59-50-7 Usage
Uses
Used in Paint and Ink Industry:
4-Chloro-3-methylphenol is used as a preservative in paint and ink formulations to prevent microbial growth and extend the shelf life of these products.
Used in Pharmaceutical Industry:
As a disinfectant and preservative, 4-Chloro-3-methylphenol is utilized in the pharmaceutical industry for various topical preparations. However, it is also a rare cause of allergic contact dermatitis and contact urticaria (CoU), with the underlying mechanism still uncertain.
Used as a Disinfectant:
4-Chloro-3-methylphenol serves as an external germicide, effectively killing or inhibiting the growth of microorganisms on surfaces and in certain applications.
Physical Properties:
4-Chloro-3-methylphenol is characterized by its colorless, white, or pinkish crystals and a slight phenolic odor. When exposed to air, it slowly turns light brown. It is shipped as a solid or in a liquid carrier, making it versatile for various applications.
Production Methods
Chlorocresol is prepared by the chlorination of m-cresol.
Air & Water Reactions
Hygroscopic. Soluble in aqueous base.
Reactivity Profile
4-Chloro-3-methylphenolS are incompatible with bases, acid chlorides, acid anhydrides, and oxidizing agents. Corrodes steel, brass, copper and copper alloys .
Health Hazard
Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution.
Fire Hazard
Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form.
Pharmaceutical Applications
Chlorocresol is used as an antimicrobial preservative in cosmetics
and pharmaceutical formulations. It is generally used in concentrations
up to 0.2% in a variety of preparations except those intended
for oral administration or that contact mucous membrane.
Chlorocresol is effective against bacteria, spores, molds, and yeasts;
it is most active in acidic media. Preservative efficacy may be
reduced in the presence of some other excipients, particularly
nonionic surfactants.
Contact allergens
Chlorocresol is a biocide used for its disinfectant and
preservative properties, in topicals or cutting fluid.
Side effects
Chlorocresol is used as a preservative in a variety of topical preparations, such as corticosteroid creams and moisturizers and in disinfectants and detergents. Three case reports implicate chlorocresol as a cause of Cou; however, whether this is due to an immunological cause is uncertain.
Walker et al. report a patient who experienced localized Cou to a number of topical medicaments and moisturizers within 30 minutes of application. Patch tests of chlorocresol and her own preparations containing chlorocresol applied for just 30 minutes produced marked urticarial responses.
A woman working in an aviary developed eyelid edema and erythema every time she used two specific disinfectants. Open and skin prick testing to 10%, but not 1%, chlorocresol was positive in this case and negative in 10 controls. This patient also experienced eyelid involvement as well as local reactions to the testing, both with superficial necrosis. Freitas et al. acknowledged that it was unusual on both aspects: for such a high concentration to be required to elicit an urticarial reaction and for superficial necrosis to occur.
A case of simultaneous delayed and immediate hypersensitivity has also been reported. Goncalo et al. report a 35-year-old laboratory worker exposed to chlorocresol in both detergents and corticosteroid creams. Patch testing was positive and the patient was diagnosed with allergic contact dermatitis to chlorocresol, which was present in numerous products. Open and skin prick testing to 1% and 5% chlorocresol were positive after 20 minutes. Ten controls were also tested, all were negative to the 1% formulation, although six were positive to 5%,[48] suspicious for a nonimmunological Cou.
Safety Profile
Poison by intravenous,
subcutaneous, and intraperitoneal routes.
Moderately toxic by ingestion. An allergen.
Mutation data reported. Incompatible with
sodium hydroxide. When heated to
decomposition it emits toxic fumes of Cl
and phosgene. See also CRESOL and
CHLOROPHENOLS.
Safety
Chlorocresol is used primarily as a preservative in topical
pharmaceutical formulations but has also been used in nebulized
solutions and ophthalmic and parenteral preparations. It should
not, however, be used in formulations for intrathecal, intracisternal,
or peridural injection.
Chlorocresol is metabolized by conjugation with glucuronic acid
and sulfate and is excreted in the urine, mainly as the conjugate,
with little chlorocresol being excreted unchanged.
