pellets

using

hydraulic

press.

Analytically

relevant

absorption

maxima

-1

(vmax, cm ) are reported.

364

Melting points were determined in open capillary glass tubes using a melting point apparatus

365

produced by Warsztat Elektromechaniczny J. Kawałkowski (Warszawa). The starting point was

366

recorded at the beginning of melting, whereas the ending point when the whole sample became liquid.

367 368

Elemental analyses were performed using CHNS Elementar Vario EL III apparatus. Each elemental composition is reported as an average of two analyses.

369 370

4.2

Synthesis and Characterization

371

4.2.1

General Procedure A – Preparation of 2-Halo-1-ferrocenylbenzyl Alcohols

372

The solution of i-PrMgCl⋅LiCl (1.3 M in THF, 1.00 eq.) was cooled down to -35 °C under

373

argon. Iodobenzene derivative (1.00 eq.) was added dropwise via syringe. The grey solution was

374

cooled down to -40 °C and stirred for 1.5 h. The solution of ferrocenecarboxaldehyde (2 M in

375

anhydrous THF, 1.00 eq.) was added to the reaction mixture via syringe. The resulting deep red

376

solution was stirred for 20 min at -40 °C, 20 min at -20 °C and 20 min at RT. Saturated aqueous

377

solution of NH4Cl was added resulting in solid formation. The suspension was stirred for 15 min and

378

diluted with EtOAc. The reaction mixture was extracted with EtOAc, combined organic layers washed

379

with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The

380

crude product was purified by flash column chromatography (hexane/EtOAc 14:1 v/v).

381 382

4.2.1.1 Synthesis of (2-Bromophenyl)ferrocenylmethanol / 2-Bromo-1-ferrocenylbenzyl Alcohol (7)

383

The title compound was prepared following General Procedure A, starting from

384

2-bromoiodobenzene (0.34 mL, 2.60 mmol). The product was obtained as an orange solid

385

(0.58 g, 1.56 mmol, 60%). TLC (SiO2; hexane/EtOAc 5:1 v/v; KMnO4 stain) Rf 0.46. 1H NMR (500

386

MHz, CDCl3) δ 7.61 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 (dd, J = 8.0, 1.5 Hz, 1H), 7.32 (td, J = 8.0, 1.5 Hz,

387

1H), 7.11 (td, J = 8.0, 2.5 Hz, 1H), 5.79 (d, J = 3.5 Hz, 1H), 4.41 (m, 1H), 4.26 (s, 5H), 4.21 (m, 1H),

388

4.17 (m, 1H), 4.14 (m, 1H), 2.65 (d, J = 3.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 142.4, 132.6,

389

128.9, 127.8, 127.5, 122.4, 93.8, 70.3, 68.5, 68.2, 67.8, 67.6, 66.3. FTIR (KBr) vmax 3515, 3430, 3076,

390

2923, 1434, 1242, 1045, 995, 823, 760, 688, 618. m.p. 107-109 °C. Elemental analysis: Calculated

391

for C17H15BrFeO: C, 55.03; H, 4.07. Found: C, 54.75; H, 4.23. The 1H and 13C NMR spectra are in

392

accordance with the analytical data reported in the literature.[35]

393

394

4.2.1.2 Synthesis

of

(2-Bromo-5-fluorophenyl)ferrocenylmethanol

/

2-Bromo-1-ferrocenyl-4-

395

fluorobenzyl Alcohol (9)

396

The title compound was prepared following General Procedure A, starting from 1-bromo-4-

397

fluoro-2-iodobenzene (1.96 g, 6.50 mmol). The product was obtained as an orange solid

398

(2.13 g, 5.48 mmol, 84%). TLC (SiO2; hexane/EtOAc 5:1 v/v; KMnO4 stain) Rf 0.51 1H NMR (500

399

MHz, CDCl3) δ 7.44 (dd, J = 9.0, 5.5 Hz, 1H), 7.37 (dd, J = 10.0, 3.5 Hz, 1H), 6.84 (dt,

400

J = 8.0, 3.0, 1.0 Hz, 1H), 5.70 (d, J = 2.0 Hz, 1H), 4.44 (m, 1H), 4.28 (s, 5H), 4.22 (td, J = 2.5, 1.5 Hz,

