| HS Code | 557663 |
| Product Name | Phenylacetic Acid |
| Iupac Name | 2-Phenylacetic acid |
| Synonyms | Benzeneacetic acid; alpha-Toluic acid; Phenylacetic acid |
| Cas Number | 103-82-2 |
| Einecs Number | 203-148-6 |
| Molecular Formula | C8H8O2 |
| Molecular Weight | 136.15 g/mol |
| Chemical Classification | Aromatic carboxylic acid |
| Appearance | White to off-white crystalline solid or powder |
| Odor | Sweet, honey-like, floral odor |
| Melting Point | 76-77 °C |
| Boiling Point | 265.5 °C at 760 mmHg |
| Density | 1.0809 g/cm³ at 25 °C |
| Solubility | Soluble in water (about 15 g/L at 25 °C), ethanol, ether, and chloroform |
| Pka | 4.31 at 25 °C |
| Logp | 1.41 |
| Vapor Pressure | 0.008 mmHg at 25 °C |
| Flash Point | 132.2 °C (closed cup) |
| Refractive Index | 1.512 (supercooled liquid) |
| Storage Conditions | Store in a cool, dry, well-ventilated area away from oxidizers and sources of ignition |
As an accredited Phenylacetic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Phenylacetic acid packaged in 25 kg net weight polyethylene-lined fiber drums with securely sealed lids and chemical-resistant labels. |
| Container Loading (20′ FCL) | Phenylacetic acid chemical in 25 kg bags, palletized, floor-loaded and secured in a 20′ FCL container for safe export. |
| Shipping | Phenylacetic acid is shipped as a non-hazardous solid in sealed, labeled containers. Keep dry and away from heat, moisture, oxidizers, and strong bases. It is not UN/DOT/IATA regulated for transport unless part of a hazardous mixture. Maintain documentation and follow DEA List I requirements where applicable. |
| Storage | Store phenylacetic acid in a cool, dry, well-ventilated area away from heat, sparks, and open flames. Keep containers tightly closed, properly labeled, and upright to prevent leaks. Protect from moisture and direct sunlight. Segregate from strong oxidizers, bases, and incompatible materials. Use corrosion-resistant containers and secondary containment where appropriate. Follow local regulations and SDS requirements. |
| Shelf Life | Phenylacetic acid has a shelf life of approximately 24 months when stored sealed in a cool, dry, dark place. |
Phenylacetic acid (CAS 103-82-2) functions as a side-chain precursor rather than a carbon source in benzylpenicillin fermentation with Penicillium chrysogenum. The acid is taken up from the broth, activated to phenylacetyl-CoA, and condensed with 6-aminopenicillanic acid by acyl-CoA:6-aminopenicillanic acid acyltransferase. Industrial fed-batch processes use a sodium phenylacetate feed solution, typically 20–30% w/w, delivered through a sterilizing-grade filter into the production vessel. The residual free phenylacetic acid concentration is maintained between 0.4 g/L and 0.8 g/L. Strain-specific inhibition thresholds are reported from 0.7 g/L to 1.5 g/L; above this range cell respiration declines and penicillin titre falls. Below 0.2 g/L the side-chain exchange step becomes rate-limiting and benzylpenicillin productivity drops. Production vessels in this route are mechanically agitated stirred-tank bioreactors with working volumes from 120,000 L to 200,000 L, fitted with multiple Rushton impellers and a ring sparger. Dissolved oxygen is held above 30% of air saturation by cascading agitation speed and airflow from 0.6 vvm to 1.0 vvm. The pH is controlled at 6.3–6.8 with aqueous ammonia, and temperature is maintained at 25–27 °C.
| Process variable | Control range | Analytical or sensor method |
|---|---|---|
| Residual phenylacetic acid in broth | 0.4–0.8 g/L | HPLC-UV at 210 nm after 0.22 µm filtration |
| pH | 6.3–6.8 | steam-sterilizable glass electrode |
| Temperature | 25–27 °C | resistance temperature detector |
| Dissolved oxygen | >30% of air saturation | polarographic DO probe |
| Aeration | 0.6–1.0 vvm | thermal mass flow meter |
After fermentation the broth is cooled to 5–10 °C and filtered on a rotary vacuum filter or cross-flow filter. The filtrate is acidified to pH 2.0–2.5 with sulfuric acid, and benzylpenicillin is extracted into butyl acetate. Back-extraction into a phosphate buffer and crystallization as the potassium or sodium salt yields the finished active substance. Benzylpenicillin potassium (CAS 113-98-4) and benzylpenicillin sodium (CAS 69-57-8) are controlled under the USP monograph and the European Pharmacopoeia monograph for benzylpenicillin. Residual phenylacetic acid is a specified related substance; liquid chromatography methods in the monographs quantify it against a phenylacetic acid reference standard.
Conversion of phenylacetic acid to the methyl and ethyl esters proceeds through acid-catalyzed esterification with the corresponding alcohol. Methanol esterification is run at reflux, 64–65 °C, while ethyl esterification is held at 78–82 °C; benzyl ester formation requires 100–120 °C under 150–200 mbar. p-Toluenesulfonic acid is charged at 0.5–1.5 mol% relative to phenylacetic acid. Water is removed by a Dean-Stark trap or by azeotropic distillation with cyclohexane to drive equilibrium conversion above 95%. The reaction mass is neutralized with sodium carbonate, washed with brine, and distilled under vacuum; finished ester purity is typically above 98% by GC-FID. Methyl phenylacetate (CAS 101-41-7), ethyl phenylacetate (CAS 101-97-3), and benzyl phenylacetate (CAS 102-16-9) are used as honey, rose, and cocoa modifiers in fragrance compounds. Typical use levels in fine fragrance concentrate are 0.05–1.5% w/w; leave-on skin products generally fall below 0.2% w/w of the ester. Food use is covered in the United States under 21 CFR 172.515 and in the European Union under Regulation (EC) No 1334/2008. Cosmetic products must meet EU Regulation (EC) No 1223/2009 and the applicable IFRA standard for the specific ester. Thermal processing above 140 °C is avoided because phenylacetic acid and its esters can undergo decarboxylation to toluene and color-forming side reactions. Terminal products include fine fragrance oils, shampoo and body wash fragrances, laundry powder perfumes, and fruit flavor emulsions.
In benalaxyl synthesis, phenylacetic acid is first converted to phenylacetyl chloride (CAS 103-80-0) because the acid chloride acylates secondary amines cleanly at low temperature. The chlorination uses thionyl chloride at 1.2–1.5 molar equivalents with dimethylformamide at 0.2–0.5 mol% as catalyst. The batch is held at 55–75 °C until gas evolution stops; excess thionyl chloride is stripped at 40 °C under 10 mbar. The resulting phenylacetyl chloride is assayed by argentometric titration after hydrolysis and is stored under nitrogen because it reacts violently with water. Acylation of methyl N-(2,6-dimethylphenyl)alaninate is run in a two-phase toluene/water system with sodium carbonate as acid scavenger. The acid chloride is charged at 1.03–1.10 molar equivalents relative to the amine at 0–10 °C, with the aqueous phase kept at pH 8–9. Overcharge above the specified mole ratio leads to N,N-diacylation and yield loss; undercharge leaves unreacted amine that is difficult to purge from the product. The reaction endpoint is confirmed by HPLC, and benalaxyl (CAS 71626-11-4) is isolated by phase separation, vacuum solvent stripping, and crystallization from methanol/water. Where benalaxyl is registered as a plant protection product, the active substance is assessed under Regulation (EC) No 1107/2009, and residue limits are set under Regulation (EC) No 396/2005. Terminal products are systemic fungicide formulations for control of oomycete pathogens in grape, potato, and ornamental crops.