Although less toxic than phenol, chlorocresol may be irritant to
the skin, eyes, and mucous membranes, and has been reported to
cause some adverse reactions when used as an excipient.
Sensitization reactions may follow the prolonged application of
strong solutions to the skin, although patch tests have shown that
chlorocresol is not a primary irritant at concentrations up to 0.2%.
Chlorocresol is recognized as a rare cause of allergic contact
dermatitis. Cross sensitization with the related preservative
chloroxylenol has also been reported. At concentrations of
0.005% w/v, chlorocresol has been shown to produce a reversible
reduction in the ciliary movement of human nasal epithelial cells in
vitro, and at concentrations of 0.1% chlorocresol produces
irreversible ciliostasis; therefore it should be used with caution in
nasal preparations. However, a clinical study in asthma patients
challenged with chlorocresol or saline concluded that preservative
might be used safely in nebulizer solution.
Chlorocresol is approved as safe for use in cosmetics in Europe at
a maximum concentration of 0.2%, although not in products
intended to come in contact with mucous membranes.
Chlorocresol at a concentration as low as 0.05% produces
ocular irritation in rabbits. Despite such reports, chlorocresol
has been tested in ophthalmic preparations.
When used systemically, notably in a heparin injection preserved
with chlorocresol 0.15%, delayed irritant and hypersensitivity
reactions attributed to chlorocresol have been reported.
LD50 (mouse, IV): 0.07 g/kg
LD50 (mouse, oral): 0.6 g/kg
LD50 (mouse, SC): 0.36 g/kg
LD50 (rabbit, dermal): >5 g/kg
LD50 (rat, dermal): >2 g/kg
LD50 (rat, oral): 1.83 g/kg
LD50 (rat, SC): 0.4 g/kg
Potential Exposure
Chlorinated phenol fungicide, microbiocide, and germicide used to control bacteria, yeasts, and
fungi.
Environmental fate
Biological. When p-chloro-m-cresol was statically incubated in the dark at 25 °C with yeast
extract and settled domestic wastewater inoculum, significant biodegradation with rapid
adaptation was observed. At concentrations of 5 and 10 mg/L, 78 and 76% biodegradation,
respectively, were observed after 7 d (Tabak et al., 1981).
Chemical/Physical. At influent concentrations (pH 3.0) of 1.0, 0.1, 0.01, and 0.001 mg/L, the
GAC adsorption capacities were 122, 63, 32, and 17 mg/g, respectively. At pH 5.5 and pH 9.0 at
influent concentrations of 1.0, 0.1, 0.01, and 0.001 mg/L, the GAC adsorption capacities were 124,
85, 58, and 40 mg/g and 99, 38, 15, and 5.5 mg/g, respectively (Dobbs and Cohen, 1980).
storage
Chlorocresol is stable at room temperature but is volatile in steam.
Aqueous solutions may be sterilized by autoclaving. On exposure to
air and light, aqueous solutions may become yellow colored.
Solutions in oil or glycerin may be sterilized by heating at 1608℃ for
1 hour. The bulk material should be stored in a well-closed
container, protected from light, in a cool, dry place.
Shipping
UN2669 Chlorocresols solution, Hazard Class:
6.1; Labels: 6.1-Poisonous materials. UN3437 Chlorocresols
solid, Hazard Class: 6.1; Labels: 6.1-Poisonous materials.
Purification Methods
Crystallise the phenol from pet ether or *C6H6. [Beilstein 6 H 381, 6 I 187, 6 II 355, 6 III 1315, 6 IV 2064.]
Incompatibilities
Chlorocresols react with boranes, alkalies, aliphatic amines, amides, nitric acid, sulfuric acid.
Contact with oxidizing agents may cause a fire and explosion hazard. Heat produces phosgene, hydrogen chloride
and chlorine gases. Corrosive to aluminum, copper, tin, and
other chemically active metals.