401

1 H), 4.17 (td, J = 2.5, 1.5 Hz, 1H), 4.12 (m, 1H), 2.68 (d, J = 3.5 Hz, 1H). 13C NMR (126 MHz,

402

CDCl3) δ 163.2, 161.2, 144.7, 133.7, 116.2, 115.0, 93.5, 70.1, 68.5, 68.3, 68.0, 67.8. 19F NMR (470

403

MHz, CDCl3) δ 113.9. FTIR (KBr) vmax 3549, 3081, 2916, 2358, 1464, 1408, 1363, 1269, 1019, 952,

404

897, 811, 628, 576. m.p. 84-86 °C. Elemental analysis: Calculated for C17H14BrFFeO: C, 52.48; H,

405

3.63. Found: C, 52.55; H, 3.53.

406 407

4.2.1.3 Synthesis of (2-Iodophenyl)ferrocenylmethanol / 2-Iodo-1-ferrocenylbenzyl Alcohol (10)

408

The title compound was prepared following General Procedure A, starting from

409

1,2-diiodobenzene (0.98 g, 2.97 mmol). The product was obtained as an orange solid

410

(0.82 g, 1.96 mmol, 66%). TLC (SiO2; hexane/EtOAc 5:1 v/v, KMnO4 stain) Rf 0.43. 1H NMR (500

411

MHz, CDCl3) δ 7.78 (dd, J = 8.0, 1.0 Hz, 1H), 7.56 (dd, J = 8.0, 1.5 Hz, 1H), 7.35 (td, J = 7.5, 1.0 Hz,

412

1H), 6.95 (td, J = 7.5, 1.0 Hz, 1H), 5.63 (d, J = 3.5 Hz, 1H), 4.45 (m, 1H), 4.27 (s, 5H), 4.22 (m, 1H),

413

4.17 (m, 1H), 4.13 (m, 1H), 2.67 (d, J = 4.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 148.6, 139.8,

414

129.9, 129.4, 98.5, 94.5, 75.9, 69.4, 68.5,67.8, 67.3. FTIR (KBr) vmax 3525, 3059, 2900, 2362, 1562,

415

1460, 1360, 1186, 1007, 920, 821, 744, 651, 535. m.p. 89-91 °C. Elemental analysis: Calculated for

416

C17H15FeIO: C, 48.84; H, 3.62. Found: C, 48.73; H, 3.53.

417 418

4.2.1

Synthesis of 3-Ferrocenylbenzo[c][1,2]oxaborol-1(3H)-ol (6)

419

4.2.1.1 Preparation with the use of XPhos Pd G2 Catalyst

420

2-(Bromophenyl)ferrocenylmethanol (7) (189 mg, 0.51 mmol, 1.00 eq.), tetrahydroxydiboron

421

(137 mg, 1.53 mmol, 3.00 eq.), XPhos Pd G2 (36 mg, 0.077 mmol, 0.15 eq.), XPhos (120 mg, 0.15

422

mmol, 0.3 eq.) and AcOK (150 mg, 1.53 mmol, 3.00 eq.) were suspended in degassed, anhydrous

423

EtOH (8 mL) at RT. The resulting orange suspension was heated up under argon to 80 °C and stirred

424

at this temperature for 2 h. The reaction mixture was cooled down to RT and filtered through a pad of

425

Celite. The filtrate was transferred into a separatory funnel and washed with water (20 mL). The

426

aqueous layer was extracted with AcOEt (3 x 10 mL). The combined organic layers were washed with

427

brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced

428

pressure. The crude material (red oil) was subjected to three consecutive resolutions by flash column

429

chromatography: (1) hexane/AcOEt 10:1 to 3:1 v/v; (2) hexane/AcOEt 8:1 v/v; (3) DCM/MeOH 100:1

430

v/v. The product was obtained as an orange oil (120 mg, 0.38 mmol, 74%). TLC (SiO2; hexane/EtOAc

431

5:1 v/v; UV, KMnO4 stain) Rf 0.26. 1H NMR (500 MHz, acetone-d6) δ 8.23 (s, 0.49H), 7.74 (m,

