Mono-Boron Calixphyrins from Aryl Boron Halides 

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Chapter 3 Mono-Boron Calixphyrins from Aryl Boron Halides

Introduction

The objectives of the work described in this chapter are to synthesise mono-boron calixphyrins using PhBX₂ (X = F, Cl) as the boron reagent rather than BF₃^.Et₂O. PhBCl₂ has been used to synthesise a mono-boron corrole compound, PhBH[H₂(Cor)], however it is believed to have arisen from the hydrolysis of the di-boron PhBHBPh(Cor) complex rather than via the insertion of a single boron.¹ Several other mono-boron porphyrinoid compounds synthesised from PhBCl₂ using triphyrin,² oxatriphyrin^3,4 and N-confused porphyrins⁵ have also been reported (Figure 3.1). Given that the reaction with BF₃^.Et₂O showed that calixphyrins preferentially formed mono-boron species over di-boron species at lower temperatures, it is likely that the reaction with PhBX₂ using similar conditions will yield mono-boron calixphyrins that represent new classes of boron porphyrinoid complexes.

Unexpected Reduction of Calixphyrin to form PhBH[H₂(Calix)]

Observations

Initial experiments used H₂(DMPTCx) as the ligand and the conditions used for the synthesis of BF₂[H(DMPTCx)] were duplicated except for replacing BF₃^.Et₂O with PhBCl₂. The ratio of PhBCl₂ to H₂(DMPTCx) was dropped from 15 to 10 molar excess since PhBCl₂ is more reactive than BF₃^.Et₂O. No boron coordination was observed when using NEt₃ as a base so N(ⁱPr)₂Et was employed instead. The addition of 10 eq. of PhBCl₂ to the reaction mixture turned the solution dark red, consistent with the formation of the protonated calixphyrin salt. Upon the addition of excess N(ⁱPr)₂Et, the solution immediately turned bright pink, unusual compared to the dark brown colour that is normally observed. TLC of the reaction mixture in CH₂Cl₂ showed that the mysterious pink compound formed straight away and was the major product of the reaction. After 30 minutes, no change is observed in the TLC and all of the starting material had been consumed indicating that this reaction is faster and more efficient compared to the BF₃^.Et₂O reactions which required overnight stirring and often left unreacted H₂(DMPTCx). When using a less polar solvent combination for TLC such as toluene:n-hexane 4:6, it was noted that there were actually two pink compounds that eluted very close together. The two compounds could be separated via column chromatography although this proved tricky due to their identical colour and their tendency to streak and overlap with each other. Repeated chromatography was often required to fully separate the two compounds. The combined yield of the two compounds was typically over 60%.
HRMS and NMR confirmed that the two compounds were isomers of each other. HRMS showed a peak at 637.3541 m/z which was consistent with the formulation PhBH[H(DMPTCx)]H⁺, the protonated form of PhBH[H(DMPTCx)], which was surprising given that the expected product was anticipated to be PhBCl[H(DMPTCx)] (672.3191 m/z) resulting from addition of PhBCl₂ and elimination of HCl, or PhBOH[H(DMPTCx)] (654.3530 m/z) arising from the hypothetical hydrolysis of the B-Cl bond. Even more perplexing was that the ¹H NMR spectrum did not match the proposed formulation, exhibiting two triplets and two doublets in the β-pyrrole region (rather than the expected four doublets), a new unknown singlet and a dramatic upfield shift of the internal N-H signal from ~14 ppm to ~8.2 ppm that integrated to two protons rather than one. COSY and NOESY NMR were able to establish that the new singlet belonged to a new meso-proton at one of the former sp²–meso carbons so during the course of the reaction, the calixphyrin ligand had been reduced so it now contained one sp²–meso carbon and three sp³–meso carbons, thus becoming a porphomethene calix[4]phyrin (1,1,1,1); “Calix” specified in italics to denote the reduced formulation (Scheme 3.1). The final product was deduced to have the PhBH moiety coordinated to the one remaining dipyrrin site and was assigned the structure PhBH[H₂(DMPTCx)]. This structure was subsequently confirmed by X-ray crystallography. Re-evaluating the HRMS data, the peak that was believed to be PhBH[H₂(DMPTCx)]⁺ is actually PhB⁺[H₂(DMPTCx)] with the loss of the B-H hydride generating the observed m/z. This also confirmed the hydridic nature of this hydrogen.
The reaction using H₂(CHPTCx) behaved in the same way as DMPTCx and gave two isomers of PhBH[H₂(CHPTCx)]. However, the PFP-substituted calixphyrins behaved differently compared to the p-tolyl calixphyrins. When using H₂(DMPFPCx), the reaction did not proceed at room temperature since [H₄(DMPFPCx)]²⁺ would precipitate out first. When refluxing chloroform is used, the reaction is completed in 30 minutes. Unlike with H₂(DMPTCx), the reaction is not clean with several pink coloured products forming, some only in trace quantity. There was one major pink product that could be isolated after several columns to remove the other pink by-products. According to ¹H NMR it had much lower symmetry than any previously isolated boron calixphyrin product so it was not the DMPFPCx analogue of PhBH[H₂(DMPTCx)]. However, HRMS indicated that it did contain a PhB moiety. When using H₂(CHPFPCx) as the ligand, only a trace of any possible product could be isolated and the NMR signals were too weak to assign a structure. Also, CHPFPCx was more resistant to reduction with the majority of the starting material returned unchanged. The reduction of a porphyrinoid ligand via the incorporation of a new meso-proton during boron complexation had been observed before by Latos-Grażyński when PhBCl₂ was inserted into oxatriphyrin in the presence of NEt₃. However, no reaction mechanism was proposed for their observations and the reduction was attributed to the addition of excess NEt₃ which was claimed to behave as a reductant.^3,4 Their observations are consistent with the incorporation of a new meso-proton in PhBH[H₂(Calix)], however it does not explain the origin of the B-H bond. Boron porphyrinoids with B-H bonds have been observed before, however none of their syntheses can explain the observations here (Figure 3.2). In boron corrole chemistry, the incorporation of a B-H-B bridge is believed to occur through the spontaneous reductive coupling of the presumed intermediate (PhBCl)₂(Cor) where the chlorides are lost and a hydride gained, presumably by addition of a proton from [HN(ⁱPr)₂Et]⁺ to a putative [(PhBBPh)(Cor)]^– intermediate. The reductive coupling step is believed to be induced by the steric demands from the two boron-phenyl groups.⁶ For PhBH[H₂(Calix)], there is no steric demand from a second boron-phenyl group so this cannot explain the observations in this case. Other examples are the subporphyrinato boron hydride complexes; however, the synthesis of the B-H bond was deliberately done by using DIBAL-H as a hydride source.⁷

Insights into the Reaction Mechanism

The reduction of the calixphyrin during boron complexation as well as the boron-hydride bond was unexpected given that the use of N(ⁱPr)₂Et during reactions with BF₃^.Et₂O did not result in any reduction. Proposing a possible mechanism for this reaction was extremely difficult since there was very little precedent in the literature and it was not known whether the reduction was due solely to the PhBCl₂, the N(ⁱPr)₂Et or the combination of both. Although no mechanism is proposed here, several reaction conditions were tried and experiments attempted in the hope that they could provide information on a possible mechanism for this unusual reduction.

Reaction Stoichiometry and Order of Reagents

The reaction typically used 10 equivalents of both PhBCl₂ and N(ⁱPr)₂Et. When the amount of PhBCl₂ and N(ⁱPr)₂Et is halved (i.e. 5 equivalents) no reaction is observed. When an excess of PhBCl₂ is used, the reaction does not proceed since the mixture presumably becomes too acidic for boron complexation to occur. However, when excess N(ⁱPr)₂Et is added, the reduction proceeds as usual thus confirming that an excess of N(ⁱPr)₂Et is required to induce the reduction reaction. Another interesting observation is that the order of the reagents added had no impact on the reaction pathway. Usually PhBCl₂ was added first before N(ⁱPr)₂Et. However, reactions where PhBCl₂ was added after N(ⁱPr)₂Et also led to instant reduction which implies that PhBCl₂ also has a role to play.

Use of Solvent

The reaction solvent was CH₂Cl₂ which has two protons. If there is possible donation of these protons to the final products, this could explain the origin of the B-H hydride or the meso-proton. The reaction was repeated in CDCl₃ and a control reaction was done in CHCl₃. NMR of the crude material of both reactions were identical and the final products from the reaction using CDCl₃ as the solvent showed that all of the signals from the products were present as protons, including the B-H bond and meso-proton. Hence it is possible to eliminate the solvent as the source of the hydride or meso-proton. The reduction was also found to proceed readily using toluene as the solvent instead.

Use of Bases Other Than N(ⁱPr)₂Et

One thing that needed to be tested was whether other bases also gave the reduced calixphyrin products when PhBCl₂ was the boron reagent. It was known from earlier experiments that the use of NEt₃ resulted in no product forming so it was possible to exclude this base. The closely related secondary amine HN(ⁱPr)₂ was tried; however, the starting material was returned unchanged and a large amount of white precipitate had formed indicating that adduct formation between HN(ⁱPr)₂ and PhBCl₂ had preferentially occurred instead. Similarly, the use of pyridine also failed to produce any boron calixphyrin product. Changing focus back to sterically hindered amines, it was proposed that the use of an amine that cannot act as a reductant should avoid the reduction product. Since the oxidation of tertiary amines typically proceeds through the extraction of an α-proton, an amine that does not contain α-protons should be sufficient. For this, 2,6-lutidine, a sterically hindered pyridine was utilised. The reaction was repeated as usual using H₂(DMPTCx) as the ligand but 2,6-lutidine replaced N(ⁱPr)₂Et. The solution did not turn pink upon the addition of base but went a darkish brown colour which is similar to other mono-boron calixphyrin reactions. After 30 minutes of stirring, the reaction was worked-up and the resulting residue purified by chromatography. A mixture of several boron calixphyrin products with very similar R_f values co-eluted with each other which were unable to be separated via repeated chromatography. The major product in the mixture was determined by NMR as having a PhBCl moiety coordinated to the dipyrromethane bonding site, PhBCl[H(DMPTCx)] (Scheme 3.2). This structure as well as the B-Cl bond was confirmed using X-ray crystallography. HRMS of the mixture showed only one peak corresponding to PhBCl[H(DMPTCx)] so the other boron calixphyrin products in the mixture most likely also have this formula. Not only was there no reduction of the ligand, the final product did not contain a boron-hydride bond. Since the reduction only occurred using N(ⁱPr)₂Et as the base, it can be assumed that the reduction is unique to N(ⁱPr)₂Et although more sterically hindered amines need to be tested before this can be fully established.

Role of N(ⁱPr)₂Et

Although N(ⁱPr)₂Et is typically used as a base, under the right conditions it can also behave as a reductant. N(ⁱPr)₂Et has been demonstrated to participate in hydrogen transfer reductions via the donation of an α-proton to the oxidant. For example, Kotani and co-workers demonstrated that N(ⁱPr)₂Et could act as a hydride donor to α,β-unsaturated ketones in the presence of a Lewis acid such as SiCl₃OTf or TiCl₄.^8,9 The N(ⁱPr)₂Et is oxidised to give an iminium ion which can rearrange into a neutral enamine or be hydrolysed into a secondary amine and an aldehyde by-product. Since there are two different alkyl chains in N(ⁱPr)₂Et, the ethyl and iso-propyl, two pathways for oxidation exist. For N(ⁱPr)₂Et, the loss of the α-proton from the ethyl group is usually observed.¹⁰
To probe the possibility of a hydrogen transfer reduction, a deuterium labelling experiment was attempted to see whether there was a transfer of an α-proton to calixphyrin. Since the α-proton on the ethyl was most likely to be transferred, the deuterium was attached here (Scheme 3.3). Firstly, acetic anhydride was reacted with diisopropylamine in the presence of DMAP to give the corresponding amide. The amide was reduced using LiAlD₄ to give N(ⁱPr)₂(CD₂CH₃) with deuterium at the α-ethyl position. ¹H NMR analysis of the resulting oil confirmed the presence of deuterium since the ethyl α-proton signals were missing. This base was then used in the reaction with calixphyrin and PhBCl₂. All peaks were visible as protons in the ¹H NMR spectrum of the resulting products which infers that no transfer of deuterium occurred.
Since the deuterium labelling experiment did not show a transfer of deuterium from the ethyl group on N(ⁱPr)₂(CD₂CH₃), the amine by-products were investigated instead to see whether another mechanistic pathway could be observed. A reaction mixture using N(ⁱPr)₂Et was quenched using D₂O and this D₂O fraction analysed using NMR and HRMS. Reference spectra of N(ⁱPr)₂Et, [DN(ⁱPr)₂Et]⁺ (protonated using DCl) as well as a possible by-products, HN(ⁱPr)₂ and [H₂N(ⁱPr)₂]⁺ were also recorded in D₂O for comparison. HRMS in positive ion mode showed a large peak at 131 m/z, consistent with [DN(ⁱPr)₂Et]⁺ however a smaller peak at 129 m/z is consistent with an oxidised [DN(ⁱPr)₂Et-2H]⁺ by-product; most likely an enamine. The ¹H NMR spectrum showed new peaks including a septet at 4.39 ppm, a quartet at 3.56 ppm and new signals at ~2.25 ppm as well as several other trace products (Figure 3.3). The chemical shifts of the new peaks did not match with any of the four reference spectra recorded above so these could be ruled out. Furthermore, the chemical shift of the by-product observed is similar to that of previously synthesised enamines.¹¹ When the integrals of the septet and quartet are compared, they indicate that the by-product has one ethyl group and one iso-propyl group which raises the possibility that the oxidation of N(ⁱPr)₂Et occurred via extraction of the α-proton on one of the iso-propyl groups rather than the ethyl group as expected. This could explain why no deuterium transfer was observed for N(ⁱPr)₂(CD₂CH₃).
A second mechanism is possible where N(ⁱPr)₂Et can act as a reductant via a radical mechanism rather than an ionic process. Several examples are known in the literature including the famous TiCl₄/(N(ⁱPr)₂Et aldol addition reaction and photoinduced electron transfer.^12,13 A reaction was done where excess 2,6-di-tert-butyl-4-methylphenol (BHT) was added as a potential radical scavenger, assuming that the reduction of calixphyrin would be supressed if the reduction occurred via a radical mechanism. However, upon slow addition of N(ⁱPr)₂Et, the reaction mixture turned pink and the same products as before were isolated; thus the reduction had not been supressed. Although this does not fully exclude a radical mechanism, it makes it more likely that the reduction is due to an ionic process.

