BENZYLIC ACID

Benzilic acid is an organic compound with formula C14H12O3 or (C6H5)2(HO)C(COOH). 
Benzilic acid is a white crystalline aromatic acid, soluble in many primary alcohols.
Benzilic Acid, also known as Diphenyl glycolic acid or Hydroxydiphenyl acetic acid, is used in organic synthesis as a starting point for preparation of glycollate pharmaceuticals. 
Ungraded products supplied by Spectrum are indicative of a grade suitable for general industrial use or research purposes and typically are not suitable for human consumption or therapeutic use.

CAS Number: 76-93-7
EC Number: 200-993-2
IUPAC Name: Hydroxydi(phenyl)acetic acid
Chemical Formula: C14H12O3

Other names: Benzilic acid, 76-93-7, Diphenylglycolic acid, 2-Hydroxy-2,2-diphenylacetic acid, Benzylic acid, hydroxy(diphenyl)acetic acid, Diphenylhydroxyacetic acid, Glycolic acid, diphenyl-, Hydroxydiphenylacetic acid, Acide diphenylhydroxyacetique, Benzilsaeure, alpha-Hydroxy-2,2-diphenylacetic acid, 2,2-Diphenyl-2-hydroxyacetic acid, alpha-Hydroxy-alpha-phenylbenzeneacetic acid, NSC 2830, alpha-phenylmandelic acid, MFCD00004447, Benzeneacetic acid, .alpha.-hydroxy-.alpha.-phenyl-, 8F6J993XXR, Mandelic acid, .alpha.-phenyl-, alpha,alpha-Diphenylglycolic acid, CHEBI:39414, Benzeneacetic acid, alpha-hydroxy-alpha-phenyl-, NSC-2830, .alpha.,.alpha.-Diphenylglycolic acid, .alpha.-Hydroxy-2,2-diphenylacetic acid, alpha,alpha-Diphenyl-alpha-hydroxyacetic acid, .alpha.-Hydroxy-.alpha.-phenylbenzeneacetic acid, .alpha.,.alpha.-Diphenyl-.alpha.-hydroxyacetic acid, Mandelic acid, alpha-phenyl-, EINECS 200-993-2, Acide diphenylhydroxyacetique [French], BRN 0521402, UNII-8F6J993XXR, Benzillic acid, AI3-06300, HSDB 7709, 4hnc, 2-hydroxy-2,2-diphenyl-acetic acid, Benzilic acid, >=99%, BENZILIC ACID [MI], SCHEMBL7066, Oprea1_231381, BENZILIC ACID [HSDB], CHEMBL578171, DTXSID0058805, BDBM81768, NSC2830, .alpha.-Hydroxydiphenylacetic acid, BBL013081, ICCB1_000122, STK315343, AKOS000120948, NSC_5311391, NCGC00165988-01, AC-13764, VS-03659, alpha-phenyl-alpha-hydroxyphenylacetic acid, CAS_6581-06-2, B0052, NS00037863, D88594, A838905, Q411740, SR-01000400770, TROSPIUM CHLORIDE IMPURITY A [EP IMPURITY], SR-01000400770-1, W-104335, DIPHENYL-HYDROXY-ACETIC ACID (BENZILIC ACID), Trospium impurity A, European Pharmacopoeia (EP) Reference Standard, 0UT, InChI=1/C14H12O3/c15-13(16)14(17,11-7-3-1-4-8-11)12-9-5-2-6-10-12/h1-10,17H,(H,15,16

Uses of Benzilic acid:
Benzilic acid is used in the manufacture of glycollate pharmaceuticals including clidinium, dilantin, flutropium, and mepenzolate which are antagonists of the muscarinic acetylcholine receptors.
Benzilic acid is used in manufacture of the incapacitating agent 3-quinuclidinyl benzilate (BZ) and is regulated by the Chemical Weapons Convention.

Benzilic acid is also monitored by law enforcement agencies of many countries, because of its use in the manufacture in hallucinogenic drugs.
Use: Benzilic Acid is an impurity of Trospium. 
Trospium is a derivative of tropine with anticholinergic property, which is used in the treatment of urinary incontinence as an antispasmodic.

Chemical Properties of Benzilic acid
Benzilic acids form is white powder
A white crystalline aromatic acid soluble in many primary alcohols, which can be prepared by heating a mixture of benzil, alcohol, and potassium hydroxide.

Uses of Benzilic acid
Benzilic Acid is an impurity of Trospium (T892800), a tropine derivative with anticholinergic activity and a antiispasmodic agent.

Preparation of Benzilic acid
Benzilic acid can be prepared by a heating mixture of benzil, ethanol ,and potassium hydroxide.
Another preparation, performed by Liebig in 1838, is the dimerization of benzaldehyde, to benzil, which is transformed to the product by the benzilic acid rearrangement reaction.