When phenylacetic acid is dehydrated via phenylacetamide to phenylacetonitrile, the downstream chemistry supplies small-molecule API building blocks. The acid is converted to phenylacetyl chloride and then to phenylacetamide (CAS 103-81-1) by reaction with aqueous ammonia at 0–5 °C, or by direct ammonolysis of methyl phenylacetate at 80–90 °C under 8–10 bar. Dehydration of phenylacetamide with phosphorus pentoxide at 1.2–1.5 mol per mol amide in refluxing xylene gives phenylacetonitrile (CAS 140-29-4), which is distilled at reduced pressure. Phenylacetonitrile is alkylated with ethyl bromide in the presence of sodium ethoxide to give 2-phenylbutyronitrile, a documented precursor to phenobarbital (CAS 50-06-6). Phenobarbital API is crystallized and released under the corresponding USP monograph; related substances are controlled under ICH Q3A. The nitrile and amide intermediates are handled as REACH-registered intermediates under strictly controlled conditions under Regulation (EC) No 1907/2006. The route is selected because the cyano group can be alkylated without protecting the aromatic ring and because the phenylacetamide intermediate avoids the uncontrolled exotherm that can occur with direct phenylacetyl chloride aminolysis in polar solvents. Terminal products are anticonvulsant active pharmaceutical ingredients and their registered intermediates.
Pharmacopoeial impurity methods for benzylpenicillin salts include phenylacetic acid as a process-related substance because the fermentation feed is never fully consumed. The liquid chromatography method uses a C18 column, 250 mm × 4.6 mm, 5 µm particle size, with phosphate buffer and acetonitrile mobile phase and UV detection at 210 nm. The phenylacetic acid peak is identified by retention time and spiking with a certified reference standard. Acceptance limits differ between the USP and European Pharmacopoeia monographs and depend on the salt form; where a limit is not harmonized, the manufacturer justifies the specification under ICH Q6A. The same reference standard is used during process validation to demonstrate that the solvent extraction and crystallization steps reduce residual phenylacetic acid below the registered specification. Batch-to-batch variation is documented during production-scale process validation runs. The terminal use is a quality-control reagent and impurity marker for API batch release and stability testing.
Reduction of phenylacetyl chloride over a sulfur-poisoned palladium catalyst in toluene at 15–25 °C yields phenylacetaldehyde, which is immediately acetalized with methanol to phenylacetaldehyde dimethyl acetal (CAS 101-48-4). The Rosenmund reduction uses hydrogen at 1–3 bar and palladium on barium sulfate; without sulfur poisoning, the catalyst over-reduces the aldehyde to 2-phenylethanol. The aldehyde is quenched into methanol containing 1.0–2.0 wt% p-toluenesulfonic acid, and water is removed by molecular sieves. The acetal is distilled at reduced pressure and used in honey and rose notes, particularly in fragrance oils and fruit flavor emulsions. Food use is covered under 21 CFR 172.515 and EU Regulation (EC) No 1334/2008; cosmetic use follows EU Regulation (EC) No 1223/2009 and IFRA standards. This route is limited to producers with hydrogenation equipment designed for acid chloride off-gas because hydrogen chloride and catalyst poisoning must be managed simultaneously. Terminal products are perfume oils, personal care formulations, and flavor emulsions.
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Phenylacetic acid, CAS 103-82-2, EINECS 203-148-6, C8H8O2, is a benzene-substituted carboxylic acid with a methylene spacer between the aromatic ring and the carboxyl group. The molecular weight is 136.15 g/mol, and the solid density is approximately 1.081 g/cm3 at 20 °C. Two commercial grade categories dominate supply chains: a technical grade with assay ≥ 98.5% and a pharmaceutical intermediate grade with assay ≥ 99.0%. The compound is supplied as white to off-white flakes or crystalline powder. Its melting range is 75–77 °C, boiling point 265 °C at 101.3 kPa, pKa 4.31 at 25 °C, and closed-cup flash point 132 °C. Industrial users select the pharmaceutical intermediate grade for penicillin G fermentation and active pharmaceutical ingredient syntheses where chloride and sulfated ash limits are tighter; technical grade is consumed in ester manufacture and agricultural intermediate chemistry.
At pH below 3.0, the undissociated acid predominates and water solubility remains low; the free acid solubility at 20 °C is approximately 1.58 g/L. Above pH 6.0, conversion to sodium or potassium phenylacetate increases aqueous solubility sufficiently for alkaline extraction from toluene or xylene process streams. The pKa of 4.31 means that the solubility switch is steepest between pH 3.5 and 5.5, which is exploited in workup sequences after benzyl cyanide hydrolysis. Cooling crystallization from acidified aqueous slurries at pH 1.5–2.0 yields a dense crystalline mass that is isolated by filtration or centrifugation. In plant practice, unclarified mother liquors containing residual nitrile-derived by-products are held in agitated stainless steel receivers; if pH is allowed to rise above 5.0, salt formation can increase recycle losses and extend phase disengagement times. The isolated solid is washed with cold deionized water and dried in a vacuum tray dryer at 50–60 °C until water content reaches ≤ 0.5%. Dissolution in ethanol, isopropanol, or toluene is used for downstream esterification or amidation.
The principal industrial route begins with benzyl chloride, which is converted to benzyl cyanide by reaction with sodium cyanide under phase-transfer conditions. The recovered benzyl cyanide is hydrolysed in glass-lined batch reactors using concentrated sulfuric acid at 100–130 °C; the reaction is exothermic and generates ammonia-containing overheads that require scrubbing before release. Production-scale hydrolysis vessels are typically equipped with anchor or retreat-curve agitators, jacket cooling, and a reflux condenser. Staged water addition controls the exotherm and prevents local acid concentration from exceeding design limits. After hydrolysis, the acidic mass is quenched into water, extracted into toluene, and clarified with activated carbon before cooling crystallization. Slow linear cooling at 5–10 °C/h and seed addition are used to maintain particle size distribution and avoid filtration delays caused by fine needle formation. Alternative carbonylation routes from benzyl chloride or benzyl alcohol are technically available, but published yield and purity data for continuous carbonylation at plant scale are limited. The benzyl cyanide hydrolysis route remains the dominant supply path because it uses widely available equipment and gives a crystalline solid that can be purified without distillation.
In submerged cultivation of Penicillium chrysogenum, phenylacetic acid is the side-chain donor for benzylpenicillin. The precursor is fed as the free acid or as a sodium salt to production-scale fermenters; the undissociated acid fraction is determined by broth pH and by the buffering capacity of the medium. Excessive free acid addition can uncouple oxidative phosphorylation and depress growth, while insufficient addition reduces the yield of benzylpenicillin relative to other penicillin biosynthetic products. Industrial fed-batch protocols therefore maintain residual phenylacetic acid in a limiting window below 1.0 g/L throughout the production phase. Online pH, dissolved oxygen, and off-gas CO2 signals are used to adjust the precursor feed rate in response to metabolic demand. Batch-to-batch variability is observed when complex nitrogen sources such as corn steep liquor shift the medium buffering capacity; production records from large-scale penicillin facilities indicate that precursor feed profiles must be re-tuned when raw material suppliers change. The free acid is also converted to phenylacetyl chloride and phenylacetamide, which serve as intermediates for non-fermentative pharmaceutical syntheses.
Esterification of phenylacetic acid with methanol or ethanol yields methyl phenylacetate and ethyl phenylacetate, both of which are used in fragrance formulations. Acid-catalysed esterification is carried out at reflux with azeotropic water removal; the reaction equilibrium is shifted by excess alcohol and continuous water separation. Compared with benzoic acid, the methylene spacer in phenylacetic acid retards crystallisation of the resulting ester and modifies the olfactory profile from sharp almond-like notes toward honey, floral, and balsamic descriptors. The esters are introduced into fragrance concentrates at levels governed by IFRA Standards; published data for specific fragrance formulations are proprietary. The free acid itself has a low odour threshold, so vapour control and closed transfer are specified for blending rooms.
Substitution is not direct in preservative or food-contact applications, where benzoic acid and its sodium salt are cleared under food-additive regulations and phenylacetic acid is not. The methylene bridge lowers acidity relative to benzoic acid and increases hydrophobicity, which changes extraction and crystallisation behaviour. Compared with 3-phenylpropionic acid, phenylacetic acid has a shorter aliphatic chain and a higher melting point; compared with phenylglycolic acid, the absence of the α-hydroxyl group removes a chiral centre and eliminates side reactions involving the alcohol function. The table below summarises the key physicochemical differences that influence solvent extraction, esterification kinetics, and regulatory classification.
| Parameter | Phenylacetic acid | Benzoic acid | 3-Phenylpropionic acid |
|---|---|---|---|
| CAS | 103-82-2 | 65-85-0 | 501-52-0 |
| Molecular weight | 136.15 g/mol | 122.12 g/mol | 150.18 g/mol |
| Melting range | 75–77 °C | 121–123 °C | 47–49 °C |
| pKa | 4.31 | 4.19 | 4.66 |
| Key downstream use | Penicillin G precursor, phenylacetate esters | Benzoate plasticizers, food preservatives | Flavors, pharmaceutical intermediates |
For amidation to phenylacetamide, phenylacetic acid requires activation through the acid chloride or through carbodiimide-mediated coupling. This is a critical difference from phenylacetyl chloride, which reacts readily with amines but is moisture-sensitive and requires corrosion-resistant handling. Producers that handle only the free acid can avoid stainless steel passivation issues caused by hydrogen chloride generation from the acid chloride, but must add a coupling step and accept a slower reaction rate.
Commercial specification sheets typically combine gas chromatographic assay, melting range, water content, and sulfated ash. Representative purchase specifications for technical and pharmaceutical intermediate grades are shown below. Values are expressed on an anhydrous basis because hygroscopic behaviour is moderate at ambient conditions but can increase at relative humidity above 60%.
| Parameter | Test method | Technical grade | Pharmaceutical intermediate grade |
|---|---|---|---|
| Assay, anhydrous basis | GC-FID | ≥ 98.5% | ≥ 99.0% |
| Melting range | ASTM E324 | 75.0–77.0 °C | 76.0–77.0 °C |
| Water content | ASTM E203 | ≤ 0.5% | ≤ 0.3% |
| Sulfated ash | Ph. Eur. 2.4.14 | ≤ 0.1% | ≤ 0.05% |
| Appearance | Visual inspection | White to off-white flakes | White crystalline powder |
Batch release also includes chloride content and appearance. Producers supplying pharmaceutical intermediate grade are expected to provide impurity profiles for benzyl chloride-derived intermediates and solvent residues; residual solvent reporting typically follows Ph. Eur. 2.4.24. The selection of a grade depends on the downstream unit operation: penicillin fermentation tolerates technical-grade material when the feed is filtered and pH-adjusted, while peptide synthesis and API work generally require pharmaceutical intermediate grade with sulfated ash below 0.05% and water content below 0.3%.
Because phenylacetic acid can be converted to phenylacetone, it is listed as a regulated precursor under United States 21 CFR 1310.02 and under European Union Regulation (EC) No 273/2004. Suppliers in regulated jurisdictions screen customer end-use documentation and record chain-of-custody data for volumes above defined thresholds. Storage in high-density polyethylene-lined fibre drums or supersacks at ≤ 40 °C and ≤ 60% RH reduces caking and dust formation. Molten storage is possible at 80–85 °C for short periods in heated stainless steel or glass-lined systems, but extended molten hold can increase colour formation and should be avoided unless a nitrogen blanket is applied. The solid is combustible, and dust accumulations should be managed according to local combustible dust standards; published data on maximum explosion pressure and KSt values for phenylacetic acid dust are limited, so conservative explosion hazard classification is applied when milling is required.
