Hydrolysis of 8-(pinacolboranyl)quinoline: where is the 8-quinolylboronic acid?

1 Introduction

Boronic acids have the general formula RB(OH)₂, however analysis of their structural and physical properties can be complicated. Boronic acids can undergo dehydration to form cyclic trimeric boroxines or polymeric anhydrides. In water, soluble anionic boronates form with typical pK_a values in the range 8~10. While isolation and characterization of boronic acids can be complicated due to reversible reactions with water, the isolation of boronic esters tends to be straightforward [1]. In particular, addition of 1,2-diols to boronic acids generally leads to high yields of the boronic esters. This reaction has been widely used to couple sugars as a basis for specific binding and detection [2].

Circa 1960, Letsinger and co-workers investigated 8-quinolylboronic acid as a potential bifunctional catalyst [3–5]. It was found that 8-quinolylboronic acid had an unusual influence on the hydrolysis of 2- and 3-chloroalcohols. The mechanism of hydrolysis was esterification of the boronic acid with the chloroalcohol, hydrogen bonding of water to the quinoline nitrogen base, and finally nucleophilic substitution to eliminate chloride. The preorganized geometry of the bifunctional catalyst was the essential feature that contributed to the enhanced reactivity toward chloroalcohols. More recently, the luminescence properties of 8-quinolylboronic acid for carbohydrate sensing have been studied [6–8].

Simultaneously inspired by the work with 8-quinolylboronic acid and recent developments in frustrated Lewis pair chemistry [9–11], and as part of our ongoing efforts to study pre-organized frustrated Lewis pairs [12–14], we embarked to prepare 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-quinoline (1). In this report, we show that 1 is readily hydrolyzed to the zwitterionic (quinolinium-8-yl)trihydroxyborate (2) or a dimeric anhydride 8,16-dihydroxy-8,16-epoxy[1,5,2,6]diazadiborocino[1,8,7-ij:5,4,3-i′j′]diquinoline (3), depending on the reaction conditions (Scheme 1). We show that it is possible to interconvert between compounds 2 and 3; however, we were not able to isolate (quinolin-8-yl)boronic acid. We present structural characterization of the protonated boronic ester (1-H⁺) as its ClO₄^– salt, the zwitterion (2), and the dimeric anhydride (3).

Scheme 1:

Structurally characterized products of the hydrolysis of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-quinoline (1).

2 Experimental

General. Solvents were obtained from commercial sources. THF and CDCl₃ were dried over CaH₂ and distilled prior to use. Acetonitrile, hexanes, and dichloromethane were dried in a PureSolv solvent dryer. Acetone and [D₆]DMSO were dried and stored over molecular sieves. All reagents were purchased from commercial sources and used without further purification. 8-Iodoquinoline was prepared according to the literature [12]. All ¹H and ¹³C NMR spectra were recorded using a Varian 200 MHz NMR spectrometer. Chemical shifts δ are given in ppm, coupling constants J are in Hz.

Safety notes: Experimental procedures involve the use ofpyrophoric agentsand the use offluoride sources.Perchloratesare potentially explosive.

3 Results and discussion

8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-quinoline (1) was synthesized by lithiation of 8-iodoquinoline followed by addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (i-PrOBpin), and further treatment with BF₃·OEt₂ in order to remove lithium isopropoxide by-product (Scheme 2) [18]. Recrystallization from acetonitrile or THF yielded microcrystalline powders not suitable for single crystal diffraction experiments. However, the compound could be isolated in its protonated form (1-H⁺) as a perchlorate salt (Table 1).

Scheme 2:

Synthesis of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-quinoline (1).

The crystal structure of 1-H⁺ as its perchlorate salt (Fig. 1) included two 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-quinolinium cations, two perchlorate anions, and one molecule of CH₂Cl₂ in the asymmetric unit, giving a formula of [1-H⁺][ClO₄^–] ·1/2CH₂Cl₂. In the 1-H⁺ cations, the pinacolboryl rings are only slightly out of plane with the quinolinium ring. This geometry appears to be enforced by a hydrogen bond between the quinolinium proton and an oxygen atom of the dioxaborolane ring (H1···O2 2.080 Å, H1AA···O4 2.000 Å). The three-coordinate boron atoms in the cations are distorted trigonal planar. The planar aromatic cations are engaged in π stacking about an inversion center in the crystal. The π stacking is evidenced by a short B1···C5 contact of 3.595 Å and a contact C7···C9 of 3.447 Å.

Fig. 1:

Structure of [1-H⁺][ClO₄^–]·1/2CH₂Cl₂ in the crystal with hydrogen atoms and solvent molecules omitted for clarity. A cation and its nearest anion are shown on the left. The right figure shows π stacking between cations with an inversion center between them. Displacement ellipsoids are shown at the 50% probability level, H atoms as spheres with arbitrary radii. Selected bond distances (Å) and angles (deg): B(1)–C(8) 1.557(8), B(1)–O(1) 1.338(7), B(1)–O(2) 1.354(7), H(1)···O(2) 2.080, H(1)···O(9) 2.116, B(1)···C(5) 3.595, C(7)···C(9) 3.447; C(7)–C(8)–B(1) 120.2(5), C(9)–C(8)–B(1) 122.4(5), C(7)–C(8)–C(9) 117.4(5).

It has been noted that (quinolin-8-yl)pinacolborane derivatives are readily hydrolyzed to boronic acids [18, 19]. As remarked above, compound 1 is hydrolyzed quite easily; however, we did not observe the neutral boronic acid. Evaporation of a solution of 1 in acetone in air led to crystals of (quinolinium-8-yl)trihydroxyborate (2) in quantitative yield. Compound 2 is poorly soluble in most solvents, except DMSO. The ¹H NMR in DMSO shows two broad singlets at δ=3.3 and 14.2 ppm for B–OH and N–H, respectively. In the crystal, multiple types of intermolecular interactions occur (Fig. 2). In addition to electrostatic forces, intermolecular hydrogen bonding and strong π stacking interactions are evident in the crystal. Intermolecular hydrogen bonding interactions were found between the iminium N–H proton and the hydroxyl groups bound to boron and between the hydroxyl groups. Strong π stacking interactions were characterized by short C···C contacts between the asymmetrically charged planar aromatic rings. Inversion centers are found between the π-stacked zwitterions, and the inversion symmetry of the aggregate maximizes the electrostatic attraction of the oppositely charged portions of the ring.

Fig. 2:

Structure of 2 in the crystal showing intermolecular hydrogen bonding (left) and π stacking (right) interactions. Displacement ellipsoids are shown at the 50% probability level, H atoms as spheres with arbitrary radii. Selected bond distances (Å) and angles (deg): B(1)–C(8) 1.627(4), B(1)–O(1) 1.415(3), B(1)–O(2) 1.422(3), B(1)–O(3) 1.393(3), B(1)···N(1) 3.022, C(2)···C(7) 3.389, C(4)···C(9) 3.324, C(2)···C(5) 3.388, C(9)···C(9) 3.438; C(7)–C(8)–B(1) 120.4(2), C(9)–C(8)–B(1) 123.8(2).

Slower hydrolysis of 1 led to a different product. Solutions of 1 in CH₃CN exposed to limited amount of moisture, such as within a closed NMR tube or vial, slowly (after a few weeks) formed crystals of the anhydride 3. Under these conditions, crystals of 3 do not include any solvent water molecules, whereas the previously reported structure of the anhydride concerns the monohydrate form [15]. The structure of 3 is presented in Fig. 3. The molecule adopts a roof shape with the (HO)BOB(OH) portion at the apex. The dihedral angle between the quinolinyl rings is ~105°. The B–N bonds lengths (1.649 and 1.656 Å), B–C bond lengths (1.624 and 1.635 Å), B–OH bond lengths (1.396 and 1.400 Å), and the B–(μ₂)O bond lengths (1.411 and 1.404 Å) only very slightly deviate from C₂ symmetry in the molecule. Similarly, the molecule 3 in the monohydrate crystal is very near to C₂ symmetry. In crystals of 3·H₂O [15] the B–C(ipso) distances (1.622 and 1.626 Å) are quite similar to those in 3, whereas the B–N distances in crystals of 3·H₂O (1.708 and 1.693 Å) are noticeably longer than in 3. The B–OH distances in 3·H₂O (1.423 and 1.427 Å) as well as the B–(μ₂)O distances (1.435 Å) are longer than in 3. The dihedral angle of the quinoline rings is ~105° in both structures. Intermolecular π stacking between the molecular units is found in the crystal.

Fig. 3:

Structure of 3 in the crystal with most of the hydrogen atoms omitted for clarity. Displacement ellipsoids are shown at the 50% probability level, H atoms as spheres with arbitrary radii. Selected bond distances (Å) and angles (deg): B(1)–N(1) 1.657(5), B(2)–N(2) 1.649(4), B(1)–C(17) 1.624(5), B(2)–C(8) 1.635(5), B(1)–O(1) 1.400(4), B(2)–O(3) 1.396(4), B(1)–O(2) 1.404(4), B(2)–O(2) 1.411(4), C(3)···C(6) 3.480, C(10)···C(10) 3.534, C(17)···C(19) 3.378, N(2)···C(15) 3.446; N(1)–B(1)–C(17) 104.7(2), N(2)–B(2)–C(8) 106.1(2), O(1)–B(1)–O(2) 112.7(3), O(3)–B(2)–O(2) 113.2(3), B(1)–O(2)–B(2) 112.8(3).