432

0.70H), 7.67 (m, 0.33H), 7.50 (m, 2H), 7.36 (m, 1H), 6.05 (s, 0.29H), 6.00 (s, 0.64H), 4.29 (q, J = 1.5

433

Hz, 0.31H), 4.25 (q, J = 2.0 Hz, 0.66H), 4.18 (m, 1H), 4.17 (s, 2H), 4.15 (m, 5H). 1H NMR (500

434

MHz, acetone-d6 + D2O) δ 7.76 (d, J = 7.00 Hz, 1H), 7.49 (m, 2H), 7.35 (m, 1H), 5.98 (s, 1H), 4.24 (q,

435

J = 1.50 Hz, 1H), 4.18 (q, J = 1.5 Hz, 1H), 4.15 (s, 5H), 4.12 (t, J = 1.5 Hz, 2H). 13C NMR (126 MHz,

436

acetone-d6 + D2O) δ 157.0, 130.4, 130.3, 127.1, 122.1, 89.8, 79.0, 68.5, 67.9, 67.3, 66.6, 65.7.

437

NMR (160 MHz, acetone-d6) δ 32.2. FTIR (KBr) vmax 3318 (br), 3100, 2919, 2361, 1609, 1481, 1434,

438

1284, 1204, 1105, 972, 821, 719, 630, 504. m.p. 122-125 °C. Elemental analysis: Calculated for

439

C17H15BFeO2: C, 64.22; H, 4.76. Found: C, 64.28; H, 4.72.

11

B

440 441

4.2.1.2 Preparation with the use of SiliaCat DPP-Pd Catalyst

442

2-(Bromophenyl)ferrocenylmethanol (7) (100 mg, 0.27 mmol, 1.00 eq.), tetrahydroxydiboron

443

(48 mg, 0.54 mmol, 2.00 eq.) and AcOK (53 mg, 0.54 mmol, 2.00 eq.) were suspended in degassed,

444

anhydrous

445

0.10 eq.) was added in one portion. The reaction mixture heated up to 80 °C under argon and stirred at

446

this temperature for 18 h. The resulting yellow suspension was diluted with MeCN

447

(3 mL), filtered through a pad of Celite and concentrated under reduced pressure. The crude material

448

(orange oil) was purified by flash column chromatography (DCM/MeOH 0.75:100 v/v). The product

449

was obtained as an orange oil (40 mg, 0.13 mmol, 47%).

450

TLC (SiO2; hexane/EtOAc 5:1 v/v; UV, KMnO4 stain) Rf 0.30. 1H NMR (500 MHz, acetone-d6 +

451

D2O) δ 7.74 (d, J = 7.0 Hz, 1H), 7.50 (m, 2H), 7.36 (tdd, J = 7.0, 1.5, 0.5 Hz, 1H), 6.00

452

(s, 1H), 4.26 (q, J = 2.0 Hz, 1H), 4.18 (q, J = 2.0 Hz, 1H), 4.15 (s, 5H), 4.13 (t, J = 1.5 Hz, 2H).

MeCN

(1.4

mL)

at

RT.

SiliaCat

DPP-Pd

(90

mg,

0.027

mmol

Pd,

453 454 455

4.2.2

Synthesis of 3-Ferrocenyl-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (11) (2-Bromo-5-fluorophenyl)ferrocenylmethanol

(9)

(198

mg,

0.51

mmol,

1.00

eq.),

456

tetrahydroxydiboron (137 mg, 1.53 mmol, 3.00 eq.), XPhos Pd G2 (36 mg, 0.077 mmol,

457

0.15 eq.), XPhos (120 mg, 0.15 mmol, 0.30 eq.) and AcOK (150 mg, 1.53 mmol, 3.00 eq.) were

458

suspended in degassed, anhydrous EtOH (8 mL) at RT. The resulting orange suspension was heated up

459

under argon to 80 °C and stirred at this temperature for 2 h. The reaction mixture was cooled down to

460

RT and filtered through a pad of Celite. The filtrate was transferred into a separatory funnel and

461

washed with water (20 mL). The aqueous layer was extracted with AcOEt (3 x 10 mL). The combined

462

organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and

463

concentrated under reduced pressure. The crude material (red oil) was purified by flash column

464

chromatography (DCM to DCM/MeOH 100:1 v/v). The product was obtained as an orange solid (160

465

mg, 0.48 mmol, 93%). TLC (SiO2; hexane/EtOAc 5:1 v/v, KMnO4 stain) Rf 0.27.

