101402-04-4

Basic information

• Product Name: (S)-4-chloro-diphenylmethanol
• Synonyms: (alphaS)-4-Chloro-alpha-phenylbenzenemethanol;(S)-p-chlorobenzhydrol;(S)-4-chloro-diphenylmethanol;(S)-(4-Chlorophenyl)(phenyl)methanol;(S)-4-Chlorobenzhydrol
• CAS NO: 101402-04-4
• Molecular Formula: C₁₃H₁₁ClO
• Molecular Weight: 218.67884
• Mol File: 101402-04-4.mol
• Article Data: 128

Chemical Properties

• Melting Point: 54-55 °C
• Boiling Point: 352.2±27.0 °C(Predicted)
• Appearance: /
• Density: 1 +-.0.06 g/cm3(Predicted)
• PKA: 13.34±0.20(Predicted)
• CAS DataBase Reference: (S)-4-chloro-diphenylmethanol(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-4-chloro-diphenylmethanol(101402-04-4)
• EPA Substance Registry System: (S)-4-chloro-diphenylmethanol(101402-04-4)

Safety Data

• Hazardous Substances Data: 101402-04-4(Hazardous Substances Data)

Usage

General Description

(S)-4-chloro-diphenylmethanol is a chemical compound with a molecular formula C13H11ClO. It is a chiral molecule, meaning it has a non-superimposable mirror image. (S)-4-chloro-diphenylmethanol is a key intermediate in the synthesis of pharmaceuticals and agrochemicals, and is also used as a building block in the production of various functional materials. It has a wide range of applications in the chemical industry, particularly in the production of chiral catalysts, ligands, and reagents. Additionally, (S)-4-chloro-diphenylmethanol has been studied for its potential antimicrobial and antifungal properties, making it a promising candidate for pharmaceutical development. Overall, this compound plays a crucial role in the synthesis of various products and has the potential for further exploration in biomedical and material science research.

Upstream product

• 119-56-2 (4-chlorophenyl)phenylmethanol 
• 106-39-8 bromochlorobenzene 
• 100-52-7 benzaldehyde 
• 958-06-5 (+/-)-(4-chlorophenyl)(phenyl)methyl acetate 
• 3262-89-3 triphenylboroxine 
• 357417-22-2 N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide 
• 99585-64-5 (2-bromophenyl)(4-chlorophenyl)methanone 
• 104-88-1 4-chlorobenzaldehyde 
• 100-58-3 phenylmagnesium bromide 
• 873-77-8 (4-chlorphenyl)magnesium bromide 
• 108-05-4 vinyl acetate 
• 108-86-1 bromobenzene 
• 313374-39-9 ethylphenylzinc 
• 1078-58-6 diphenylzinc 

Relevant articles and documents

Application of a Heterogeneous Chiral Titanium Catalyst Derived from Silica-Supported 3-Aryl H8-BINOL to Enantioselective Alkylation and Arylation of Aldehydes

A 3-aryl H8-BINOL was grafted on the surface of silica gel using a hydrosilane derivative as a precursor, and the resulting silica-supported ligand (6 mol %) was employed in the enantioselective alkylation and arylation of aldehydes in the pres

Enantioselective additions of diphenylzinc to aldehydes using chiral pyrrolidinylmethanol derivatives as catalysts

The enantioselective addition of diphenylzinc to aldehydes using a series of chiral ligands derived from (S)-proline afforded secondary alcohols in high yields and with high enantiomeric excesses of up to 92.6%. The configuration of the secondary alcohol enantiomer obtained was found to be dependent on the catalyst used.

Catalytic enantioselective aryl transfer to aldehydes using chiral 2,2'-bispyrrolidine-based salan ligands

Chiral C2-symmetric diamines have emerged as versatile auxiliaries or ligands in numerous asymmetric transformations. Chiral 2,2'-bispyrrolidine-based salan ligands were prepared and applied to the asymmetric aryl transfer to aldehydes with arylboronic acids as the source of transferable aryl groups. The corresponding diarylmethanols were obtained in high yields with moderate to good enantioselectivitives of up to 83% ee.

Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a "polar Gate" in Stereorecognition of Diaryl Ketones

Diaryl ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as "difficult-to-reduce" ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora (KpADH) has been identified as a robust biocatalyst due to its high conversion of diaryl ketone substrate (4-chlorophenyl)(pyridine-2-yl)ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a "polarity scanning" strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2-CPMKProR and Mu-S5-CPMKProS were more favorable in the formation of prereaction states. Interestingly, a quadrilateral plane formed by α-carbons of four residues (N136, V161, C237, and G214) was identified at the entrance of the substrate binding pocket of Mu-S5; this plane acts as a "polar gate" for substrates. Due to the discrepancy in charge characteristics between chlorophenyl and pyridine substituents, the pro-S orientation of CPMK is defined when it passes through the "polar gate" in Mu-S5, whereas the similar plane in wild-type is blocked by several aromatic residues. Our result paves the way for engineering stereocomplementary ADH toward bulky diaryl ketones and provides structural insight into the mechanism of stereoselective inversion.

Chiral zinc amidate catalyzed additions of diethylzinc to aldehydes

A series of bifunctional spiro ligands bearing “carboxamide–phosphine oxide” groups and ethylzinc carboxamidates from these ligands as catalysts for Et2Zn additions to aldehydes were reported. Excellent yields were obtained with moderate ee′s in Et2Zn additions to benzaldehyde derivatives, implying effectiveness of our newly designed catalytic structures as well as mediocre stereocontrol by these chiral ligands. Possible transition states were suggested based on the crystal structures of two ligands.

2-Piperidino-1,1,2-triphenylethanol: A Highly Effective Catalyst for the Enantioselective Arylation of Aldehydes

Here we report the use of 2-piperidino-1,2,2-triphenylethanol (5) as an outstanding catalyst for the ligand-catalyzed arylation of aldehydes. The use of 5 and a 2/1 mixture of Et2Zn/Ph2Zn provided the corresponding chiral diarylcarbinols with enantiomeric excess of up to 99% ee. The effect of temperature on the reaction enantioselectivity was studied and the inversion temperature (Tinv) was determined to be 10 °C for reaction with p-tolylaldehyde. Most remarkably, lowering the amount of catalyst (5) to 0.5 mol % still afforded excellent levels of enantiocontrol (93.7% ee). Kinetics of the catalyzed and uncatalyzed arylation of aldehydes was studied by means of in situ FT-IR. The background uncatalyzed addition rates to p-tolylaldehyde when using pure Ph2Zn and Et2Zn/Ph 2-Zn (2/1) suggest that in the latter case a mixed zinc species forms (EtPhZn) minimizing the undesired nonselective addition. Formation of EtPhZn was modeled at the DFT calculation level. A four-center TS (TS-V) corresponding to the Et/Ph scrambling was localized along with two dimers (D-IV and D-VI). The model supports the hypothesis that Et/Ph exchange is a kinetically facile process. Gas evolution experiments during the formation of the active catalyst showed that the formation of an active site with a ONZn-Et (10) moiety is kinetically favored over ONZn-Ph (11). Finally, the phenyl transfer to benzaldehyde was modeled at the PM3(tm) level through anti and syn 5/4/4 tricyclic TS structures for both 10 and 11. The model could correctly predict the sense and selectivity of the overall process and predicted that 11 should be more selective than 10.

New and improved ligands for highly enantioselective catalytic diphenylzinc additions to aryl aldehydes

By introducing electron-withdrawing fluorine atoms to a chiral 1,1'- binaphthyl ligand (R)-1, a new catalyst (S)-5d has been obtained which shows improved catalytic properties for the asymmetric diphenylzinc addition to aldehydes. This new ligand allows the synthesis of chiral diarylcarbinols with high enantioselectivity in shorter reaction time under simple reaction conditions.

