4-Chlorobutyryl chloride(4-chloro-butanoylchlorid) is a colorless to pale yellow liquid with a strong irritating property. Its molecular formula is C₄H₆Cl₂O and it is an important organic synthetic intermediate. The most significant structural feature of this compound lies in the fact that its molecule simultaneously contains a highly reactive acyl chloride group (-COCl) and a chlorine atom at the end of the carbon chain. This dual-functional group design makes it highly valuable in chemical reactions. The acyl chloride group readily undergoes acylation reactions with various nucleophilic reagents (such as alcohols, amines), efficiently constructing amide or ester bonds.
While the chlorine atom at the end can undergo intramolecular cyclization under alkaline conditions to form a four-membered ring lactone (γ-butyrolactone), or undergo substitution reactions with other nucleophilic reagents to extend the carbon chain. Therefore, it is widely used in drug chemistry (such as in the synthesis of certain psychotropic drugs and cardiovascular drugs), pesticides, and the preparation of monomers for high-molecular materials. Due to its intense hydrolysis when exposed to water or moisture and the release of corrosive hydrogen chloride gas, the operation must be carried out under strict anhydrous conditions and with adequate ventilation, and there are special requirements for storage and transportation.
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Chemical Formula |
C4H6Cl2O |
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Exact Mass |
140 |
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Molecular Weight |
141 |
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m/z |
140 (100.0%), 142 (63.9%), 144 (10.2%), 141 (4.3%), 143 (2.8%) |
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Elemental Analysis |
C, 34.08; H, 4.29; Cl, 50.29; O, 11.35 |
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A chemical synthesis method of 4-chlorobutyryl chloride, characterized in that the method described is: in the absence of solvent or organic solvent, as shown in Formula (II) γ- The chlorination reaction of butyrolactone and bis (trichloromethyl) carbonate is carried out under the action of an organic amine catalyst at a temperature of 50 to 180 ℃.
After the reaction is completed, the reaction liquid is treated to obtain it as shown in Formula (I); The amount of catalyst added is γ- The method for synthesizing product provided by the present invention has the advantages of easy availability of raw materials, simple and safe operation, and is suitable for industrial production.
A process method for manufacture and purification of product, comprising the following steps: γ- The crude it was synthesized by the reaction of butyrolactone and sulfoxide chloride under the catalysis of a mixed catalyst, and then purified.
The purity of the finished product was ≥ 99%, the purity of impurities was<0.30%, and the yield was ≥ 90%.The waste gas generated in the production of it is comprehensively utilized to produce 30% hydrochloric acid and sodium sulfite solution, and the tailings are used for the production of 4-chlorobutyrate.
The invention has simple process, convenient operation, high yield, high product purity, almost no discharge of three wastes, and is environmentally friendly.
The preparation method is to place butyrolactone, anhydrous zinc chloride, and sulfoxide chloride in a reaction flask, stir at 55 ℃ for 12 hours, and collect 4-chloro-butanoylchlorid by reduced pressure distillation.
From γ- Butyrolactone is obtained by chlorination. take γ- Butyrolactone and zinc chloride were stirred and heated, and reacted at 55-60 ℃ for 1 h. Slowly add sulfoxide chloride at 60 ℃ and react for 2h.
Raise the temperature to 80 ℃ within 5-6 hours. Let stand overnight, distill the upper clear liquid at atmospheric pressure, and then steam again once. Collect the fraction to obtain 4-chloro-butanoylchlorid.
From laboratory curiosities to industrial pillars
In the vast expanse of organic chemistry, 4-Chlorobutyryl Chloride was once a humble "minor player" in the laboratory. However, thanks to its unique chemical properties and wide applicability, it gradually became a core intermediate in fields such as medicine, pesticides, and polymer materials, achieving a magnificent transformation from a laboratory curiosity to an industrial pillar.
The Chemical Reaction Catalyst in the Laboratory
In the molecular structure of 4-chlorobutyldichloroformate, the coexistence of the acyl group (-COCl) and the chlorine atom (-Cl) endows it with extremely high reactivity. In the laboratory, it was initially used as an acylation reagent and participated in the manufacture of complex organic molecules. For example, in drug manufacture, it can react with amine and alcohol compounds to form amide or ester bonds, providing key fragments for the molecular framework of antiviral drugs and antibiotics. This "modular" synthetic ability makes it an indispensable tool in new drug research and development.
The manufacture method has also undergone optimization from complex to simple. In the early days, scientists prepared 4-chloro-butanoylchlorid through the chlorination reaction of 1,4-dichloro-1,4-butenedioic acid with hydrogen chloride. However, the raw materials were difficult to obtain and the reaction conditions were strict. With technological advancements, a one-step manufacture route using γ-butanone as the raw material, catalyzed by zinc chloride and chlorosulfone chlorination, gradually became the mainstream. This method has easy-to-obtain raw materials, safe operation, and a significant increase in reaction yield, laying the foundation for the industrial production of 4-chloro-butanoylchlorid.
