Equilibrium acidities of BINOL type chiral phenolic hydrogen bonding donors in DMSO

Abstract

The pK_a values of fifteen BINOL type chiral phenolic catalysts were determined by the overlapping indicator method in DMSO via UV spectrophotometric titrations. The acidities cover the range from 9.30 to 16.43. The pK_a gap between BINOL and 2-naphthol was explained by IR spectrum data, crystal structure and ¹H NMR. The relationship between the pK_a values of 3,3′-modified BINOLs and Hammett ortho substituent constants (σ_o⁻) was investigated and a good correlation (R² = 0.984) was obtained. The results may be helpful for the rational design and development of novel BINOL type phenolic catalysts, sensors and ligands.

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Introduction

1,1′-Binaphthyl-2,2′-diol (BINOL) is one of the most representative axially chiral C₂ symmetric molecules in organic chemistry.¹ The steric hindrances between 2,2′-hydroxyls and between 8,8′-hydrogens restrict the free rotation of the two 2-naphthol units around the 1,1′-bond, which orient the chirality of BINOL. The two optically active enantiomers of BINOL can readily be resolved and both possess a thermally stable chiral configuration even at high temperature under neutral conditions.² Although BINOL was first reported in 1873,³ its potential as a chirality source was not recognized until the early 1970s when Cram initiated his pioneering work of high chiral recognition by utilizing optically active BINOL based macrocycle hosts.⁴ Soon afterwards in 1979, Noyori first reported that chiral BINOL could serve as a superb ligand in the enantioselective reduction of ketones and aldehydes.⁵ Inspired by these monumental contributions, great efforts have been devoted to develop structurally diverse BINOL derivatives, and a tremendous amount of achievements has been reported in research fields such as molecular recognition,^1e,i metal-mediated asymmetric catalysis^1b–d,g and chiral material building.^1a,6 Recently, with the advent and dramatic blossoming of the area of organocatalysis,⁷ BINOL has also been recognized as a unique scaffold for designing hydrogen bonding donor organocatalysts^1f,h,7e and a broad array of asymmetric transformations, such as alkenyl(alkynyl)boration,⁸ allyl(propargyl)boration⁹ and MBH reaction¹⁰ have been realized. Today, the versatile BINOL backbone has been identified as one of the most privileged chirality inducers.¹¹

It's worth mentioning that the hydrogen bonding interaction between BINOL and other molecules plays a key role in different fields, especially in molecule recognition^1e,i and organocatalysis (Scheme 1).^1f,h,8–10 Thus, the hydrogen bonding strengths, generally represented by donors’ equilibrium acidities,¹² must drastically influence the capability of recognition and activation. Although, as an essential physical organic parameter, the pK_a value of BINOL has been frequently cited in reports, we were astonished to find that the strictness of citation has been largely ignored.^1b,7e,13 To the best of our knowledge, there are only a few reports on the dissociation constant of BINOL in aqueous or mixed protic solvents without a systematic discussion of the substitution effect.¹⁴ Therefore, accurate pK_a measurements of BINOL and its derivatives are significantly desirable.

Scheme 1 Representative applications promoted by BINOLs.

In the past decade, great attention has been attracted by the field of equilibrium acidities of Brønsted acid type organocatalysts in DMSO,¹⁵ owing to the development of numerous classes of novel catalysts. Our group has also reported the pK_a values of some widely used hydrogen bonding organocatalysts including thioureas,^15a squaramides,^15h proline derivatives^15j and cinchona alkaloids.^15k Herein, we report the determination of the pK_a values of BINOL type phenolic catalysts.

Results and discussion

As shown in Scheme 2, thirteen (S)-BINOL derivatives and two similar diol catalysts were selected as target compounds. The pK_a values were measured by means of the indicator overlapping method via UV/vis spectrophotometric titration in DMSO.¹⁶ As illustrated by the example of catalyst 1 (Fig. 1), a solution of 2-Br-9-PhS-FH was titrated into the K-dimsyl solution until the base was completely consumed, during which the weight of the cell and the UV spectrum were both recorded (Fig. 1a). Then, a solution of catalyst 1 was added and the weight of the cell and the corresponding spectrum were also recorded after each titration. The equilibrium acidity of catalyst 1 could be obtained from the data of the changed absorbance (Fig. 1b). The indicators employed in this study are shown in Scheme 3. The results of the pK_a values are summarized in Table 1.