The benzilic acid rearrangement takes place with a yield greater than 90% for benzil itself and with lesser yields for substituted benzils, depending upon the kind and number of groups. 
In several cases where the substitute groups were in the ortho-positions to the carbonyl groups, the rearrangement proceeds with yields of 60% to 70%, for instance, o-tolil and mesityl phenyl diketone.

Nesitil was found to he hindered greatly enough that no detectable rearrangement takes place. 
The purpose of this work was to locate the point beyond which the rearrangement no longer takes place because of steric hindrance. 
The plan was to increase the hindrance gradually until the rearrangement was prevented; the reaction was carried out using three hindered diketones.

Benzilic acid is used in the manufacture of glycollate pharmaceuticals including clidinium, dilantin, flutropium, and mepenzolate which are antagonists of the muscarinic acetylcholine receptors.

Benzilic acid is a white crystalline aromatic acid soluble in many primary alcohols. 
Benzilic acid can be prepared by heating mixture of benzil, alcohol and potassium hydroxide. 
The other preparation way is through benzaldehyde, which dimerizates to benzil and it is further transformed by benzilic acid rearrangement to benzilic acid. 
This reaction was also the first example of benzilic acid rearrangement preformed by Liebig in 1838.

Principle: In the first step alcohol group of benzoin is oxidized to ketone group forming benzil in presence of concentrated nitric acid.
Nitration of aromatic ring is not occurring as sulphuric acid is totally absent in the whole process. 
In the second step on treatment with hydroxide ion molecular rearrangement occurs to 1,2-diketone forming potassium salt of α-hydroxy acid which on acidification yield α-hydroxy acid (benzilic acid).

Since its discovery the Benzilic acid rearrangement has been the subject of a number of mechanistic studies and successfully employed in key steps in the synthesis of a number of important target molecules. 
In this review we look at the advances that have been made over the last 20 years in understanding the mechanism of this rearrangement (including the stereochemical aspects), whilst reviewing some important syntheses where this particular rearrangement was used as a key step.

General advice
Consult a physician. Show this safety data sheet to the doctor in attendance.
Move out of dangerous area.

Synthesis Reference(s)
The Journal of Organic Chemistry, 29, p. 1631, 1964 DOI: 10.1021/jo01029a509

Safety Profile
Moderately toxic by subcutaneousroute. 
Slightly toxic by ingestion. 
When heated todecomposition it emits acrid smoke and irritating vapors.

Purification Methods
Crystallise benzilic acid from *benzene (ca 6mL/g), or hot H2O.

For most of the experiments we have performed this semester, we have set out to convert one chemical into another with various different methods. 
For a synthetic organic chemist the product of one reaction is often used as the reactant in another.  
This is also the situation that occurs in biochemistry where different chemical pathways use a newly synthesized product to be a reactant for the next reaction in that pathway.

This is particularly important for the current experiment because the first chemical transformation occurs using a vitamin as the "co-enzyme" for the synthesis of benzoin.
While enzymes are normally considered to the biological catalysts in cells, Benzilic acid is often a co-enzyme, derived from a vitamin, that actually performs the biochemical transformation. 
Thiamine, vitamin B1, will be used in the current experiment to convert benzaldehyde into benzoin.  

The benzoin produced in the first experiment will then be used in the second to produce benzil.  
Likewise, the benzil will then be used to synthesize benzilic acid. 
Hence, a multi-step synthesis of different compounds. 
These new compounds can then be used in various different applications, some of which are for medicinal purposed.

The student can research their ultimate uses to observe that no chemical synthesis is for naught. 
The last experiment requires the student to devise a method to convert benzaldehyde into benzoic acid, perhaps employing oxidation methods used previously, or use a method that might be new to the student, even something not previously discussed during lecture or lab. 
Therefore, to provide a variety of methods for producing benzoic acid, students should work independently, examining general oxidation methods for converting aldehydes into acids obtained searching the chemical literature.

Reaction mechanism
The reaction is a representative of 1,2-rearrangements. 
The long-established reaction mechanism was first proposed in its entirety by Christopher Kelk Ingold, and has been updated with in silico data as outlined below. 
The reaction is second order overall in terms of rate, being first order in diketone and first order in base.

A hydroxide anion attacks one of the ketone groups in 1 in a nucleophilic addition to form the alkoxide . 
The next step requires a bond rotation to conformer 3 which places the migrating group R in position for attack on the second carbonyl group. 
In a concerted step, the migrating R group attacks the α-carbonyl group forming another alkoxide with concomitant formation of a keto-group at the other carbon.

This migration step is rate-determining. 
This sequence resembles a nucleophilic acyl substitution. 
Calculations show that when R is methyl the charge build-up on this group in the transition state can be as high as 0.22 and that the methyl group is positioned between the central carbon carbon bond!