The Molecular Architect of the Pharmaceutical Industry
In the pharmaceutical field, the "architect" role of 4-chlorobutyldichloroformate is particularly prominent. It is a key intermediate for synthesizing anti-tumor drugs and antibacterial drugs. For instance, in the manufacture path of haloperidol (an antipsychotic drug), 4-chlorobutyldichloroformate undergoes an acylation reaction to introduce specific functional groups, providing active sites for subsequent molecular modifications. Moreover, it can also be used to synthesize the intermediate of the plant growth regulator antistatic, which regulates the balance of plant hormones to enhance the crop's resistance to lodging and indirectly ensure food security.
Its high reactivity and selectivity make the pharmaceutical manufacture process more efficient and controllable. Scientists can achieve high yields and high purity of the target product by precisely regulating reaction conditions (such as temperature, solvent, and catalyst dosage), thereby reducing production costs and environmental pollution. The application of this "green chemistry" concept has further promoted the popularization of 4-chloro-butanoylchlorid in the pharmaceutical industry.
The "Innovative Engine" of Pesticides and Polymer Materials
In the field of pesticides, 4-chloro-butanoylchlorid is an important raw material for synthesizing herbicides and insecticides. It can combine with aromatic amines and heterocyclic compounds through acylation reactions to form molecules with biological activity. For example, some new herbicides enhance their targeting and persistence by introducing the 4-chloro-butanoylchlorid group, while reducing the impact on non-target organisms. This demand for "precision agriculture" has driven the continuous growth of 4-chloro-butanoylchlorid in the pesticide market.
In the field of polymer materials, 4-chlorobutyldichloride acts as a "functionalization modifier". It can be used to synthesize high-performance materials such as polyamides and polyesters by introducing chlorine atoms, thereby enhancing the heat resistance and chemical corrosion resistance of the materials. For instance, in the aerospace industry, polymers containing 4-chlorobutyldichloride groups are used to manufacture lightweight and high-strength structural materials, meeting the requirements for use in extreme environments.
The "Future Outlook" of the Industrial Pillar
Nowadays, 4-chloro-butanoylchlorid is no longer a "curious substance" in the laboratory, but an indispensable part of the global chemical industry chain. Its market demand continues to grow with the rapid development of industries such as medicine, pesticides, and new materials. According to market research institutions, in the next five years, the global market size of 4-chloro-butanoylchlorid will expand at an annual rate of more than 5%, with the Asia-Pacific region becoming the main driving force for growth.
Looking to the future, the research and development direction of 4-chloro-butanoylchlorid will focus on two major areas: Firstly, through catalytic technology, optimize the manufacture route to further enhance atomic utilization and reaction yield, achieving "zero emissions" production; Secondly, expand its application in emerging fields such as new energy and biomedicine, for example, as an additive in lithium-ion battery electrolytes or a synthetic raw material for gene therapy carriers. These innovations will drive 4-chloro-butanoylchlorid to upgrade from an "industrial pillar" to a "strategic new material", contributing to the sustainable development of human society.
Irreplaceability analysis
4-Chlorobutyryl Chloride is a highly active acylation reagent, demonstrating unique and irreplaceable characteristics in the fields of medicine, pesticides, and organic manufacture. The synergistic effect between the acyl chloride group (-COCl) and the chlorine atom (-Cl) in its molecular structure endows it with extremely high reactivity and selectivity, making it a key tool for constructing complex molecular structures. The following provides an in-depth analysis of its irreplaceability from three dimensions: technical characteristics, application scenarios, and market trends.
Technical Characteristics: High activity and selectivity to establish core barriers
The acyl group of 4-chlorobutyldichloride has extremely strong electrophilic properties and can efficiently react with alcohols and amines to form ester or amide products. This reaction can be carried out under mild conditions, with few by-products and high yield.
For example, in the manufacture of haloperidol (a butyrylbenzene-based antipsychotic drug), 4-chlorobutyldichloride is introduced with specific functional groups through acylation reaction, providing active sites for subsequent molecular modification.
If other acylation reagents are used, more stringent reaction conditions (such as high temperature and high pressure) may be required, or the yield of the target product may significantly decrease.
Furthermore, the chlorine atom of 4-chlorobutyldichloride can participate in nucleophilic substitution reactions, further expanding its reaction pathways.
For instance, in the manufacture of certain chlorine-containing pesticides, it can introduce specific groups through substitution reactions of the chlorine atom, enhancing the biological activity of the pesticides.
This "dual reactivity" gives it unique flexibility in molecular construction and makes it difficult to be replaced by a single functional reagent.