H NMR (500 MHz, acetone-d6) δ 8.23 (s, 0.42H), 7.77 (m, 0.64H), 7.69 (m, 0.40H), 7.21 (m, 1H),

466

1

467

7.14 (m, 1H), 6.04 (s, 0.31H), 5.99 (s, 0.62H), 4.34 (m, 0.34H), 4.30 (m, 0.63H), 4.17 (m, 8H). 1H

468

NMR (500 MHz, acetone-d6 + D2O) δ 7.79 (br, 1H), 7.20 (br, 1H), 7.12 (br, 1H), 5.97 (br, 1H), 4.28

469

(br, 1H), 4.15 (br, 8H). 1H NMR (500 MHz, acetonitrile-d3) δ 7.75 (m, 1H), 7.19 (m, 1H), 7.13 (m,

470

1H), 6.77 (s, 0.66 H), 5.99 (s, 1H), 4.20 (m, 1H), 4.16 (m, 8H). 1H NMR (500 MHz, acetonitrile-d6 +

471

D2O) δ 7.74 (m, 1H), 7.19 (m, 1H), 7.11 (m, 1H), 5.95 (s, 1H), 4.16 (m, 1H), 4.13 (m, 8 H). 13C NMR

472

(126 MHz, acetone-d6 + D2O) δ 165.7, 163.7, 159.4, 132.6, 132.5, 114.8, 114.7, 109.2, 109.0, 89.2,

473

78.6, 68.6, 68.0, 67.5, 66.6. 11B NMR (160 MHz, acetone-d6) δ 31.4. 19F NMR (470 MHz, acetone-d6

474

+ D2O) δ 111.3. FTIR (KBr) vmax 3294, 3093, 2916, 2358, 1611, 1436, 1231, 1104, 914, 824, 726,

475

631,

476

C, 60.78; H, 4.20. Found: C, 60.56; H, 4.00.

508.

m.p.

94-96

°C.

Elemental

analysis:

Calculated

for

C17H14BFFeO2:

477 478

4.3

Electrochemical Studies / Experimental Setup for Electrochemical Studies

479

Cyclic voltammetric (CV) experiments were carried out using an Autolab potentiostat

480

PGSTAT 12, in a three-electrode system. The disc glassy carbon electrode (φ = 3 mm) was used as a

481

working electrode. As the reference and counter electrodes, the Ag/AgCl/3 M KCl and platinum plate

482

were used, respectively. All experiments were carried out in acetonitrile with the addition of an excess

483

of tetrabutylammonium hexafluorophosphate (TBAHFP). The concentration of the investigated

484

ferrocene derivatives was 1 mM.

485 486

Acknowledgments

487

The corresponding author would like to thank Mr Artur Kasprzak (Faculty of Chemistry, Warsaw

488

University of Technology) for insightful discussions, sharing his experience in the chemistry of

489

ferrocene as well as his assistance with NMR measurements.

490 491

Funding

492

This work was supported by the National Science Centre of Poland within the PRELUDIUM grant

493

No. 2015/19/N/ST5/00745 to K.M.B. Financial support from the National Science Centre of Poland

494

within the ETIUDA doctoral scholarship No. 2017/24/T/ST5/00298 to K.M.B. is also acknowledged.

495 496

Conflict of Interest

497

The authors declare no conflict of interest.

498 499

Appendix A. Supplementary data

500

Supplementary data to this article can found online at [DOI].

501 502

503

References

504

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549 550

experimental-computational

study

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Highlights •

A two-step method for the preparation of 3-ferrocenylbenzoxaborole is reported.

•

Ferrocenecarboxaldehyde was used as the starting material.

•

2-Halo-1-ferrocenylbenzyl alcohols served as synthetic intermediates.

•

Two 3-ferrocenylbenzoxaboroles were synthesized and characterized.

•

Preliminary electrochemical studies of the obtained compounds were carried out.

Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: