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Pivaloyl chloride

Pivaloyl chloride, also known as trimethylacetyl chloride, is an organochlorine compound with the chemical formula (CH₃)₃CC(O)Cl and a molecular weight of 120.58 g/mol.^[1] It appears as a colorless to pale yellow fuming liquid with a pungent odor and is highly reactive due to its acyl chloride functional group.^[2] Pivaloyl chloride has key physical properties including a melting point of -56 °C, a boiling point of 105–106 °C at standard pressure, a density of 0.980 g/mL at 20 °C, and a flash point of 8 °C, making it flammable and volatile.^[1] It reacts vigorously with water to form pivalic acid and hydrochloric acid, and it is soluble in organic solvents but decomposes in aqueous environments.^[1] Safety-wise, it is highly toxic by inhalation, ingestion, or skin absorption, causing severe burns, respiratory irritation, and potential systemic effects; it is classified as corrosive to skin and eyes, harmful if swallowed, and fatal if inhaled.^[2] In organic synthesis, pivaloyl chloride serves primarily as an acylating agent for preparing amides, esters, and other derivatives, particularly in pharmaceutical production such as synthetic acid amides and phenol ester medicaments.^[1] It is utilized in the manufacture of active pharmaceutical ingredients including penicillins like ampicillin, cephalosporins such as cephalexin and cefazolin, and other drugs like dipivefrin, as well as in agrochemicals for herbicides and antiviral or anti-inflammatory agents.^[3] Commercially, it is synthesized by reacting pivalic acid with thionyl chloride or phosgene, often under controlled conditions to manage the exothermic reaction and byproducts.^[4]

Nomenclature and structure

Names and identifiers

Pivaloyl chloride is the acid chloride derivative of pivalic acid.^[2] Its systematic IUPAC name is 2,2-dimethylpropanoyl chloride.^[2] Common names include pivaloyl chloride and trimethylacetyl chloride.^[2] The molecular formula is C₅H₉ClO.^[2] The CAS Registry Number is 3282-30-2.^[2] Other identifiers include the SMILES notation CC(C)(C)C(=O)Cl and the InChI InChI=1S/C5H9ClO/c1-5(2,3)4(6)7/h1-3H3.^[2]

Molecular geometry

Pivaloyl chloride features a central carbonyl group (C=O) bonded to a chloride atom, forming the characteristic acid chloride functional group, with a tert-butyl group ((CH₃)₃C–) attached to the carbonyl carbon. This arrangement results in the structural formula (CH₃)₃CCOCl, where the planar acid chloride moiety is influenced by resonance between the carbonyl oxygen and the chlorine, shortening the C=O bond length to approximately 1.20 Å.^[5] The bond angle at the carbonyl carbon, specifically the C–C(=O)–Cl angle, is approximately 120°, consistent with the trigonal planar geometry around the carbonyl carbon in acid chlorides, as observed in related compounds like acetyl chloride (121.2°).^[6] The bulky tert-butyl substituent introduces significant steric hindrance, shielding the electrophilic carbonyl carbon and restricting nucleophilic approach compared to less hindered acid chlorides such as acetyl chloride. This steric bulk alters the electron density distribution around the carbonyl, with the three methyl groups of the tert-butyl creating a congested environment that influences the molecule's reactivity in nucleophilic acyl substitution reactions.

Physical and chemical properties

Physical characteristics

Pivaloyl chloride is a colorless to pale yellow fuming liquid at room temperature.^[2]^[1] It exhibits a pungent, acrid odor attributable to its high volatility.^[2] The compound has a melting point of -56 °C and a boiling point of 105–106 °C at 760 mmHg.^[7]^[1] Its density is 0.979 g/cm³ at 20 °C, and the refractive index is approximately 1.412 (n₂₀^D).^[8]^[1] Pivaloyl chloride is soluble in common organic solvents such as dichloromethane and diethyl ether but reacts vigorously with water.^[9]^[1] The fuming behavior observed in air arises from its reactivity toward atmospheric moisture, consistent with its acyl chloride functionality.^[2]

Property	Value	Conditions
Appearance	Colorless to pale yellow fuming liquid	Room temperature
Odor	Pungent, acrid	-
Melting point	-56 °C	-
Boiling point	105–106 °C	760 mmHg
Density	0.979 g/cm³	20 °C
Refractive index	1.412	20 °C (n₂₀^D)
Solubility	Soluble in dichloromethane, diethyl ether; reacts with water	-

Stability and reactivity

Pivaloyl chloride demonstrates moderate thermal stability, decomposing in the gas phase at temperatures between 80°C and 153°C into isobutene, carbon monoxide, and hydrogen chloride, with the decomposition becoming more pronounced above 150°C. This compound undergoes rapid and exothermic hydrolysis upon contact with water, yielding pivalic acid and hydrogen chloride.