Since compounds 2 and 3 are related in their degree of hydration, we set out to interconvert the two forms (Scheme 3). In order to open the dimeric anhydride molecule, fluoride was added as KHF₂ to 3 in a THF-water mixture. It is well known that addition of KHF₂ to boronic acids leads to organotrifluoroborates [20]. In this case, the presumed organofluoroborate intermediate hydrolyzes to form 2. To complete the reverse reaction, 2 was dissolved in concentrated HCl and neutralized with NaHCO₃, which led to 3. Thus 2 and 3 are interconvertible, and we note that 2 is formed in acidic conditions while 3 is formed in basic conditions. It is interesting that 2 forms at low pH, as one would readily expect protonation of the quinoline nitrogen atom but not the addition of hydroxide to boron. However, protonation leads to a cationic Lewis acid with apparent high affinity for hydroxide ions, resembling recently developed fluoride and cyanide ion receptors [21]. It is also worth mentioning that the aminoborane 1-(NPh₂)-2-[B(C₆F₅)₂]C₆H₄ induces heterolytic cleavage of the H–OH bond to form a zwitterion; however this process is driven by the strongly electrophilic borane [22].

Scheme 3:

Interconversion between 2 and 3.

We could not isolate the uncoordinated, monomeric 8-quinolylboronic acid, and suggest that the molecule may be difficult to isolate. Both molecules 2 and 3 likely form via 8-quinolylboronic acid as an intermediate. Interestingly, 2 is similar to one of the postulated intermediates in the hydrolysis of chloroalkanes by 8-quinoline boronic acid [23]. With respect to the degree of hydration, 8-quinolylboronic acid is an intermediate in the conversion of 2 to 3 since loss of an equivalent of water from 2 or addition of an equivalent of water to 3 should yield the uncoordinated, monomeric 8-quinolylboronic acid. Although several papers report the synthesis and application of 8-quinolylboronic acid, [3–7, 24–26] its crystal structure has not been determined except its dimer form. In fact, a powder X-ray pattern of a commercially obtained sample of ‘8-quinolylboronic acid’ indicates that the sample is actually 3·H₂O (CCDC 635581) [15] according to simulation of its powder pattern from the single crystal data (Fig. 4). The elusive nature of the monomeric Lewis base-free 8-quinolylboronic acid may not be surprising. In the context of frustrated Lewis pair chemistry, frustration arises from steric bulk that surrounds the Lewis centers. In the absence of steric bulk, the frustration will be relieved upon formation of intra- or inter-molecular dative bonds. With little steric bulk surrounding the Lewis centers in 8-quinolylboronic acid, one should expect the molecule to dimerize. The reaction is further thermodynamically driven with the loss of water upon formation of the B–O–B bridge.

Fig. 4:

Comparison of (top) simulated powder X-ray diffraction pattern for 3, (middle) simulated powder X-ray diffraction pattern for 3·H₂O (CCDC 635581) [15], and (bottom) measured powder X-ray diffraction pattern for a commercial sample of ‘8-quinoline boronic acid’.

While we could not isolate monomeric Lewis base-free 8-quinolylboronic acid, it may exist transiently in solution. We note that ‘8-quinolylboronic acid’ or derivatives have been utilized successfully in Suzuki coupling reactions [24, 25, 27–32]. In the mechanism, boronate ions are typically invoked as solution intermediates that transfer an aryl group to Pd in a transmetalation step that ultimately leads to C–C bond formation upon reductive elimination from the Pd center. Thus molecules of 2 or, in basic conditions, an equilibrium between 3 and a monomeric borate could provide the reaction intermediate.

4 Conclusion

In summary, 8-quinolylboranes are susceptible to rapid hydrolysis; however, the expected product, 8-quinolylboronic acid has not been observed in the monomeric Lewis base-free form. Instead, 8-quinolylboronic acid may exist transiently and react with water to form the zwitterionic (quinolinium-8-yl)trihydroxyborate or a dimeric anhydride. We show that commercially available ‘8-quinolylboronic acid’ is actually the dimeric form as its monohydrate. Despite the elusive nature of the monomeric Lewis base-free 8-quinolylboronic acid, its repeated use in Suzuki coupling indicates that its other forms essentially perform like a typical boronic acid.