Silanediol versus chlorosilanol: hydrolyses and hydrogen-bonding catalyses with fenchole-based silanes

Biphenyl-2,2’-bisfenchyloxydichlorosilane (7, BIFOXSiCl2) is synthesized and employed as precursor for the new silanols biphenyl-2,2’-bisfenchyloxychlorosilanol (8, BIFOXSiCl(OH)) and biphenyl-2,2’-bisfenchyloxysilanediol (9, BIFOXSi(OH)2). BIFOXSiCl2 (7) shows a remarkable stability against hydrolysis, yielding silanediol 9 under enforced conditions. A kinetic study for the hydrolysis of dichlorosilane 7 shows a 263 times slower reaction compared to reference bis-(2,4,6-tri-tert-butylphenoxy)dichlorosilane (14), known for its low hydrolytic reactivity. Computational analyses explain the slow hydrolyses of BIFOXSiCl2 (7) to BIFOXSiCl(OH) (8, Ea = 32.6 kcal mol−1) and BIFOXSiCl(OH) (8) to BIFOXSi(OH)2 (9, Ea = 31.4 kcal mol−1) with high activation barriers, enforced by endo fenchone units. Crystal structure analyses of silanediol 9 with acetone show shorter hydrogen bonds between the Si–OH groups and the oxygen of the bound acetone (OH···O 1.88(3)–2.05(2) Å) than with chlorosilanol 8 (OH···2.16(0) Å). Due to its two hydroxy units, the silanediol 9 shows higher catalytic activity as hydrogen bond donor than chlorosilanol 8, e.g., C–C coupling N-acyl Mannich reaction of silyl ketene acetals 11 with N-acylisoquinolinium ions (up to 85% yield and 12% ee), reaction of 1-chloroisochroman (18) and silyl ketene acetals 11 (up to 85% yield and 5% ee), reaction of chromen-4-one (20) and silyl ketene acetals 11 (up to 98% yield and 4% ee).

Unlike the hydrolysis of BIFOP-Cl (6) to BIFOP-OH, the dichlorosilane 7 is not hydrolyzed by aqueous potassium hydroxide solution [53]. The heterolytic reaction of solid BIFOXSiCl 2 (7) in an aqueous KOH solution is negligible (<1% yield, Table 1, Scheme 3 in a) H 2 O and b) H 2 O/KOH). The reluctance against hydrolysis of BIFOXSiCl 2 (7) can be explained by the hydrophobic aryl backbone and the fenchyl groups, which result in a decrease of the solubility of BIFOXSiCl 2 (7) in water. Thus, a H 2 O/THF mixture is used to increase solubility and yields (Table 1, Scheme 3c). While the solubility of BIFOXSiCl 2 (7) in H 2 O/THF greatly increases (clear solution), potassium hydroxide is needed as a strong  (7) to BIFOXSi(OH) 2 (
At H 2 O/THF reflux conditions, the hydrolysis of dichlorosilane 13 yields silanediol 1 with >99% yield, after a reaction time of two seconds (Scheme 4, addition of H 2 O, with instant extraction with Et 2 O). The stability of dichlorosilane 14, which has been previously reported by Spirk et al. [60], has been found to be higher than that of dichlorosilane 13 under the same condi-Scheme 4: Hydrolysis of dichlorosilanes 13 and 14 to their corresponding silanediols 1 and 15 [51,60].