(CH_3)_3CCOCl + H_2O \rightarrow (CH_3)_3CCOOH + HCl

^[2] As a result of its hydrolytic reactivity, pivaloyl chloride is highly moisture-sensitive and also fumes in air, producing corrosive hydrogen chloride vapors that pose handling risks.^[2] It shows incompatibility with a range of substances, including alcohols (which promote esterification), amines (leading to amide formation or hydrochloride salts), strong bases, strong acids, oxidizing agents, and metals (potentially causing ignition or gas evolution); these interactions can generate heat, flammable gases, or hazardous byproducts.^[10]^[2] When maintained under anhydrous conditions in tightly sealed, corrosion-resistant containers at room temperature in a cool, dry, well-ventilated area away from ignition sources, pivaloyl chloride exhibits good storage stability, remaining viable for several months without significant degradation.^[10]

Synthesis

Historical methods

The first synthesis of pivaloyl chloride was achieved by the Russian chemist Aleksandr Butlerov in 1874 through the reaction of pivalic acid with phosphorus pentachloride.^[11] This pioneering method followed the general equation for acid chloride formation:

(CH_3)_3CCOOH + PCl_5 \rightarrow (CH_3)_3CCOCl + POCl_3 + HCl

Butlerov's work marked the initial preparation of this branched-chain acyl chloride, building on his earlier discoveries in aliphatic chemistry.^[12] In the early 20th century, alternative routes emerged using thionyl chloride as the chlorinating agent on pivalic acid, producing pivaloyl chloride along with sulfur dioxide and hydrogen chloride gases:

(CH_3)_3CCOOH + SOCl_2 \rightarrow (CH_3)_3CCOCl + SO_2 + HCl

This approach became a common laboratory technique for acid chlorides, offering milder conditions compared to phosphorus-based reagents.^[13] These early methods often resulted in low yields, attributed to the significant steric hindrance from the tert-butyl group, which impeded nucleophilic attack and favored side reactions, including the formation of phosphorus oxychloride byproducts in the PCl₅ process.^[14] Despite these challenges, they provided essential historical insight into adapting acid chloride preparation for sterically demanding branched carboxylic acids, laying groundwork for subsequent synthetic advancements.^[15]

Industrial and laboratory preparation

Pivaloyl chloride is primarily produced industrially and in laboratory settings by the reaction of pivalic acid with thionyl chloride, typically at 40-60 °C for about 2 hours, yielding 75-95%.^[16] The reaction proceeds as follows:

(CH_3)_3CCOOH + SOCl_2 \rightarrow (CH_3)_3CCOCl + SO_2 + HCl

This method is favored for its relative simplicity, milder conditions, and scalability despite the steric hindrance of pivalic acid.^[16] Alternative chlorinating agents, such as phosgene or phosphorus trichloride, have been used in specific processes. For example, phosgene can react with pivalic acid to form the product with yields exceeding 90% under catalyzed conditions, though its toxicity limits widespread adoption:

(CH_3)_3CCOOH + COCl_2 \rightarrow (CH_3)_3CCOCl + CO_2 + HCl

^[13] In some laboratory preparations, pivalic acid is refluxed with phosphorus trichloride (PCl₃), followed by distillation, achieving yields of around 80%.^[17] Other routes include carbonylation of tert-butyl chloride, derived from isobutene, in the presence of catalysts like SbCl₅ in liquid SO₂, forming a pivaloyl chloride complex.^[18] A less common pathway involves carbonylation of tert-butyl cyanide (pivalonitrile) followed by chlorination.^[19] Purification typically involves fractional distillation under reduced pressure to remove byproducts such as HCl and residual phosphorus compounds, ensuring high purity (>98%) for both industrial and laboratory applications.^[13]

Reactions and applications

General reactivity

Pivaloyl chloride, as a sterically hindered acid chloride, primarily undergoes nucleophilic acyl substitution reactions, in which the electrophilic carbonyl carbon is attacked by nucleophiles such as alcohols or amines. The general mechanism involves addition of the nucleophile to the carbonyl, followed by elimination of chloride, yielding the corresponding ester or amide and hydrochloric acid as a byproduct. This can be represented by the equation:

\ce{(CH3)3CCOCl + NuH -> (CH3)3CCONu + HCl}

where \ce{NuH} denotes the nucleophile.^[20] The bulky tert-butyl group in pivaloyl chloride introduces significant steric hindrance around the carbonyl carbon, reducing the rate of nucleophilic attack compared to less hindered acid chlorides like acetyl chloride. This steric effect favors reactions with smaller, less hindered nucleophiles and enhances selectivity, for instance, in protecting primary alcohols over secondary ones in polyhydroxy compounds.^[21]^[22]^[23] The hydrochloric acid byproduct generated in these substitutions is highly corrosive and often requires scavenging with a base such as pyridine to neutralize it and prevent side reactions or protonation of the nucleophile. Under harsh conditions, such as elevated temperatures or in the presence of strong bases, pivaloyl chloride can undergo elimination or decomposition, forming isobutene as a key product alongside other volatiles like carbon dioxide. While less reactive overall than acetyl chloride due to steric factors, this reduced reactivity can confer greater selectivity in targeted acylations.^[11]^[24]^[25]

Synthetic utility

Pivaloyl chloride serves as a versatile reagent in organic synthesis, particularly for introducing a bulky pivaloyl protecting group to alcohols and amines, which is selectively removable under basic hydrolysis conditions. This approach is especially valuable in carbohydrate chemistry, where the steric hindrance of the tert-butyl moiety enables regioselective acylation of primary hydroxyl groups, minimizing side reactions in polyfunctional substrates. For instance, treatment of glucose derivatives with pivaloyl chloride in the presence of a base yields selectively protected products at the 6-position, facilitating subsequent manipulations while preserving other functionalities.^[26] The protecting group is cleaved efficiently with potassium carbonate in methanol, restoring the original hydroxyl or amine without affecting acid-sensitive moieties.^[27] In peptide synthesis, pivaloyl chloride is employed to form mixed anhydrides with carboxylic acids, activating them for efficient amide bond formation. The reaction proceeds via deprotonation of the carboxylic acid followed by nucleophilic attack on the acyl chloride, generating the mixed anhydride intermediate:

\text{RCOOH} + (CH_3)_3\text{CCOCl} \rightarrow \text{RCO-O-CO-C(CH}_3)_3 + \text{HCl}

This intermediate then reacts with amines to afford amides with minimal racemization, owing to the rapid coupling kinetics and the bulk of the pivaloyl group, which disfavors oxazolone formation. The method is particularly useful for challenging couplings involving N-methylated amino acids, where traditional reagents fail due to steric congestion.^[28] Pivaloyl chloride also participates in Vilsmeier-type reactions when combined with dimethylformamide (DMF), forming an iminium chloride complex that acts as a mild chlorinating agent for converting alcohols to chlorides. This procedure involves mixing the alcohol with pivaloyl chloride and DMF at room temperature, yielding chlorides in moderate to good yields (50-85%) for primary and secondary alcohols, with tolerance for sensitive functional groups like esters and ketones. The mechanism likely involves activation of the alcohol as a pivalate ester, followed by chloride displacement via the Vilsmeier-Haack-type intermediate, offering a cost-effective alternative to thionyl chloride.^[29] The inherent steric bulk of pivaloyl chloride makes it ideal for reactions requiring control over acylation selectivity, such as preventing over-acylation in multifunctional molecules. In nucleoside or oligosaccharide synthesis, the tert-butyl group's hindrance directs acylation to less sterically encumbered sites, enabling mono-protection of diols or polyamines without exhaustive conditions. This selectivity arises from the pivaloyl group, which imposes significant kinetic barriers to further substitution.^[26] Recent developments have leveraged pivaloyl chloride in green chemistry protocols, particularly for water-mediated amide and peptide couplings that avoid organic solvents. In 2022, a scalable method was reported using pivaloyl chloride to generate mixed anhydrides in aqueous media at neutral pH, achieving yields up to 95% for dipeptide synthesis while recycling water and minimizing waste. This approach aligns with sustainable principles by employing an inexpensive reagent and reducing environmental impact compared to traditional anhydrous conditions.

Uses

Pharmaceutical production

Pivaloyl chloride serves as a key acylating agent in the synthesis of active pharmaceutical ingredients (APIs), particularly for beta-lactam antibiotics like cephalosporins, where it enables side-chain attachment to the 7-aminocephalosporanic acid core. This acylation step modifies the antibiotic's pharmacological properties, such as stability and antibacterial spectrum. In the production of cefazolin, for example, pivaloyl chloride reacts with tetrazole-1-acetic acid in the presence of triethylamine to form a mixed anhydride intermediate, which is then coupled to the cephalosporin nucleus under controlled conditions to yield the final API.^[30] Similarly, it is employed in the synthesis of cephalexin, cefaclor, and other cephalosporins, as well as penicillins including ampicillin and amoxicillin, where the bulky pivaloyl group provides steric protection during key reaction steps.^[31]^[32]^[33] In the realm of antiviral therapeutics, pivaloyl chloride is instrumental in preparing intermediates for HIV protease inhibitors, often through acylation of amino acid derivatives to build the peptidomimetic backbone. For instance, it acylates lithiated intermediates or phenylalanine moieties to construct P2-carboxamide functionalities in potent inhibitors, enhancing binding affinity to the protease enzyme.^[34]^[35] Pivaloyl chloride also plays a vital role as an intermediate in prodrug synthesis, forming pivaloyl esters that mask polar functional groups and improve oral bioavailability of antiviral drugs. Pivaloyloxymethyl (POM) esters, derived from reactions involving pivaloyl chloride, are commonly applied to nucleotide analogs for HIV and herpesvirus treatments, such as prodrugs of acyclovir and foscarnet, which undergo enzymatic cleavage in vivo to release the active form.^[36]^[37] These pharmaceutical processes typically employ batch reactions, where pivaloyl chloride is added dropwise to the substrate and base (e.g., triethylamine) at low temperatures to control exothermicity, with the resulting HCl neutralized as a salt that is filtered or extracted to avoid degradation of acid-sensitive intermediates.^[38] In the broader market context, pivaloyl chloride contributes to approximately 5-10% of acid chloride consumption in pharmaceutical production as of 2025, reflecting its specialized utility in high-value drug syntheses amid a global acid chlorides market valued at around USD 2.8 billion.^[39]^[40]

Agrochemical applications

Pivaloyl chloride serves as a versatile acylating agent in the synthesis of various agrochemicals, particularly in the production of insecticides and herbicides. Its reactivity allows for the formation of stable amide and ester bonds in multi-step synthetic routes, enabling the creation of active ingredients that target specific pests while minimizing off-target effects. In industrial processes, it is integrated into scalable reactions with high yields, often exceeding 60-70% in key steps, to meet the demands of large-scale agricultural production.^[41]^[42] In insecticide synthesis, pivaloyl chloride is employed to acylate intermediates for neonicotinoid analogs and other pest control agents. For instance, it facilitates the preparation of pyridine-based structures, such as 3-((2S)-1-methylpyrrolidin-2-yl)-4-phenylpyridine, by reacting with amine precursors under controlled conditions, yielding compounds with enhanced insecticidal activity against Lepidoptera and other pests. Additionally, it is used in the acylation of urea derivatives to produce pyrazole-based insecticides and acaricides, as demonstrated in patented processes where it reacts with N-methylated amines in solvents like dichloromethane to form amides with yields around 54%. These applications highlight its role in developing selective insect growth regulators and contact insecticides.^[43]^[42] For herbicide production, pivaloyl chloride plays a crucial role in the final esterification step of pinoxaden, a selective graminicide used to control grass weeds in cereal crops. In this process, it acylates the hydroxyl group of the pyrazolidinedione intermediate (NOA 407854) under basic conditions, typically achieving 64% yield over the aminolysis and acylation sequence with 99.9% purity after purification. This step ensures the formation of the pivalate ester, which contributes to the compound's stability and efficacy in field applications. The steric bulk of the pivaloyl group provides selective acylation benefits, aiding in the development of auxinic-like herbicides such as derivatives related to 2,4-D analogs through analogous esterification routes.^[44]^[45]