A highly enantioselective and catalytic aryl transfer reaction using mixed triarylbismuthane and dialkylzinc reagents

Highly enantioselective and catalytic aryl transfer reactions to aromatic aldehydes by using mixed triarylbismuthane and dimethylzinc reagents were studied. In the presence of a chiral β-amino alcohol catalyst, chiral diarylmethanols with up to 97 % ee were obtained. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Zn(salen)-catalyzed enantioselective phenyl transfer to aldehydes and ketones with organozinc reagent

Abstract A chiral zinc complex of salen was found to be an efficient catalyst for the phenyl transfer of organozinc reagent to aromatic aldehydes and ketones. High enantioselectivities were obtained in reactions of both aromatic aldehydes and ketones (up to 97% and 92% ee, respectively).

Synthesis of aminomethyl quinazoline based ruthenium (II) complex and its application in asymmetric transfer hydrogenation under mild conditions

The new chiral aminomethyl quinazoline (amq) type ligand derived from L-phenylalanine was synthesized and coordinated with [RuCl2(PPh3)dppb] to obtain ruthenium(II) complex. This catalyst displayed considerable reactivity (up to 97% ee and 99% conversion) in the asymmetric transfer hydrogenation of ketones using 2-propanol as a hydrogen source in the presence of NaOiPr.

Hydroclassified Combinatorial Saturation Mutagenesis: Reshaping Substrate Binding Pockets of KpADH for Enantioselective Reduction of Bulky-Bulky Ketones

A hydroclassified combinatorial saturation mutagenesis (HCSM) strategy was proposed for reshaping the substrate binding pocket by dividing 20 amino acids into four groups based on their hydrophobicity and size. These smart HCSM libraries could significantly reduce screening effort especially for the simultaneous mutagenesis of three or more residues and lacking high throughput screening methods. Employing HCSM strategy, the stereoselectivity of KpADH, an alcohol dehydrogenase from Kluyveromyces polysporus, was efficiently improved to 99.4% ee. (4-Chlorophenyl)(pyridin-2-yl)methanone (CPMK), generally regarded as a "hard-to-reduce" ketone, was used as a model substrate, and its corresponding chiral alcohol products could be utilized as antihistamine precursors. The best variant 50C10 displayed higher binding affinity and catalytic efficiency toward CPMK with KM/kcat of 59.3 s-1·mM-1, 3.51-fold that of KpADH. Based on MD simulations, increased difference between two binding pockets, enhanced hydrophobicity, and π-π and halogen-alkyl interactions were proposed to favor the enantioselective recognition and substrate binding in 50C10. Substrate spectrum analysis revealed that 50C10 exhibited improved enantioselectivity toward diaryl ketones especially with halo- or other electron-withdrawing groups. As much as 500 mM CPMK could be asymmetrically reduced into chiral diaryl alcohols with ee of 99.4% and a space-time yield of 194 g·L-1·d-1 without addition of external NADP+. This study provides an effective mutagenesis strategy for the protein engineering of substrate specificity and enantioselectivity.

Remarkably efficient enantioselective titanium(IV)-(R)-H 8-BINOLate catalyst for arylations to aldehydes by triaryl(tetrahydrofuran)aluminum reagents

Novel asymmetric triarylaluminum AlAr3(THF) additions to aldehydes catalyzed by 10 mol % of the titanium(IV) complex of (R)-H8-BINOL ligand are reported. The catalytic system is extremely efficient with reactions completing within 10 min. The system applies to the most diversified aldehydes to date, and more than 20 aldehydes were examined to afford diarylmethanols having an electron-donating or an electron-withdrawing group at the 2-, 3-, or 4-position on the aryl moiety, linear or branched 1-aryl aliphatic alcohols, aryl furyl methanols, 1-aryl allylic alcohols, and, especially, 1-aryl propargylic alcohols in excellent enantioselectivities of ≥90% ee, except for the case of 1-naphthyl addition to benzaldehyde. Noteworthily, diarylmethanols in both R- and S-configurations can be obtained. Copyright

The Mg-oppenauer oxidation as a mild method for the synthesis of aryl and metallocenyl ketones

Magnesium alkoxides undergo a hydride-transfer oxidation with benzaldehyde as the oxidant. This magnesium variant of the Oppenauer oxidation was used for the synthesis of polyfunctional biaryl ketones. LiCl was found to promote this reaction by enhancing the solubility of magnesium alkoxides. This mild oxidation method was especially useful for preparing ketones bearing a metallocenyl unit as well as various new ferrocenyl ketones and tricarbonylchromium complexes. This last class of ketones was reduced with the CBS catalyst (CBS = Corey-Bakshi-Shibata, diphenyl oxazaborolidine) to chiral benzhydrol complexes with high enantioselectivity enabling an asymmetric synthesis of electronrich or -poor benzhydryl alcohols (up to 94% ee).