Computational analyses
Nucleophilic substitution at silicon is already discussed with S N 2 mechanism, following a backside attack opposite of the leaving group, as well as a front side attack near the leaving group [62][63][64][65][66][67][68]. A backside attack at the silicon in dichlorosilane 7 and monochlorosilanol 8 is blocked by the backbone, making a consideration of the mechanism not necessary. A mechanism with a pentacoordination at the silicon is assumed for the hydrolyses of BIFOXSiCl 2 (7) to BIFOXSiCl(OH) (8) as intermediate and BIFOXSI(OH) 2 (9) as product [65][66][67]. Two pathways (front attack mechanism (front) or side attack mechanism (side)) for the approaching water molecule are considered (Scheme 5).  (8). For 8 ax the OH group is parallel situated to the biaryl axis. For 8 eq the OH group is orthogonal oriented to the biaryl axis. The fenchyl groups are abbreviated with (*) for more clarity.
In both, front attack and side attack, the attacking water molecule is in plane with the Cl-Si-Cl unit for the first hydrolysis step. For the second hydrolysis step, analogue pathways are considered. These trajectories lead to three transition structures each, for the hydrolysis of BIFOXSiCl 2 (7) and BIFOXSiCl(OH) (8, Figure 4).
Geometry optimizations and frequency computations are performed in gas phase with B3LYP-D3BJ/6-31G(d) at 298 K. For single point energies, M06-2X-D3/6-311++G(d,p) in the solvent THF with the PCM model is used [69,70]. The free Gibbs energies of the respective structures are discussed. The activation energy (E a ) is the difference between the educt and the TS and the reaction energy (E r ) is the difference between the educts and products of the respective steps. The mechanism of hydrolysis, only one molecule of water per hydrolysis step is considered. Additional interactions by THF and water are only considered by the PCM model. Starting with BIFOXSiCl 2 (7), the side and front1 attack mechanism are resulting in BIFOXSiCl(OH) 8 eq . The front2 attack mechanism results in BIFOXSiCl(OH) 8 ax ( Figure 5).
From BIFOXSiCl(OH) 8 eq only the front attack mechanism TS front2 8 eq is possible, which also leads to BIFOXSi(OH) 2 (9), but with the highest E a (40.2 kcal mol −1 , Table 3, entry 5, Figure 5 and Figure 11). In accordance with the crystal structure analysis of BIFOXSiCl(OH) (8, Figure 13), it can be seen that the more stable isomer BIFOXSiCl(OH) 8 ax corresponds to the synthesized isomer. Considering the lowest E a for both steps, the first hydrolysis step is the rate-determining step (7 to 8 eq , TS front1 7 E a = 32.6 kcal mol −1 vs 8 ax to 9, TS side 8 ax E a = 31.4 kcal mol −1 , Table 3, entries 1 and 6, Figure 6 and Figure 9), which agrees with the experimental hydrolysis. Under H 2 O/THF reflux conditions, no BIFOXSiCl(OH) (8) has been isolated, but has to be synthesized separately (Scheme 3, Figure 2 and Figure 3). Both front attack TS have much lower energy, than the TS resulting by side attack mechanism, for the first hydrolysis step (TS front2 7 E a = 33.2 kcal mol −1 , TS front1 7 E a = 32.6 kcal mol −1 vs TS side 7 E a = 37.3 kcal mol −1 , Table 3, entries 1-3, Figures 6-8). Responsible for the lower E a is an additional stabilization by an interaction of the remaining chloro atom to the attacking water (dotted line to the Cl(ax) Figure 6 and Cl(eq) Figure 7). The small energy difference for the TS front1 7 and TS front2 7 is to explained by additional C-H interactions between the fenchyl groups to the leaving chloride (four dotted lines in TS front2 7, Figure 7, five dotted lines in TS front1 7, Figure 6). Through the approach of the attacking water molecule in the side attack mechanism, the chloro atoms are forced to get closer to each other leading to electrostatic repulsion ( Figure 8). Stabilizing C-H interaction from the fenchyl group to the exiting chloride can be found as well (one dotted line in TS side 7, Figure 8).
At the second step, the side mechanism leads to a lower energy barrier (TS side 8 ax E a = 31.4 kcal mol −1 , Table 3, entry 6, Figure 9) than the front attack mechanisms (TS front1 8 ax E a = 33.4 kcal mol −1 , TS front2 8 eq E a = 40.2 kcal mol −1 , Table 3, entries 4 and 5, Figure 10 and Figure 11). In the former mechanism the chloro atom comes closer to the already present hydroxy group (Figure 9).
A contact between the OH(ax) and the Cl(eq) is found, in addition to the C-H interaction (dotted line, Figure 9), which stabilized the leaving Cl ion with a weak hydrogen bond. In the front attack mechanisms for the second hydrolytic step only stabilizing C-H interactions from the fenchyl group to the chloro atom occur (dotted line, Figure 10 and Figure 11).
The silanol group is a better hydrogen bond acceptor than an alcohol group for single hydrogen bonds (CH 3 OH (11.88 kcal mol −1 ) vs SiH 3 OH (16.43 kcal mol −1 ), Table 4, entries 1 and 2), which is more acidic and inconsistent with the results of West et al. [73]. In case of double hydrogen bonds in the glyoxal based system, both are equally strong, because of a third hydrogen bond, a rebond from where water is the acceptor and the oxygen in the ring is the donor ((CH 2 ) 2 O 2 Si(OH) 2 (15.21 kcal mol −1 ) vs (CH 2 ) 2 O 2 C(OH) 2 (15.26 kcal mol −1 ), Table 4, entries 6 and 8), Two possible geometries can be observed for SiCl(OH) 3 . On the one hand with two hydrogen bridges to water (13.60 kcal mol −1 ,  Table 4, entries 11 and 12). In here, the BIFOXSi(OH) 2 (9) binds the chlorid stronger with two hydrogen bridges, than BIFOXSiCl(OH) (8) with just one hydrogen bridge. The BIFOXSi(OH) 2 (9) dimer forms hydrogen bridges, which are stronger than hydrogen bridges with water, but less stronger than hydrogen bridges to chloride (50.97 kcal mol −1 vs 29.18 kcal mol −1 vs 19.88 kcal mol −1 , Table 4, entries 13, 12, and 10).

