4'-tert-Butyl-4-chlorobutyrophenone
[CAS# 43076-61-5]

Identification

• Classification: Chemical reagent >> Organic reagent >> Aromatic ketone
• Name: 4'-tert-Butyl-4-chlorobutyrophenone
• Synonyms: 4-Chloro-1-[4-(tert-butyl)phenyl]-1-butanone
• Molecular Formula: C₁₄H₁₉ClO
• Molecular Weight: 238.75
• CAS Registry Number: 43076-61-5
• EC Number: 256-077-8
• SMILES: CC(C)(C)C1=CC=C(C=C1)C(=O)CCCCl

Properties

• Density: 1.0±0.1 g/cm³ Calc.^*
• Melting point: 47 - 49 °C (Expl.)
• Boiling point: 347.9±35.0 °C 760 mmHg (Calc.)^*, 410.1 - 414.7 °C (Expl.)
• Flash point: 207.6±17.1 °C (Calc.)^*
• Index of refraction: 1.505 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS05;GHS07;GHS09 Danger
• Risk Statements: H302-H317-H318-H411
• Safety Statements: P261-P264-P264+P265-P270-P272-P273-P280-P301+P317-P302+P352-P305+P354+P338-P317-P321-P330-P333+P317-P362+P364-P391-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Serious eye damage	Eye Dam.	1	H318
Skin sensitization	Skin Sens.	1	H317
Acute toxicity	Acute Tox.	4	H302
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315

• Transport Information: UN 3077

Discovery and Applications

4'-tert-Butyl-4-chlorobutyrophenone is an organic compound that belongs to the class of aryl ketones, specifically substituted phenylbutyrophenones. Its molecular structure consists of a phenyl ring substituted at the para position with a tert-butyl group and a side chain featuring a 4-chlorobutyrophenone moiety. The presence of both a bulky tert-butyl group and a reactive chlorobutyryl side chain makes this compound useful as an intermediate in organic synthesis and pharmaceutical development.

The compound is structurally derived from 4-chlorobutyrophenone, with a tert-butyl group added at the para position of the aromatic ring. The tert-butyl group is known for its strong electron-donating effects via hyperconjugation, as well as its steric bulk, which can influence the reactivity and selectivity of further chemical transformations. The 4-chlorobutyryl side chain, on the other hand, provides a site for nucleophilic substitution and other carbon–carbon or carbon–heteroatom bond-forming reactions.

4'-tert-Butyl-4-chlorobutyrophenone is typically synthesized through the Friedel–Crafts acylation of tert-butylbenzene using 4-chlorobutyryl chloride in the presence of a Lewis acid catalyst such as aluminum chloride (AlCl₃). This reaction proceeds through the formation of an acylium ion intermediate, which then undergoes electrophilic aromatic substitution at the para position relative to the tert-butyl group. The result is selective introduction of the 4-chlorobutyryl moiety onto the aromatic ring.

This compound is often used as a key intermediate in the synthesis of pharmaceuticals, agrochemicals, and specialty chemicals. Its chlorinated side chain allows for substitution with a wide variety of nucleophiles, including amines, thiols, and alcohols, leading to the formation of more complex structures. In particular, it can be used in the synthesis of heterocyclic compounds, amide derivatives, and biologically active molecules. In medicinal chemistry, related aryl ketones are studied for their potential central nervous system (CNS) activity, including interactions with dopaminergic and serotonergic receptors.

Analytical characterization of 4'-tert-butyl-4-chlorobutyrophenone is typically conducted using spectroscopic methods such as nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, and mass spectrometry (MS). The carbonyl (C=O) stretch appears prominently in the IR spectrum, and the compound’s molecular weight and fragmentation patterns can be confirmed via electron ionization mass spectrometry. In the ¹H NMR spectrum, characteristic signals include the tert-butyl methyl protons (as a singlet), the methylene protons adjacent to the carbonyl and chlorine atoms, and the aromatic protons.

The compound is usually a solid or viscous oil at room temperature and may require purification by distillation under reduced pressure or recrystallization from suitable solvents. It should be stored in a dry, cool environment, away from moisture and light, to prevent hydrolysis of the carbonyl or substitution reactions at the chlorine-bearing carbon.

In terms of safety and handling, 4'-tert-butyl-4-chlorobutyrophenone should be treated with care, as chlorinated ketones may be irritating to skin, eyes, and respiratory tract. Appropriate personal protective equipment, including gloves and eye protection, is recommended when handling the substance. Its reactivity toward nucleophiles also warrants precaution when used in reactions involving bases or nucleophilic solvents.

In summary, 4'-tert-butyl-4-chlorobutyrophenone is a synthetically valuable aryl ketone that serves as a versatile intermediate in organic chemistry. Its structural features allow for diverse chemical modifications, making it useful in the development of complex molecules for pharmaceutical and industrial applications.

References

2021. A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome. Cell Reports, 35(4).
DOI: 10.1016/j.celrep.2021.109040

2005. 4-tert-Butyl-γ-chlorobutyrophenone. Acta Crystallographica Section E Structure Reports Online, 61(10).
DOI: 10.1107/s1600536805028771

2020. Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 117(47).
DOI: 10.1073/pnas.2005463117