Synthesis and stereochemistry of chiral aza-boraspirobifluorenes with tetrahedral boron-stereogenic centers

Abstract

We have synthesized chiral aza-boraspirobifluorenes and evaluated their structural and photophysical properties. Enantiomers were separated by chiral HPLC on a semi-preparative scale, and the absolute stereochemistry was determined by comparison of experimental circular dichroism (CD) spectra and theoretical electronic CD (ECD) spectra. A kinetic analysis combined with theoretical calculations revealed that the rate-determining step of the racemization involves the cleavage of the B–N bond.

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Introduction

Chiral tetrahedral boron compounds are promising optical materials^1–4 that exhibit circular dichroism (CD) or circular polarized luminescence (CPL), and that have been applied for stereoselective transformations.^5–12 A classic tetrahedral borane with four B–C bonds (BC₄) was reported by Torssell in 1962 (Fig. 1a).¹³ Due to the high stability of the B–C bonds, BC₄ boranes exhibit high stereochemical stability.¹⁴ To date, chiral tetrahedral boranes with B–N,^15–27 B–O,^28–31 B–H,^32,33 and boron–heteroatom^34–37 bonds have been synthesized and the stereochemistry of the compounds has been studied extensively. For example, Toyota has reported stable chiral tetrahedral boranes with three B–C bonds and one B–N bond (BC₃N), and examined the racemization process (Fig. 1b).³⁸ Here, the cleavage of the B–N bond is the rate-determining step. Recently, He has reported the enantioselective synthesis of BC₃N and BC₂N₂ boranes via asymmetric copper-catalyzed azide–alkyne cycloaddition (CuAAc) reactions and studied their stereochemical stability.³⁹

Fig. 1 (a) Chiral tetrahedral boranes with four B–C bonds (BC₄) reported by Torssel et al.; (b) chiral tetrahedral boranes with three B–C bonds and one B–N bond (BC₃N); (c) an achiral spiro BC₃N borane (aza-boraspirobifluorene); (d) this work: chiral spiro BC₃N boranes.

Aza-boraspirobifluorenes, synthesized first by Ingleson et al. in 2015,⁴⁰ are neutral tetrahedral boranes with a BC₃N framework, in which the boron atom links an orthogonal π-conjugated pair of a borafluorene and an aza-borafluorene (Fig. 1c). Fukagawa et al. have applied these chemicals to organic fluorescent materials, i.e., OLEDs.^41–43 We envisioned that chiral aza-boraspirobifluorenes, whose optical resolution and stereochemical stability have not yet been reported,⁴⁴ could be synthesized from substituted borafluorenes (Fig. 1d). In the present study, we synthesized chiral aza-boraspirobifluorenes and evaluated their stereochemical stability. The mechanism of the racemization process is discussed based on the obtained kinetic data. The photophysical properties, including circular dichroism (CD) spectra of the homochiral compounds, were also studied.

Results and discussion

We synthesized chiral aza-boraspirobifluorene analogue 1 by two methods (Tables 1 and 2). Compound 1a was obtained in 35% yield by the reaction of 2-(2-(dibromoboraneyl)phenyl)pyridine (2)⁴⁵ with an excess (4.0 equiv.) of Grignard reagent 3a (Table 1, entry 1). Other substituted aza-boraspirobifluorenes (1b–e) were obtained from the reaction of 2 with the corresponding Grignard reagents (3b–e) in 18–40% yield (entries 2–6).⁴⁶ The methoxy-substituted compounds 1b and 1e were obtained in higher yield than the other products (entries 2 and 5).

Table 1 Synthesis of aza-boraspirobifluorenes 1a–f

Entry	Reagent	R^1	R^2	1	Yield (%)
a The Grignard reagent was prepared by the reaction of the dibromobiphenyl derivatives, I2-activated Mg, DIBAL-H, and LiCl.
1	3a	H	H	1a	35
2	3b	H	H	1b	40
3	3c ^a	H	H	1c	20
4	3d	Me	H	1d	18
5	3e	OMe	H	1e	40
6	3f ^a	CF3	H	1f	15

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Table 2 Synthesis of aza-boraspirobifluorenes 1g–i

Entry	Reagent	R^3	1	Yield (%)^a
a Yield over two steps based on compound 4.
1	6	Me	1g	24
2	7	OMe	1h	43
3	8	CF3	1i	33

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Aza-boraspirobifluorenes with substituted pyridine rings were obtained via a different route (Table 2). Treatment of compound 4 with ⁿBuLi (2.0 equiv.), followed by the addition of a solution of BCl₃ (1.0 equiv.), furnished chloroborafluorene 5.^47,48 A solution of 5 was added to aryl lithium 6, and 1g was isolated in 24% yield (entry 1). The 4-methoxy derivative (1h) and 4-trifluoromethyl derivative (1i) were obtained from the corresponding aryl lithium in 43% and 33% yield, respectively (entries 2 and 3).