Chloride binding
The X-ray crystal structures of chlorosilanol 8 ( Figure 17) and silanediol 9 ( Figure 16) with co-crystallized acetone indicate the ability of binding ions or molecules via hydrogen bonds. To in- Table 5: Bond lengths and angles of hydrogen bonds in X-ray crystal structures of BIFOXSiCl(OH) (8) and BIFOXSi(OH) 2 (9).
In DCM the highest yield is isolated, but that is due to a fast background reaction [45]. With toluene as solvent, no background reaction is observed (Table 9, entry 9). To stabilize and improve the ion pair, polar solvents are tested as diethyl ether and dimethylformamide gave no conversion and starting material is obtained (Table 7, entries 4 and 5), acetonitrile and acetone increase the yield (Table 7, entries 6 and 7), but without any enantiomeric excess. In toluene, BIFOXSi(OH) 2 (9), forms 43% yield at −80 °C and 5% ee ( Table 7, entry 8). At higher temperature, 12 is isolated with 52% yield and 12% ee (−60 °C, Table 7, entry 9). Further aromatic solvents are tested ( Table 7, entries 10-13), but without any improvement in yield or ee.  Variation of the catalyst loading suggests a ratio of 10 mol % of BIFOXSi(OH) 2 (9, Table 8, entries 1-4) to be optimal. An increase of temperature results in decreasing yields and ee (Table 8, entries 5-8). The highest ee is found with 20 mol % catalyst (12% ee, 52% yield, Table 7, entry 9).
The substrate scope is broadened with 1-chloroisochroman (18) as alternative substrate (Table 10). The reaction mechanism is Scheme 7: Hydrogen-bond-catalyzed nucleophilic substitution of 18 with BIFOXSi(OH) 2 (9) and nucleophile silyl ketene acetals 11. 18 and 9 form an activated electrophile ion pair complex which yields C-C coupling product 19 (Table 10).    analogue to the N-acyl Mannich reaction (Scheme 6 vs Scheme 7). The catalyst abstracts and binds the chloride anion and forms an ion pair [cat•Cl] − and oxocarbenium ion [18] + . Silyl ketene acetal 11 reacts with this ion pair complex to product 19 [77,78]. Only with DCM as solvent, product 19 of the reaction has been isolated (Table 10). Silanediol 9 and silyl ketene acetal 11a provide the highest yield (85%, Table 10, entry 5). The substitution pattern on the silyl ketene has a direct influence on the yield.
The highest yield is reached with TMS substitution (silanediol 9, 85% yield, Table 10, entry 5; chlorosilanol 8, 54% yield, Table 10, entry 9). The yield decreases as the substituents become larger (Table 10, entries 6-8, 10 and 11). This trend can also be seen in the uncatalyzed reaction (Table 10, entries 13,14). Only for 11c and silandiol 9 a considerable ee with 5% is determined (Table 10, entries 7 and 11). Chlorosilanol 8 does not show catalytic activity for the reaction of 18 with 11a, as the background reaction is slightly faster (54% vs 58%, Table 10, entries 9 and 13). With increasing of the steric demand of the nucleophilic silyl group, the background reaction slows down and chlorosilanol 8 has a positive influence on the yields and the enantiomeric excess.
DFT computations reveal two different hydrolysis mechanisms and explain the unusual low reactivity of BIFOXSiCl 2 (7) and BIFOXSiCl(OH) (8, Table 3) with sterically demanding endo fenchone groups. For BIFOXSiCl(OH) (8) two isomers (8 eq vs 8 ax ) are found computationally. Chlorosilanol 8 ax , with the axial Si-OH alignment, is the thermodynamically more stable isomer (ΔE r = 2.7 kcal mol −1 , Table 3), in accordance with X-ray crystal structure analyses of 8 ( Figure 13). The first hydrolysis has a higher activation barrier than the second step, and thus appears to be rate-determining.
Both new hydrogen bond catalysts can be used for the C-C coupling in the N-acyl Mannich reaction with activated isochinolin 10, 1-chloroisochroman (18) and chromone 21 with different silyl ketene acetals. Due to more efficient bifunctional Si(OH) 2hydrogen bonding, silandiol 9 tops chlorosilanol 8, also on catalytic application.