Incompatibilities
Chlorocresol can decompose on contact with strong alkalis,
evolving heat and fumes that ignite explosively. It is also
incompatible with oxidizing agents, copper, and with solutions of
calcium chloride, codeine phosphate, diamorphine hydrochloride,
papaveretum, and quinine hydrochloride. Chlorocresol is corrosive
to metals and forms complex compounds with transition metal
ions; discoloration occurs with iron salts. Chlorocresol also exhibits
strong sorption or binding tendencies to organic materials such as
rubber, certain plastics, and nonionic surfactants.
Chlorocresol may be lost from solutions to rubber closures, and
in contact with polyethylene may initially be rapidly removed by
sorption and then by permeation, the uptake being temperature
dependent. Presoaking of components may reduce losses due to
sorption, but not those by permeation. Chlorocresol may also
be taken up by polymethylmethacrylate and by cellulose acetate.
Losses to polypropylene or rigid polyvinyl chloride are usually
small.
At a concentration of 0.1%, chlorocresol may be completely
inactivated in the presence of nonionic surfactants, such as
polysorbate 80. However, other studies have suggested an
enhancement of antimicrobial properties in the presence of
surfactants. Bactericidal activity is also reduced, due to
binding, by cetomacrogol, methylcellulose, pectin, or cellulose
derivatives. In emulsified or solubilized systems, chlorocresol
readily partitions into the oil phase, particularly into vegetable oils,
and higher concentrations will be required for efficient preservation.
Waste Disposal
A good candidate for rotary
kiln incineration at a temperature range of 820 to 1600C
and residence times of seconds for liquids and gases, and
hours for solids.
Regulatory Status
Included in the FDA Inactive Ingredients Database (topical creams
and emulsions). Included in nonparenteral and parenteral medicines
licensed in the UK. Included in the Canadian List of Acceptable
Non-medicinal Ingredients.
In Europe, chlorocresol is approved for use in cosmetics at a
maximum concentration of 0.2%; however, it is prohibited for use
in products intended to come into contact with mucous membranes.
In Japan, use of chlorocresol in cosmetics is restricted to a level of
0.5 g/100 g.
Check Digit Verification of cas no
The CAS Registry Mumber 59-50-7 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 9 respectively; the second part has 2 digits, 5 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 59-50:
(4*5)+(3*9)+(2*5)+(1*0)=57
57 % 10 = 7
So 59-50-7 is a valid CAS Registry Number.
InChI:InChI=1/C7H7ClO/c1-5-2-3-6(8)7(9)4-5/h2-4,9H,1H3
59-50-7Relevant academic research and scientific papers
Activator free, expeditious and eco-friendly chlorination of activated arenes by N-chloro-N-(phenylsulfonyl)benzene sulfonamide (NCBSI)
Misal, Balu,Palav, Amey,Ganwir, Prerna,Chaturbhuj, Ganesh
supporting information, (2021/01/04)
N-Chloro-N-(phenylsulfonyl)benzene sulfonamide (NCBSI) has been explored for the first time as a chlorinating reagent for direct chlorination of various activated arenes and heterocycles without any activator. A comparative in-silico study was performed to determine the electrophilic character for NCBSI and commercially available N-chloro reagents to reveal the reactivity on a theoretical viewpoint. The reagent was prepared by an improved method avoiding the use of hazardous t-butyl hypochlorite. This reagent was proved to be very reactive compared to other N-chloro reagents. The precursor of the reagent N-(phenylsulfonyl)benzene sulfonamide was recovered from aqueous spent, which can be recycled to synthesize NCBSI. The eco-friendly protocol was equally applicable for the synthesis of industrially important chloroxylenol as an antibacterial agent.
para-Selective chlorination of cresols and m-xylenol using sulfuryl chloride in the presence of poly(alkylene sulfide)s
Smith, Keith,Hegazy, Amany S.,El-Hiti, Gamal A.