The solid-state structures of 1a–i were examined by X-ray crystallography. Single crystals of 1a–i were obtained from their solutions by slow evaporation of the solvent. The thermal-ellipsoid plot of rac-1a is shown in Fig. 2. These crystals contained (R)-1a and (S)-1a in a ratio of 1 : 1 within an achiral crystal system (P2₁/c). The tetrahedral BC₃N framework with an intramolecular B–N bond was confirmed. The torsion between the planes of the 2-phenylpyridine and biphenyl moieties was nearly orthogonal (θ = 86.4°). The B–N bond was slightly shorter (1.615(2) Å) than those of other borane–amine complexes (1.67–1.76 Å),^49,50 and close to the length of the B–C bonds (1.60–1.62 Å).⁵¹

Fig. 2 Molecular structure of 1a with thermal ellipsoids at 50% probability; hydrogen atoms are omitted for clarity.

Selected bond lengths and angles around the boron atom in 1a–f are compiled in Table 3. There is no clear relationship between the substituent introduced to the aza-boraspirobifluorene and the length of the B–N bond: the bond is slightly longer in 1a (1.615(2) Å) and slightly shorter in 1h (1.588(7) Å), while the bond length of other compounds remained constant (1.603(3)–1.61 0(10) Å). The tetrahedral character of the dihedral angle (THC_DA)^49,52 for the spiro atoms of 1a–i was ∼50%. These values are affected by the substituents on the pyridine ring (R³) and decrease from 62% to 29% in the order 1h (OMe) > 1g (Me) > 1i (CF₃). The very small value for 1i can be explained by the reduced Lewis basicity of the nitrogen atom upon introducing an electron-withdrawing group, which leads to an increased three-coordinated character of the boron atom. The bond lengths of B–C¹ (1.690(20) Å) and B–C² (1.700(10) Å) in 1i are slightly longer than those in the other compounds.

Table 3 Selected bond lengths and bond angles of 1a–i ^a

	Bond length/Å				Bond angle (°)		THCDA (%) ^b
	B–N	B–C^1	B–C^2	B–C^3	C^1BC^2	C^3BN
a See Fig. 2 for assignment of the bond lengths and bond angles. b The tetrahedral character of the dihedral angle (THCDA) was calculated based on six angles around the boron atom using the equation in ref. 22.
1a	1.615(2)	1.615(2)	1.619(2)	1.607(2)	99.8(1)	96.9(1)	50
1b	1.605(3)	1.608(3)	1.624(3)	1.607(3)	99.6(2)	96.7(2)	49
1c	1.603(4)	1.623(4)	1.616(3)	1.600(3)	99.6(2)	97.1(2)	49
1d	1.604(2)	1.611(3)	1.624(3)	1.609(3)	99.8(2)	97.3(2)	51
1e	1.604(2)	1.617(3)	1.622(2)	1.614(3)	99.8(1)	97.3(1)	51
1f	1.603(3)	1.618(2)	1.623(3)	1.605(2)	99.7(1)	97.4(1)	51
1g	1.610(10)	1.610(10)	1.620(10)	1.620(10)	101.1(6)	97.6(6)	54
1h	1.588(7)	1.650(10)	1.593(9)	1.610(10)	100.6(5)	98.4(5)	62
1i	1.610(2)	1.690(20)	1.700(10)	1.608(2)	91.1(8)	97.0(1)	29

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UV/vis absorption and photoluminescence spectroscopy in CH₂Cl₂ were examined to understand the optical properties of 1a–f. Fig. 3 shows the UV/vis absorption and fluorescence spectrum of 1d. We observed an absorption band around 260–340 nm with a peak (λ_{max, abs.}) at 266 nm and a broad fluorescence band around 300–440 nm with two peaks (λ_{max, em.}) at 338 nm and 386 nm. Fluorescence spectra of other aza-boraspirobifluorenes composed of simple substituents emitted violet-blue fluorescence with λ_{max, em.} in the range of 334–463 nm (for details, see the ESI†).

Fig. 3 Absorption (dashed) and fluorescence (solid) spectrum of 1d (5 μM in CH₂Cl₂).

Next, we examined the separation of the enantiomers and the stereochemical stability of aza-boraspirobifluorenes 1a–i (Fig. 4a). Using chiral HPLC, rac-1d was separated into two fractions (fr1-1d: ee > 99%; fr2-1d: ee > 99%). The CD spectra of fr1-1d and fr2-1d display mirrored Cotton effects (Fig. 4b). The spectrum for fr1-1d displayed a positive Cotton effect at 275 nm and a negative Cotton effect at 323 nm. The observed spectrum of fr-1d was in good agreement (within 10 nm) with the calculated ECD spectrum of (S)-1d (Fig. 4b).^53–55 Based on these results, we assigned the absolute configuration of fr1-1d as (S)-1d and that of fr2-1d as (R)-1d.