Computational Details
In this work computations were performed using GAUSSIAN 09 [79]. Geometry optimizations and frequency computations were performed at the B3LYP-D3BJ/6-31G(d) level of theory. Zero-point energies were scaled by 0.96 [80]. Single point energies were performed at the M06-2X-D3/6-311++G(d,p) level of theory using the PCM method.

Synthesis BIFOXSi(OH) 2 (9):
In a dried Schlenk flask BIFOXSiCl 2 (7, 1 g, 1.8 mmol, 1 equiv) was solved in THF (25 mL) and H 2 O (25 mL). The solution was heated to reflux and stirred overnight. Then the solution was concentrated in vacuo and purified by silica gel flash column chromatography (n-hexane/ethyl acetate 9:1, R f : 0.26). BIFOXSi(OH) 2 (9) was obtained as white solid (0. 78 50.5 mg, 10 equiv) was added. The reaction mixture was heated and stirred as stated. After the reaction time the mixture was extracted two times with diethyl ether (2 mL) and concentrated in vacuo. The residue was solved in THF (5 mL). A sample (0.5 mL) was transferred to a GC vial and n-tetradecane solution (0.01 M in THF, 0.5 mL) was added as standard for GC analysis.
General procedure for the N-acyl Mannich reaction of isoquinolin 16 with silyl ketene acetals 11 to product 12: In a heat dried Schlenk tube isoquinolin (16, 11 μL, 0.1 mmol, 1 equiv) was solved in solvent (4 mL) and cooled to 0 °C under inert gas atmosphere. To this solution 2,2,2-trichlorethoxycarbonyl chloride (15 μL, 0.11 mmol, 1.1 equiv) was added. The cooling was removed. The solution warmed to 20 °C and stirred for 30 min. After this the solution was cooled to reaction temperature. The catalyst was added and stirred for 10 minutes. Then silyl ketene acetall 11 (0.15 mmol, 1.5 equiv) was added and the reaction mixture stirred for 6 h. The reaction was quenched by adding NaOMe (0.2 mL, 0.5 M in MeOH), filtered through silica gel with ethyl acetate as eluent and concentrated in vacuo. After further purification by silica gel flash column chromatography (n-hexane/ethyl acetate 95:5) product 12 was obtained. The enantiomeric excess is determined by chiral HPLC analysis (see Supporting Information File 1).
General procedure for addition of silyl ketene acetals 11 to 1-chloroisochroman (18) to product 19: In a heat dried Schlenk tube 1-chloroisochroman (18, 0.15 mmol, 0.3 mL of 0.5 M in toluene) was solved in solvent (1.2 mL) under inert gas atmosphere and cooled to −60 °C. After this catalyst (0.03 mmol, 0.2 equiv) was added and stirred for 10 min. Then silyl ketene acetal 11 (0.22 mmol, 1.5 equiv) was added and the resulting reaction mixture was stirred for 6 h. The reaction was quenched by adding NaOMe (0.2 mL, 0.5 M in MeOH), concentrated in vacuo and purified by silica gel flash column chromatography (n-hexane/Et 2 O 9:1). The enantiomeric excess is determined by chiral HPLC analysis (see Supporting Information File 1).
General procedure for addition of silyl ketene acetals 11 to chromone 20 to product 22: In a heat dried Schlenk tube chromone 20 (14.6 mg, 0.1 mmol, 1 equiv) was solved in 2 mL dried toluene under inert gas atmosphere. TIPSOTf (29.5 μL, 0.11 mmol, 1.1 equiv) was added and heated to 60 °C for 1 h. After this, the reaction mixture was cooled to −80 °C, catalyst (0.02 mmol, 0.2 equiv) and silyl ketene acetal 11 (0.14 mmol, 1.25 equiv), solved in 2 mL dried toluene, were added. The resulting reaction mixture was stirred for 4 h. The reaction was quenched by adding 3 M HCl (0.2 mL), concentrated in vacuo and purified by silica gel flash column chromatography (n-hexane/ethyl acetate 9:1). The enantiomeric excess is determined by chiral HPLC analysis (see Supporting Information File 1).

Supporting Information
Supporting Information File 1 Copies of all NMR spectra, HPLC graphs, GC graphs of the kinetic study.