, p. 345 - 356 (2020/03/23)
Chlorination of o-cresol, m-cresol, and m-xylenol using sulfuryl chloride in the presence of a range of poly(alkylene sulfide)s and a Lewis acid (aluminum or ferric chloride) has been studied. The sulfur containing catalysts used led to the production of para-chlorophenols in high yields and higher para/ortho ratios than for reactions in the absence of such poly(alkylene sulfide)s. The effectiveness of the polymers was found to be dependent on the length of the spacer groups between the sulfur atoms. For example, polymers with shorter spacers provided high yields of 4-chloro-o-cresol (ca. 97%), while polymers with at least one longer spacer provided high yields of both 4-chloro-m-cresol (up to 94.6%) and 4-chloro-m-xylenol (up to 97.6%).
Regioselective chlorination of phenols in the presence of tetrahydrothiopyran derivatives
Smith, Keith,Williams, Des,El-Hiti, Gamal A.
, p. 529 - 538 (2019/06/13)
Four six-membered cyclic sulfides, namely tetrahydrothiopyran, 3-methyltetrahydrothiopyran, 4-methyltetrahydrothiopyran and 4,4-dimethyltetrahyrdrothiopyran have been used as moderators in chlorination reactions of various phenols with sulfuryl chloride in the presence of aluminum or ferric chloride. On chlorination of phenol, ortho-cresol and meta-cresol the para/ortho chlorination ratios and yields of the para-chloro isomers are higher than when no cyclic sulfide is used for all of the cyclic sulfides, but chlorination of meta-xylenol is less consistent, with some cyclic sulfides producing higher p/o ratios and others producing lower ratios than reactions having no sulfide present.
Ion-Pair-Directed Borylation of Aromatic Phosphonium Salts
Lee, Bernadette,Mihai, Madalina T.,Stojalnikova, Violeta,Phipps, Robert J.
, p. 13124 - 13134 (2019/06/17)
Control of positional selectivity in C-H activation reactions remains a challenge for synthetic chemists. Noncovalent catalysis has the potential to be a powerful strategy to address this challenge. As a part of our ongoing investigations into the use of ion-pairing interactions in site-selective catalysis, we demonstrate that several classes of aromatic phosphonium salts undergo iridium-catalyzed C-H borylation with a high selectivity for the arene meta position. This is achieved using a bifunctional bipyridine ligand bearing a pendant sulfonate group, which had previously been successful for borylation of aromatic ammonium salts. In this case, the phosphonium salts give a higher meta selectivity than the corresponding ammonium salts. We propose that the high selectivity occurs due to an attractive electrostatic interaction between the substrate and the ligand in the transition state for borylation.
Rate enhancements due to ultrasound in isoquinolinium dichromate and isoquinolinium chlorochromate catalyzed chlorination of aromatic compounds in presence of KHSO4/KCl
Rajanna,Rao, A. Sambashiva,Chakravarthi,Reddy, K. Rajendar
, p. 167 - 170 (2017/12/26)
Chlorination of aromatic compounds underwent magnificent rate accelerations in isoquinolinium dichromate and isoquinolinium chlorochromate catalyzed chlorination of aromatic hydrocarbons in the presence of KCl and KHSO4. Reaction times reduced highly significantly from 4-5 h in conventional protocol to 30-40 min under sonication, followed by high yields of monochloro derivatives as products with high regioselectivity.
Regioselective synthesis of important chlorophenols in the presence of methylthioalkanes with remote SMe, OMe or OH substituents
Smith, Keith,Al-Zuhairi, Ali J.,Elliott, Mark. C.,El-Hiti, Gamal A.
, p. 607 - 621 (2018/07/13)
Various methylthio alcohols, methoxy(methylthio)alkanes and bis(methylthio)alkanes have been used as regioselectivity modifiers in the chlorination reactions of various phenols at room temperature. The process involves the use of a slight excess of sulfuryl chloride in the presence of aluminum or ferric chloride as an activator. Methylthio alcohols, methoxy(methylthio)alkanes and bis(methylthio)alkanes having 2 and 3 methylene groups as a spacer were found to be good for the para-selective chlorination of o-cresol and phenol. On the other hand, methylthio alcohols, methoxy(methylthio)alkanes and bis(methylthio)alkanes having 6 and 9 methylene groups were found to be good for the selective para-chlorination of m-xylenol and m-cresol. Calculations using density functional theory on bis(methylthio)alkanes have suggested two different types of stable chlorinated intermediates depending on the number of methylene units as a spacer.