Scheme 2 Studied BINOL type phenolic catalysts in this work.

Fig. 1 (a) Absorption spectra of the anion derived from 2-Br-9-PhS-FH for various added amounts of 2-Br-9-PhS-FH during the titration. (b) Absorption spectra of the anion derived from 2-Br-9-PhS-FH for various added amounts of catalyst 1 during the titration.

Scheme 3 Indicators’ structures and their pK_a values in DMSO.^16,17

Table 1 pK_a values of BINOL type phenolic catalysts in DMSO

Catalyst	pKa value	Indicator^a
a FH = fluorene; 9-(2-Cl-Ph)-NHN-FH = 9-fluorenone-2-chlorophenylhydrazone. b See ref. 18.
1	12.98 ± 0.05^b	2-Br-9-PhS-FH
2	11.95 ± 0.03	2,7-diBr-9-PhS-FH
3	10.39 ± 0.03	9-CO2Me-FH
4	9.78 ± 0.02	4-NO2-3-CF3-phenol
5	9.44 ± 0.02	4-NO2-3-CF3-phenol
6	9.30 ± 0.03	4-NO2-3-CF3-phenol
7	10.93 ± 0.03	2,7-diBr-9-PhS-FH
8	10.89 ± 0.01	2,7-diBr-9-PhS-FH
9	9.99 ± 0.01	9-CO2Me-FH
10	9.68 ± 0.03	9-CO2Me-FH
11	10.73 ± 0.01	2,7-diBr-9-PhS-FH
12	12.35 ± 0.02	9-(2-Cl-Ph)-NHN-FH
13	11.92 ± 0.04	2,7-diBr-9-PhS-FH
14	10.45 ± 0.02	2,7-diBr-9-PhS-FH
15	16.43 ± 0.02	9-(3-Cl-Ph)-FH

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As shown in Table 1, the pK_a values of studied hydrogen bonding donor catalysts cover the range of 9.30–16.43, which fall in the acidity range of thioureas/squaramides. Compared with 2-naphthol (pK_a = 17.14 in DMSO),¹⁹ the acidity of BINOL (catalyst 1) increased by about 4 pK units, which agrees well with the previous calculation results (13.22 in DMSO).¹⁵ⁱ Evidenced by IR spectrum data,²⁰ almost only the intermolecular hydrogen bond between BINOL and solvent molecules was observed in DMSO, indicating that BINOL's acidity can't be enhanced by “OH⋯OH” intramolecular hydrogen bonding. However, a strong intramolecular hydrogen bonding was clearly observed in mono deprotonated BINOL and derivatives,²¹ which may primarily account for this great acidification phenomenon (Scheme 4).

Scheme 4 Proposed dissociation equilibrium of BINOL in DMSO.

For 2–11, each of which bears identical substituents at the 3,3′-positions, their acidities are all stronger than the unmodified BINOL. Unexpectedly, even substituted by the methyl group, catalyst 2's pK_a value is also lower than BINOL by about 1 pK unit. This peculiar increase of acidity may be attributed to the steric interaction in the ortho position, which also exists in ortho-substituted phenol and protonated aniline.²² While for 3–6, which are substituted by halogen atoms, the acidities increase in an order which is opposite to that of the substituents’ electro-negativities. In order to investigate the substituent effect, the relationship between pK_a values of catalysts 1–7 and corresponding Hammett σ_o⁻ constants²³ was then investigated and a good correlation (R² = 0.986) was obtained in the regression analysis (Fig. 2). However, to our surprise, unmodified BINOL deviated badly from linearity,¹⁸ indicating that the ortho effect significantly influences the chemical environment around the OH groups of 3,3′-modified BINOL derivatives. For 12, which is partially hydrogenated from 5, the pK_a value increases by about 3 units compared with 5. This pK_a gap may be attributed to the combination of both electronic and steric effects aroused by the reduction on the naphthol ring.