Synthesis of new alkoxy/sulfonate-substituted carbene precursors derived from [2.2]paracyclophane and their application in the asymmetric arylation of aldehydes

A series of novel planar chiral alkoxy/sulfonate-substituted carbene precursors have been designed and synthesized. They were used as N-heterocyclic carbene ligands in the Rh-catalyzed asymmetric addition of arylboronic acids to aromatic aldehydes, affording chiral diarylmethanols with high yields and moderate enantioselectivities.

Enantioselective rhodium-catalyzed addition of arylboronic acids to aldehydes using chiral spiro monophosphite ligands

Highly efficient rhodium-catalyzed asymmetric addition of arylboronic acids to aldehydes has been realized by using chiral spiro monophosphite ligands, affording diarylmethanols in excellent yields and good enantiomeric excesses.

Me-bipam for enantioselective ruthenium(II)-catalyzed arylation of aldehydes with arylboronic acids

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Asymmetric 1,4-addition of organoboronic acids to α,β-unsaturated ketones and 1,2-addition to aldehydes catalyzed by a palladium complex with a ferrocene-based phosphine ligand

A combination of palladium with ferrocene-based phosphine ligand with a carbon-bromine bond was found to be a good catalyst for the 1,4-addition of arylboronic acids to α,β-unsaturated ketones and the 1,2-addition to aldehydes. Using Pd(dba)2 and (S,Rp)-[1-(2-bromoferrocenyl)ethyl]diphenylphosphine (S,Rp)-1, 3-phenylcyclohexanone was obtained from the reaction of 2-cyclohexen-1-one with phenylboronic acid in the presence of K2CO3 in toluene at room temperature after 3 h in 92% yield with 76% ee. In the 1,2-addition of 4-methylphenylboronic acid to benzaldehyde, 96% of (4-methylphenyl)phenylmethanol was afforded after 24 h, while the enantiomeric excess was only 6%.

Highly enantioselective addition of in situ prepared arylzinc to aldehydes catalyzed by a series of atropisomeric binaphthyl-derived amino alcohols

The direct addition of in situ prepared arylzinc to aldehydes with chiral binaphthyl-derived amino alcohols as catalysts can afford optically active diarylmethanols in high yields and with excellent enantioselectivities (up to 99% ee, ee = enantiomeric excess). By using a single catalyst, both enantiomers of many pharmaceutically interesting diarylmethanols can be obtained by the proper combination of various arylzinc reagents with different aldehydes; this catalytic system also works well for the phenylation of aliphatic aldehydes to give up to 96 % ee.

Triarylborane ammonia complexes as ideal precursors for arylzinc reagents in asymmetric catalysis

(Chemical Equation Presented) The value of arylboranes as precursors for arylzinc reagents in asymmetric catalysis is demonstrated. Kinetic studies on the transmetalation reaction with zinc reagents rationalize the observed differences of three classes of arylboranes in catalytic applications. By using the stable and easily accessible triarylborane ammonia complexes, an array of chiral diarylmethanols in high yield and enantioselectivity was synthesized.

Organosilanols as catalysts in asymmetric aryl transfer reactions

(Chemical Equation Presented) Various ferrocene-based organosilanols have been synthesized in four steps starting from achiral ferrocene carboxylic acid. Applying these novel planar-chiral ferrocenes as catalysts in asymmetric phenyl transfer reactions to substituted benzaldehydes afforded products with high enantiomeric excesses. The best result (91% ee) was achieved in the addition to p-chlorobenzaldehyde with organosilanol 2b, which has a tert-butyl substituent on the oxazoline ring and an isopropyl group on the silanol fragment.