Use of Boron Reagents Similar to PhBCl₂

Among the Lewis acidic boron reagents used to synthesise boron calixphyrins, PhBCl₂ is unique in the respect that a reduction of the ligand occurs during coordination. No reduction was observed when BF₃^.Et₂O was used to synthesise mono-boron calixphyrins even with N(ⁱPr)₂Et as the base, hence the boron is involved in the reduction process. There are two notable differences between the two boron reagents. Firstly, PhBCl₂ has more labile B-Cl bonds compared to stronger B-F bonds. Secondly, PhBCl₂ is more sterically hindered due to the phenyl ring.
The first experiment was to see whether the weaker B-Cl bonds contributed to the reduction so the boron reagent was changed to BCl₃. A 1 mol L^-1 solution of BCl₃ in CH₂Cl₂ was added to a solution of calixphyrin in CH₂Cl₂ followed by N(ⁱPr)₂Et. The reaction did not turn pink but stayed a dark red colour throughout. A small amount of a possible di-boron calixphyrin product B₂O(OH)₂(DMPTCx) was detected by HRMS of the crude mixture; however, most of the starting free-base calixphyrin (> 80%) was returned unchanged. It was also possible to isolate several bright orange and pink coloured bands via chromatography, albeit in very low yields and not sufficient for NMR analysis. Positive ion HRMS of one of the bands returned an m/z of 551.3186. When compared to the free-base H₂(DMPTCx) which is detected as [H₃(DMPTCx)]⁺ in HRMS and has m/z 549.2943, this was consistent with the incorporation of two protons into H₂(DMPTCx) to form H₃(DMPTCx), the free-base form of the reduced ligand (Scheme 3.4). Despite the extremely low yields of reduction products, this indicated that the weaker B-Cl bonds could be a factor in the reduction.
Further reactions were carried out see whether other boron reagents with the formula PhBX₂ underwent the reduction reaction. This would determine if steric effects from the coordination of a bulky phenyl boron moiety to calixphyrin was driving the reduction. This was a presumed reason given for the reduction of oxatriphyrin during the reaction with PhBCl₂.^3,4 PhBF₂ was chosen as a reagent due to the stronger B-F bonds which in BF₃^.Et₂O had been shown to not form reduced products. No B-H bond formation was observed in the corresponding boron corrole chemistry when PhBF₂ was used as a reagent.¹⁴ PhBF₂ was synthesised by refluxing PhBCl₂ in NaBF₄ for one hour and distilling the resulting liquid.¹⁵ PhBF₂ fumes and decomposes rapidly upon exposure to air so had to be handled under strictly anhydrous conditions. The PhBF₂ was added to a solution of H₂(DMPTCx) in dry CH₂Cl₂ followed by the addition of N(ⁱPr)₂Et. The reaction turned a brown colour which was consistent with the formation of a mono-boron calixphyrin without reduction. TLC indicated only one product had formed and there were no pink bands. The product was isolated via chromatography and using NMR and HRMS assigned as PhBF[H(DMPTCx)], an analogue of BF₂[H(DMPTCx)] (Scheme 3.5). X-ray crystallography confirmed this assignment. The use of PhBF₂ as the boron reagent avoided the reduction step which indicated that steric hindrance alone is not a factor in the reduction.

Table of Contents
Abstract 
Acknowledgements 
List of Figures 
List of Schemes
List of Tables 
List of Abbreviations and Symbols 
Chapter 1: Introduction 
1.1: Porphyrins and Porphyrinoids
1.2: Calixphyrins
1.3: Phthalocyanines and Porphyrazines
1.4: Boron Porphyrinoids
1.5: Potential Applications of Boron Porphyrinoids .
1.6: Objectives of PhD Thesis
1.7: Notes on Terminology used in Thesis
1.8: References for Chapter 1
Chapter 2: Mono-Boron Calixphyrins from Boron Trifluoride
2.1: Introduction
2.2: Preparation of BF2[H(Calix)]
2.3: Preparation of BF2[H(Calix)]
2.4: Preparation of BF2[H2(PFPCx)]
2.5: Summary
2.6: Experimental
2.7: References for Chapter 2
Chapter 3: Mono-Boron Calixphyrins from Aryl Boron Halides 
3.1: Introduction
3.2: Unexpected Reduction of Calixphyrin to form PhBH[H2(Calix)]
3.3: Characterisation of Other Mono-Boron Calixphyrins with Coordinated PhBX (X = H, F, Cl)
3.4: Summary
3.5: Experimental Procedures
3.6: References for Chapter 3
Chapter 4: Di-Boron Calixphyrins 
4.1: Introduction
4.2: Preparation of B2OF2(Calix)
4.3: Di-Boron Calixphyrins from PhBCl2
4.4: Summary
4.5: Experimental Procedures
4.6: References for Chapter 4
Chapter 5: Boron Porphyrazines 
5.1: Introduction
5.2: Boron Porphyrazines from Boron Trihalides
5.3: Boron Porphyrazines from PhBCl2
5.4: Functionalisation of Boron Porphyrazines
5.5: Summary
5.6: Experimental Procedures
5.7: References for Chapter 5
Chapter 6: Boron Phthalocyanines 
6.1: Introduction
6.2: Boron Phthalocyanines from Boron Trihalides
6.3: Boron Phthalocyanines from PhBCl2
6.4: Synthesis of PhBOBPh(Pc)
6.5: DFT Calculations
6.6: Summary
6.7: Experimental Procedures
6.8: References for Chapter 6
Chapter 7: Summary and Future Work 
7.1: Boron Calixphyrins
7.2: Boron Porphyrazines
7.3: Boron Phthalocyanines
Bibliography
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Synthesis of Boron Porphyrinoids