Fig. 4 (a) HPLC chart of 1d; column: YMC CHIRAL Amylose-SA (L × D: 250 mm × 4.6 mm; particle size: 5 μm); detector: photo diode array (PDA) detector at 254 nm; eluent: n-hexane : CHCl₃ : i-PrOH = 93 : 2 : 5; elution rate: 0.8 mL min⁻¹; (b) experimental CD spectra (solid) and theoretical ECD spectra (dashed) calculated at the M06-2X/6-31+G(d,p) level, whereby the structures of 1d were optimized at the B3LYP/6-31G(d,p) level: (S)-1d (red) and (R)-1d (blue).

With the separated homochiral compounds in hand, we studied the racemization of 1 under various conditions. Heating a solution of (S)-1d in DMSO to 145 °C induced racemization.^56,57 The rate constant of racemization (k_rac) of (S)-1d at 145 °C (4.00 × 10⁻⁵ s⁻¹) was determined by a first-order kinetic analysis.^58–60 The kinetic parameters (145 °C: ΔG^‡ = 33.7 kcal mol⁻¹, ΔH^‡ = 26.8 kcal mol⁻¹, and ΔS^‡ = −16.6 cal K⁻¹ mol⁻¹), which were determined by an Eyring-Polanyi plot at three different temperatures (135–145 °C), were higher than those of other reported BC₃N systems.^39,40

The kinetic parameters for racemization of 1a–i are summarized in Table 4. For 1a–c, which carry a substituent at the 2-position of the borafluorene ring (R¹), ΔG^‡ increases from 32.9 kcal mol⁻¹ to 34.9 kcal mol⁻¹ (145 °C) in the order 1b (R¹ = OMe) < 1a (R¹ = Me) < 1c (R¹ = CF₃). A similar trend was observed for ΔG^‡ of 1d–f, which increases in the order 1e (R² = OMe) ≃ 1d (R² = Me) < 1f (R² = CF₃). At present, we assume that the electron-withdrawing group increases the Lewis acidity of the boron atom and that the presence of a stronger B–N bond retards the racemization. For 1g–i, which carry a substituent at the 4-positon of the aza-borafluorene ring (R³), a clear substituent effect was observed. ΔG^‡ decreases from 33.4 to 31.0 kcal mol⁻¹ in the order 1g (R³ = OMe) > 1h (R³ = Me) > 1i (R³ = CF₃). This result can be rationalized in terms of the reduced basicity of the nitrogen atom upon introducing the electron-withdrawing group. In accordance with these results, 1i, which contains a MeO group at the 2-position of the borafluorene ring and a CF₃ group at the 4-position of the aza-borafluorene ring, showed the lowest activation energy (ΔG^‡ = 31.0 kcal mol⁻¹). Based on the kinetic data obtained, we concluded that the rate-determining step of the racemization involves the cleavage of the B–N bond.

Table 4 Summary of the kinetic parameters for the racemization of 1a–i

	R^1	R^2	R^3	k rac (145 °C) 10^−5/s^−1	ΔG^‡ (145 °C)/kcal mol^−1	ΔH^‡/kcal mol^−1
1a	Me	H	H	5.76	33.4	28.4
1b	OMe	H	H	11.3	32.9	29.6
1c	CF3	H	H	0.984	34.9	33.9
1d	H	Me	H	4.00	33.7	26.8
1e	H	OMe	H	4.04	33.7	31.6
1f	H	CF3	H	1.84	34.4	27.1
1g	Me	H	Me	2.70	33.4	28.4
1h	Me	H	OMe	1.77	34.4	30.7
1i	Me	H	CF3	114	31.0	23.5

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The mechanism of racemization was further examined by theoretical calculations. The characteristic structures and the energy levels for the inversion process of (S)-1d, which were calculated at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level, are shown in Fig. 5. The cleavage of the B–N bond and the rotation of the B–C³ bond can proceed viaInt. The process from GS-(S) to IntviaTS-1 is favored with an activation energy of ΔG^‡ = 36.8 kcal mol⁻¹. The length of the B–N bond increases from 1.62 Å (GS) to 4.11 Å (TS-1). The rotational intermediate Int contains the 5-phenylborafluorene moiety, which carries a three-coordinated boron atom with no B–N interaction. Another transition state (TS-2) was obtained for the formation of the B–N bond.

Fig. 5 Energy diagram for the chirality inversion from (S)-1d to (R)-1d; all calculations were carried out at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level.

Conclusions

We synthesized chiral aza-boraspirobifluorenes and examined their molecular structures as well as their photophysical properties. The enantiomers were separated via chiral HPLC. The racemization of aza-boraspirobifluorenes proceeded at elevated temperatures, and the kinetic parameters were determined to understand the mechanism of the isomerization. This study thus offers important insights into the stereochemistry of chiral tetrahedral borane compounds.

Conflicts of interest

There are no conflicts to declare.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2203027–2203033, 2176259 and 2215757. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2dt03303h

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