Application Scenarios: Rigid Demand in the Pharmaceutical and Pesticide Industries
Pharmaceutical Industry
4-chloro-butanoylchlorid is a key intermediate for synthesizing anti-tumor drugs, antibacterial drugs, and antipsychotic drugs. Taking fluphenazine as an example, its antagonistic effect on dopamine receptors is 20-40 times that of chlorpromazine, making it a potent low-dose antipsychotic drug. 4-chloro-butanoylchlorid provides the core fragment for the molecular framework of fluphenazine through an acylation reaction. If replaced with other intermediates, the synthesis route may need to be redesigned, increasing research and development costs and cycles. Moreover, in the research and development of antiviral drugs, 4-chloro-butanoylchlorid can be used to construct amide bonds, providing stability and biological activity to the drug molecules. Its role cannot be replaced.
Pesticide Industry
The productis an important raw material for synthesizing herbicides and insecticides. For example, certain new herbicides enhance the targeting and persistence of weeds by introducing the 4-chlorobutyryl group, while reducing the impact on non-target organisms. This "precision agriculture" demand has driven the continuous growth of the product in the pesticide market. If other acylation reagents are used, the molecular structure may need to be adjusted to maintain biological activity, resulting in increased research and development risks.
I. Precursor Exploration (Late 19th Century – Early 20th Century)
There is no single discoverer of 4-chlorobutyryl chloride. Its emergence originated from the systematic development of aliphatic acyl chlorides and halogenated carboxylic acid chemistry between the late 19th and early 20th centuries.
From 1850 to 1900, chemists mastered the preparation of acyl chlorides from fatty acids using thionyl chloride and phosphorus pentachloride.
Between 1880 and 1910, ring-opening and halogenation reactions of C4 cyclic and chain compounds such as succinic acid and γ-butyrolactone (GBL) were extensively investigated, laying theoretical and methodological groundwork for the synthesis of 4-chloro-butanoylchlorid.
From 1900 to 1940, organic synthesis focused on simple aliphatic derivatives. Halogenated acyl chlorides gradually became important synthetic building blocks due to their high reactivity, yet 4-chloro-butanoylchlorid had not been systematically reported or produced on a large scale during this period.
II. First Synthesis and Literature Documentation (1940s – 1950s)
In the 1940s, surging demand for highly reactive difunctional intermediates in pharmaceutical and military industries during World War II accelerated research on halogenated acyl chlorides.
From 1950 to 1957, 4-chloro-butanoylchlorid was explicitly reported in academic literature for the first time. The core synthetic route relied on ring-opening chlorination of γ-butyrolactone: with thionyl chloride as the chlorinating agent and zinc chloride as the catalyst, the reaction proceeded at 50–120 °C to produce 4-chloro-butanoylchlorid in a single step.
In 1957, the Journal of the American Chemical Society (JACS) first documented its structural characterization, including boiling point, refractive index and elemental analysis, marking its official recognition as an organic synthetic intermediate. An alternative route via acylation of 4-chlorobutyric acid with thionyl chloride was also reported in the same period, but it delivered a low yield below 60% and never became a mainstream method.
III. Process Optimization and Initial Industrialization (1960s – 1970s)
From the 1960s to the 1970s, the global pharmaceutical and agrochemical industries expanded rapidly, triggering a sharp rise in demand for 4-chloro-butanoylchlorid, a key intermediate for antihistamines, quinolone antibiotics and herbicides.
Continuous process improvements were carried out from 1965 to 1972. Phosgene was adopted to replace thionyl chloride, pushing the yield up to 90%–95%, while its extreme toxicity limited practical application.
After 1970, the thionyl chloride-organic amine catalytic system became the dominant process, achieving a stable yield of 80%–87% with balanced safety and cost performance.
In the early 1970s, manufacturers in Europe and the United States realized hundred-ton-scale mass production, with product purity exceeding 98%, and the compound was established as a standard industrial intermediate.
IV. Application Expansion and Technological Maturity (1980s to Present)
After the 1980s, the applications of 4-chloro-butanoylchlorid expanded beyond pharmaceuticals and agrochemicals to polymers and advanced new materials. It is utilized for synthesizing degradable polyester PGBL and functional polymer materials.
From 1990 to 2020, the advancement of green chemistry drove technological innovation. Bis(trichloromethyl) carbonate (BTC) was used as a substitute for thionyl chloride to reduce sulfur dioxide emissions.
Continuous flow reaction technology further enhanced production efficiency and operational safety. To date, 4-chloro-butanoylchlorid has become a globally applied high-value-added fine chemical intermediate.
Its development history serves as a typical epitome of the evolution of organic synthesis from fundamental research to industrial implementation.
FAQ
What is 4-chlorobutyryl chloride used for?
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4-Chlorobutyryl chloride is a colorless to yellowish liquid with a pungent odor. It hydrolyses in the presence of water. It hydrolyses in the presence of water. 4-Chlorobutyryl chloride (4-CBCl) is mainly used in the production of pharmaceuticals and agrochemicals.
What is the density of 4-chlorobutyryl chloride?
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density. 1.26 g/mL at 25 °C (lit.)
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