The benzilic acid rearrangement is formally the 1,2-rearrangement of 1,2-diketones to form α-hydroxy–carboxylic acids using a base. 
This reaction receives its name from the reaction of benzil with potassium hydroxide to form benzilic acid. 
First performed by Justus von Liebig in 1838, Benzilic acid is the first reported example of a rearrangement reaction.

Molar mass: 228.247 g·mol−1
Appearance: white solid
Density: 1.08 g/cm3
Melting point: 150 to 152 °C

Boiling point: 180 °C
Solubility in water: 2 g/L (20 °C)
Molecular Weight: 228.24 g/mol
XLogP3: 2.3

Hydrogen Bond Donor Count: 2
Hydrogen Bond Acceptor Count: 3
Rotatable Bond Count: 3
Exact Mass: 228.078644241 g/mol

Monoisotopic Mass: 228.078644241 g/mol
Topological Polar Surface Area: 57.5Ų
Heavy Atom Count: 17
Complexity: 245
Covalently-Bonded Unit Count: 1
Compound Is Canonicalized: Yes

Benzilic acid has become a classic reaction in organic synthesis and has been reviewed many times before.
Benzilic acid can be viewed as an intramolecular disproportionation reaction, as one carbon center is oxidized while the other is reduced.

The reaction has been shown to work in aromatic, semi-aromatic, aliphatic, and heterocyclic substrates. 
The reaction works best when the ketone functional groups have no adjacent enolizable protons, as this allows aldol condensation to compete. 
The reaction is formally a ring contraction when used on cyclic diketones. 
Benzilic acid has been found that aryl groups more readily migrate than alkyl groups, and that aryl groups with electron-withdrawing groups migrate the fastest.

The carboxylic acid in intermediate is less basic than the alkoxide and therefore reversible proton transfer takes place favoring intermediate which is protonated on acidic workup to the final α-hydroxy–carboxylic acid. 
Calculations show that an accurate description of the reaction sequence is possible with the participation of water molecules taking responsibility for the stabilization of charge buildup. 
They also provide a shuttle for the efficient transfer of one proton in the formation of intermediate.

The above mechanism is consistent with all available experimental evidence.
The equilibrium between species 1 and 2 is supported by 18O Isotopic labeling experiments. 
In deuterated water, carbonyl oxygen exchange occurs much faster than the rearrangement, indicating that the first equilibrium is not the rate-determining step.

Further experiments showed a larger relative rate in a deuterated solvent system compared to a non-deuterated solvent system of otherwise identical composition. 
This was explained as being due to the greater relative basicity of the deuterated hydroxide anion compared to the normal hydroxide anion, and was used to indicate that hydrogen migration did not occur in the rate determining step of the reaction. 
This ruled out a concerted mechanism for the reaction, as hydrogen transfer would occur in the rate determining step.

Variations
Benzilic ester rearrangement
This reaction is identical to the normal benzilic acid rearrangement, except that an alkoxide or an amide anion is used in place of a hydroxide ion. 
The alkoxide used should not be easily oxidizable (such as potassium ethoxide) as this favors the Meerwein–Ponndorf–Verley reduction pathway as a side reaction. 
The reaction is second order overall in terms of rate, being first order in terms of alkoxide and first order in terms of diketone. 
The product of the reaction is an α-hydroxy–ester or an α-hydroxy-amide.

Alpha-ketol rearrangement
The alpha-ketol rearrangement is an interconversion of a hydroxyl alpha to a carbonyl to the complementary carbonyl and hydroxyl groups, with migration of a substituent. 
Benzilic acid is mechanistically equivalent to the benzyllic acid rearrangement at the point after the nucleophile attacks the 1,2-dicarbonyl. 
This variation of the reaction has been known to occur in many substrates bearing the acyloin functional group. 

Question:
Why does benzilic acid only precipitates in acidic solution and why does the pH needs to be < 2 to precipitate the benzilic acid?

Effect of pH on Structure:
The pH of the solution can be used to assess the acidity or alkalinity of a solution. 
The pH of solution is important since the structure of some compounds can be altered at different pH values. 
Some compounds have groups in their structures that can undergo acid-base reactions.

Benzilic acid was synthesized through a multistep reaction from the starting material of benzaldehyde and through the formations of benzoin and benzil.  
The first reaction produced benzoin by using the thiamine hydrochloride catalyst, followed by an oxidation reaction to produce benzil, and a rearrangement to synthesize benzilic acid.  
By utilizing crystallization, pure solid products of each step were collected and analyzed through IR, NMR spectroscopy, and other physical properties.

About Benzilic acid
Benzilic acid is registered under the REACH Regulation and is manufactured in and / or imported to the European Economic Area, for intermediate use only.
Benzilic acid is used in formulation or re-packing, at industrial sites and in manufacturing.