Fig. 2 Correlation between the pK_a values of 3,3′-modified BINOLs and the Hammett substituent constants (σ_o⁻).

For 7–11, which are substituted by aromatic groups at the 3,3′-position, their acidities increased by 2–3 pK units compared with BINOL. With regard to 7, 8 and 11, extending the conjugated system of the substituent may weakly enhance the acidities. For 9 and 10, the acidities were strengthened by about 1 pK unit when strong electron-withdrawing groups (NO₂, CF₃) were introduced into the Ph substituent. It is well accepted that the Lewis acidities of BINOL–metal complexes which may directly affect their catalytic activities can easily be tuned by varying the electronic effect of the substituents. Thus, the pK_a values discussed above must be valuable for quantitatively estimating the influences caused by modifications at 3,3′-positions.

Finally, three similar hydrogen bonding donor catalysts were also investigated. Linked by two BINOL units at their 3-positions, catalyst 13 with four OH groups exhibited a lower pK_a value than the single BINOL by 1 pK unit. For 14 (VANOL), the acidity is stronger than its isomer 7 by 0.44 pK units, which may be interpreted by the pK_a gap between the two positional isomers of naphthol.¹⁸ While, for 15 (SPINOL) containing a spirocyclic framework, the acidic strength is much weaker than that of BINOL by 3 pK units. Due to the higher rigid scaffold of SPINOL, the intramolecular hydrogen bond is almost forbidden in its mono deprotonated form, which may primarily account for the magnitude of pK_a increment. In addition, a strong homoconjugation phenomenon was observed exclusively during the measurement of the acidity of SPINOL, which also powerfully supports the hypothesis we proposed above.

Conclusions

In summary, we have determined the pK_a values of 15 representative BINOL type hydrogen bonding donor catalysts in DMSO by adopting the classical overlapping indicator method. The pK_a values are in the range of 9.30–16.43. The relationship between the pK_a values of several 3,3′-modified BINOL derivatives and the Hammett ortho substituent constants was investigated and a good correlation was demonstrated. We believe that these data should be helpful in providing a clearer insight into the mechanism of recognition and catalysis. Furthermore, the results we reported here may benefit the advances in rational design and development of novel BINOL and other diol type catalysts, sensors and ligands.

Experimental

General experimental methods

The UV spectrum measurements were performed on a Hitachi U-3000 UV/vis spectrometer. Commercial reagents were used as received, unless otherwise stated. Catalyst 1 was used after recrystallization from ethyl acetate. Catalysts 2–13 were synthesized according to the literature procedures.²⁴ Catalysts 14 and 15 were purchased from Daicel Chiral Technologies (China) Co, Ltd.

pK_a measurement

The treatment of DMSO and base (K-dimsyl solution) strictly followed the description in the literature.^16a The determinations of the pK_a values were carried out under an atmosphere of argon. A solution of the indicator with known pK_a value and concentration (1.3–2.0 × 10⁻² M) was added dropwise to a solution of K-dimsyl (1.0–1.5 mL, 0.5–1.0 × 10⁻³ M), then a work calibration curve was obtained from the spectrum and the weight of cell was recorded after each addition of the titrant. After the base was completely consumed by adding excess indicator solution, which is monitored by a UV/vis spectrophotometer, a solution of the target compound with known concentration (1.3–2.0 × 10⁻² M) was added. The corresponding pK_a value was obtained from the change of absorbance and the amount of target compound recorded after each addition of the titrant. The equilibrium acidity of the target compound was calculated according to eqn (1) and (2). Each target compound was measured at least two times against the corresponding indicator demonstrated in Scheme 3 by the method described above.

The interferences of anion absorption between catalysts 9, 10 and the corresponding indicator were serious during pK_a determination and the problem was solved by a “double wavelength calculation method” developed by our group which is unpublished.

Acknowledgements

We thank the 973 Program (2012CB821600) and NSFC (21390400 and 21421062) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: UV/Vis spectra of BINOL type phenolic catalysts in DMSO (Fig. S1–S13). See DOI: 10.1039/c6qo00252h

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