Examination of Selectivity in the Oxidation of ortho- and meta-Disubstituted Benzenes by CYP102A1 (P450 Bm3) Variants
Munday, Samuel D.,Dezvarei, Shaghayegh,Lau, Ian C.-K.,Bell, Stephen G.
, p. 2512 - 2522 (2017/07/12)
Cytochrome P450 CYP102A1 (P450 Bm3) variants were used to investigate the products arising from the P450 catalysed oxidation of a range of disubstituted benzenes. The variants used all generated increased levels of metabolites compared to the wild-type enzyme. With ortho-halotoluenes up to six different metabolites could be identified whereas the oxidation of 2-methoxytoluene generated only two aromatic oxidation products. Addition of an ethyl group markedly shifted the selectivity for oxidation to the more reactive benzylic position. Epoxidation of an alkene was also preferred to aromatic oxidation in 2-methylstyrene. Significant minor products arising from the migration of one substituent to a different position on the benzene ring were formed during certain P450-catalysed substrate turnovers. For example, 2-bromo-6-methylphenol was formed from the turnover of 2-bromotoluene and the dearomatisation product 6-ethyl-6-methylcyclohex-2,4-dienone was generated from the oxidation of 2-ethyltoluene. The RLYF/A330P variant altered the product distribution enabling the generation of certain metabolites in higher quantities. Using this variant produced 4-methyl-2-ethylphenol from 3-ethyltoluene with ≥90 % selectivity and with a biocatalytic activity suitable for scale-up of the reaction.
Highly Selective Synthesis of Chlorophenols under Microwave Irradiation
Xiong, Yawen,Duan, Hongdong,Meng, Xia,Ding, Zhaoyun,Feng, Weichun
, (2016/06/14)
Oxychlorination of various phenols is finished in 60 minutes with high efficiency and perfect selectivity under microwave irradiation. These reactions adopt copper(II) chloride (CuCl2) as the catalyst and hydrochloric acid as chlorine source instead of expensive and toxic ones. Oxychlorination of phenols substituted with electron donating groups (methyl, methoxyl, isopropyl, etc.) at ortho- and meta-positions is accomplished with higher conversion rates, lower reaction time, and excellent selectivity. A proposed reaction mechanism is deduced; one electron transfers from CuCl2 to phenol followed by the formation of tautomeric radical that can be rapidly captured by chlorine atom and converts into para-substituted product.
A process for synthesizing the between chlorine -cresol green
-
Paragraph 0031-0033, (2017/06/24)
The invention provides a green synthesis technique of p-chloro-m-cresol, which comprises the following step: reacting by using m-cresol as a raw material, tetrachloroethylene as a solvent and sulfuric chloride as a chlorinating agent to prepare the p-chloro-m-cresol, wherein the mole ratio of the m-cresol to the tetrachloroethylene is 1:(0.5-1.5), and the mole ratio of the m-cresol to the sulfuric chloride is 1:(0.9-1.1).Compared with the prior art, the technique provided by the invention has the advantages of short reaction time, high solvent recovery rate, clean and environment-friendly production process and high degree of automation, and the m-cresol conversion rate after the reaction finishes is up to 98%; and thus, the technique has favorable industrialization prospects.
Comparison of cyclic and polymeric disulfides as catalysts for the regioselective chlorination of phenols
Smith, Keith,Al-Zuhairi, Ali J.,El-Hiti, Gamal A.,Alshammari, Mohammed B.
, p. 74 - 85 (2015/10/20)
Two cyclic and two polymeric disulfides have been synthesized and established to be useful catalysts for the chlorination of m-xylenol, o-cresol, m-cresol and phenol using freshly distilled sulfuryl chloride in the presence of aluminum or ferric chloride as a co-catalyst at room temperature. The yields of p-isomers and para/ortho ratios were higher compared to cases where no catalyst was used with most catalysts for most phenols even when a very low concentration of disulfide was used.