Chiral 1,1′-binaphthylazepine-derived amino alcohol catalyzed asymmetric aryl transfer reactions with boroxine as aryl source

Using chiral 1,1′-binaphthylazepine-derived amino alcohol as catalyst, the direct addition of in situ prepared arylzinc (with triphenylboroxine as aryl source) to various aryl aldehydes can afford optically active diarylmethanols in high yields and enantioselectivities (up to 96%).

Application of β-hydroxysulfoximines in catalytic asymmetric phenyl transfer reactions for the synthesis of diarylmethanols

(Chemical Equation Presented) Enantiomerically enriched diarylmethanols have been prepared by catalyzed asymmetric phenyl transfer reactions onto aromatic aldehydes with use of readily available β-hydroxysulfoximines as catalysts. As the aryl source, combinations of diethylzinc with either diphenylzinc or triphenylborane have been applied affording arylphenylmethanols with up to 93% ee in good yields. Various functionalized aldehydes and heterocyclic substrates are tolerated, yielding synthetically relevant products.

Fine tuning the enantioselectivity and substrate specificity of alcohol dehydrogenase from Kluyveromyces polysporus by single residue at 237

Here, S237 was identified to be important in fine tuning the substrate specificity and enantioselectivity of alcohol dehydrogenase from Kluyveromyces polysporus (KpADH). In the reduction of a diaryl ketone, (4-chlorophenyl)-(pyridin-2-yl)-methanone (1a), the highest and lowest enantioselectivity of 96.1% and 27.0% e.e. (R) were obtained with S237A and S237C. Kinetic parameters analysis revealed that S237G, S237A, S237H and S237D displayed improved kcat/Km toward 1a. Various prochiral ketones, including acetophenone, 4-chloroacetophenone and ethyl 2-oxo-4-phenylbutyrate could be asymmetrically reduced by S237C, S237G and S237E with > 99% e.e. This study provides guidance for the application of KpADH in the preparation of chiral secondary alcohols.

Catalyzed asymmetric aryl transfer reactions to aldehydes with boronic acids as aryl source

Chiral diaryl methanols are important intermediates for the synthesis of biologically active compounds. Here, we describe a flexible method for their catalyzed asymmetric synthesis from readily available starting materials. Noteworthy is the fact that wit

STEREOSELECTIVE REDUCTION OF SUBSTITUTED BENZOPHENONES BY MICROORGANISMS I.

Debaryomyces marama enentioselectively reduces p-Cl-benzophenone to the S-alcohol with high enantiomeric excess.

Binaphthyl-prolinol chiral ligands: Design and their application in enantioselective arylation of aromatic aldehydes

Binaphthyl-prolinol ligands were designed and applied in enantioselective arylation of aromatic aldehydes and sequential arylation-lactonization of methyl 2-formylbenzoate. Under optimized conditions, the reactions provided the desired diarylmethanols and 3-aryl phthalides in up to 96% yields with up to 99% ee and up to 89% yields with up to 99% ee, respectively. In particular, essentially optically pure 3-aryl phthalides (over 99% ee) were obtained in large quantities through recrystallization. This journal is

Rhizopus arrhizus mediated SAR studies in chemoselective biotransformation of haloketones at ambient temperature

We have demonstrated a green chemistry approach using the fungus Rhizopus arrhizus for the reductive dehalogenation and synthesis of chiral secondary carbinols and halohydrins of pharmaceutical importance in mild, inexpensive, and environmental friendly process at ambient temperature. In the present study, we have succeeded in unravelling the relationship between the position of the substituent group in the structure of substrate and bioreduction activity of the fungus Rhizopus arrhizus. The asymmetric reduction of the carbonyl group to corresponding chiral halohydrin takes place with good yield and excellent enantiomeric excess (≥92%) when the substituent halogen is on the aromatic nucleus. However, novel results concerning reductive dehalogenation are obtained when halogen is incorporated in the alkyl side chain. Thus, the fungus Rhizopus arrhizus has great potential to bring chemoenzymatic biotransformation of halo ketones. Various influential processing parameters such as microbe selection, temperature, pH, etc. were also investigated to optimize the growth of biocatalyst.