Safety and handling

Health and environmental hazards

Pivaloyl chloride poses significant acute health risks due to its corrosive and toxic nature. It is classified under GHS as fatal if inhaled (H330), with an LC50 for rat vapor exposure of 1.43–1.64 mg/L over 4 hours, indicating high inhalation toxicity.^[7] Contact with skin or eyes causes severe burns and damage (H314), as it reacts vigorously with moisture to release hydrochloric acid.^[7] Ingestion is harmful (H302), with an oral LD50 in rats of 638 mg/kg, potentially leading to gastrointestinal corrosion.^[7] Its pungent odor serves as a warning for exposure, acting as a lacrymator that irritates eyes and mucous membranes.^[7] Data on chronic effects are limited, with no specific studies identifying long-term toxicity, carcinogenicity, or reproductive hazards for pivaloyl chloride itself.^[46] However, its corrosive properties may contribute to respiratory sensitization or irritation upon repeated low-level exposure, and related acid chlorides show low systemic toxicity in repeated dermal studies on animals, though reversible liver effects have been noted in hydrolysis products of related acid chlorides, such as 2-ethylhexanoic acid.^[47] The compound is not listed as a carcinogen by IARC, NTP, ACGIH, or OSHA.^[7] Hydrochloric acid, a byproduct upon hydrolysis, acts as an irritant but is not carcinogenic.^[7] Environmentally, pivaloyl chloride exhibits moderate aquatic toxicity, with an LC50 of 287 mg/L for zebrafish (Danio rerio) over 96 hours and an EC50 of 320 mg/L for Daphnia magna over 24 hours.^[48]^[49] It reacts rapidly with water, limiting direct persistence, and no components are known to be non-degradable in wastewater treatment.^[50] Biodegradability data for the compound in soil are unavailable, but its hydrolysis product, pivalic acid, shows moderate persistence with low mobility in soil.^[7] No specific OSHA permissible exposure limit (PEL) has been established for pivaloyl chloride; however, general controls for corrosive vapors apply, with recommendations to maintain levels below irritation thresholds using ventilation.^[7] Acute Exposure Guideline Levels (AEGL-2) suggest 0.1 ppm for 4-hour exposure to avoid irreversible effects.^[51]

Storage and disposal

Pivaloyl chloride must be stored in airtight containers made of glass or Teflon to prevent moisture ingress, under an inert atmosphere such as nitrogen, and maintained at temperatures between 0 and 10 °C in a cool, dry, well-ventilated area away from water, heat, sparks, and incompatible materials like bases, alcohols, and amines.^[9]^[7] Due to its reactivity with water, which can lead to violent hydrolysis, storage conditions emphasize exclusion of humidity and use of compatible, sealed vessels.^[51] For transportation, pivaloyl chloride is designated by UN number 2438 (trimethylacetyl chloride), classified in Hazard Class 6.1 (inhalation hazard) with subsidiary hazards 3 (flammable liquid) and 8 (corrosive), Packing Group I, requiring labels for all applicable hazards; maximum quantities per package are restricted under DOT regulations (e.g., limited to 1 L in inner packagings for certain modes), and it is often prohibited for air transport by IATA.^[2]^[7] Disposal requires neutralization with a base such as aqueous sodium hydroxide to convert the acid chloride to the pivalate salt, followed by controlled incineration at a licensed facility equipped for hazardous waste; all processes must adhere to RCRA guidelines as a corrosive and ignitable hazardous waste.^[52] In the event of a spill, personnel should evacuate the area, provide ventilation, absorb the liquid with an inert material like sand or vermiculite using non-sparking tools, and prevent entry into waterways or drains.^[7] Safe handling necessitates the use of personal protective equipment, including a full face shield, chemical-resistant gloves (e.g., neoprene or Teflon), impermeable protective clothing, and a NIOSH-approved respirator for vapor exposure.^[7]

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AEGLs (Acute Exposure Guideline Levels) ; 10 minutes, NR, 0.2 ppm ; 30 minutes, NR, 0.2 ppm ; 60 minutes, NR, 0.16 ppm ; 4 hours, NR, 0.1 ppm ...Missing: PEL | Show results with:PEL
[51]
[PDF] Acid Chlorides and Chloroformates - Safety and Handling - BASF
A preferred disposal route is to pretreat with ammonium or sodium carbonate solution to neutralize and destroy the acid chloride or chloroformate. The ...<|control11|><|separator|>