Haloform reaction

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Haloform reaction
Named after Adolf Lieben
Reaction type Substitution reaction
Identifiers
Organic Chemistry Portal haloform-reaction
RSC ontology ID RXNO:0000689

In chemistry, the haloform reaction (also referred to as the Lieben haloform reaction) is a chemical reaction in which a haloform (CHX3, where X is a halogen) is produced by the exhaustive halogenation of an acetyl group (R−C(=O)CH3, where R can be either a hydrogen atom, an alkyl or an aryl group), in the presence of a base. [1] [2] [3] The reaction can be used to transform acetyl groups into carboxyl groups (R−C(=O)OH) or to produce chloroform (CHCl3), bromoform (CHBr3), or iodoform (CHI3). Note that fluoroform (CHF3) can't be prepared in this way.

Haloform reaction scheme Haloform Reaction Scheme.png
Haloform reaction scheme

Mechanism

In the first step, the halogen dis-proportionates in the presence of hydroxide to give the halide and hypohalite.

If a secondary alcohol is present, it is oxidized to a ketone by the hypohalite:

Bromoform 1.svg

If a methyl ketone is present, it reacts with the hypohalite in a three-step process:

1. Under basic conditions, the ketone undergoes keto-enol tautomerisation. The enolate undergoes electrophilic attack by the hypohalite (containing a halogen with a formal +1 charge).

Haloform Schritt 1.svg

2. When the α(alpha) position has been exhaustively halogenated, the molecule reacts with hydroxide, with −CX3 being the leaving group stabilized by three electron-withdrawing groups. In the third step the −CX3 anion abstracts a proton from either the solvent or the carboxylic acid formed in the previous step, and forms the haloform. At least in some cases (chloral hydrate) the reaction may stop and the intermediate product isolated if conditions are acidic and hypohalite is used.

Haloform Schritt 2.svg

Scope

Substrates are broadly limited to methyl ketones and secondary alcohols oxidizable to methyl ketones, such as isopropanol. The only primary alcohol and aldehyde to undergo this reaction are ethanol and acetaldehyde, respectively. 1,3-Diketones such as acetylacetone also undergo this reaction. β-ketoacids such as acetoacetic acid will also give the test upon heating. Acetyl chloride and acetamide do not undergo this reaction. The halogen used may be chlorine, bromine, iodine or sodium hypochlorite. [4] Fluoroform (CHF3) cannot be prepared by this method as it would require the presence of the highly unstable hypofluorite ion. However ketones with the structure RCOCF3 do cleave upon treatment with base to produce fluoroform; this is equivalent to the second and third steps in the process shown above.

Applications

Laboratory scale

Negative and positive iodoform test Jodoformprobe.jpg
Negative and positive iodoform test

This reaction forms the basis of the iodoform test which was commonly used in history as a chemical test to determine the presence of a methyl ketone, or a secondary alcohol oxidizable to a methyl ketone. When iodine and sodium hydroxide are used as the reagents a positive reaction gives iodoform, which is a solid at room temperature and tends to precipitate out of solution causing a distinctive cloudiness.

In organic chemistry, this reaction may be used to convert a terminal methyl ketone into the analogous carboxylic acid.

Industrially

It was formerly used to produce iodoform, bromoform, and even chloroform industrially.[ citation needed ]

A variant of this reaction is used to manufacture deuterated chloroform, in reaction of hexachloroacetone with heavy water catalysed by base: [5] [6]

O=C(CCl3)2 + D2O → 2 CDCl3 + CO2

Further variant uses decomposition of calcium trichloroacetate in heavy water: [7]

Ca(CCl3CO2)2 + D2O → 2 CDCl3 + CaCO3 + CO2

As a by-product of water chlorination

Water chlorination can result in the formation of haloforms if the water contains suitable reactive impurities (e.g. humic acid). [8] [9] There is a concern that such reactions may lead to the presence of carcinogenic compounds[ which? ] in drinking water. [10]

History

The haloform reaction is one of the oldest organic reactions known. [11] In 1822, Georges-Simon Serullas added potassium metal to a solution of iodine in ethanol and water to form potassium formate and iodoform, called in the language of that time hydroiodide of carbon. [12] In 1832, Justus von Liebig reported the reaction of chloral with calcium hydroxide to form chloroform and calcium formate. [13] The reaction was rediscovered by Adolf Lieben in 1870. [14] The iodoform test is also called the Lieben iodoform reaction. A review of the haloform reaction with a history section was published in 1934. [2]

Related Research Articles

<span class="mw-page-title-main">Haloalkane</span> Group of chemical compounds derived from alkanes containing one or more halogens

The haloalkanes are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely used commercially. They are used as flame retardants, fire extinguishants, refrigerants, propellants, solvents, and pharmaceuticals. Subsequent to the widespread use in commerce, many halocarbons have also been shown to be serious pollutants and toxins. For example, the chlorofluorocarbons have been shown to lead to ozone depletion. Methyl bromide is a controversial fumigant. Only haloalkanes that contain chlorine, bromine, and iodine are a threat to the ozone layer, but fluorinated volatile haloalkanes in theory may have activity as greenhouse gases. Methyl iodide, a naturally occurring substance, however, does not have ozone-depleting properties and the United States Environmental Protection Agency has designated the compound a non-ozone layer depleter. For more information, see Halomethane. Haloalkane or alkyl halides are the compounds which have the general formula "RX" where R is an alkyl or substituted alkyl group and X is a halogen.

Chloroform, or trichloromethane, is an organochloride with the formula CHCl3 and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and PTFE. Chloroform was once used as an inhalational anesthetic between the 19th century and the first half of the 20th century. It is miscible with many solvents but it is only very slightly soluble in water.

<span class="mw-page-title-main">Elimination reaction</span> Reaction where 2 substituents are removed from a molecule in a 1 or 2 step mechanism

An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one- or two-step mechanism. The one-step mechanism is known as the E2 reaction, and the two-step mechanism is known as the E1 reaction. The numbers refer not to the number of steps in the mechanism, but rather to the kinetics of the reaction: E2 is bimolecular (second-order) while E1 is unimolecular (first-order). In cases where the molecule is able to stabilize an anion but possesses a poor leaving group, a third type of reaction, E1CB, exists. Finally, the pyrolysis of xanthate and acetate esters proceed through an "internal" elimination mechanism, the Ei mechanism.

<span class="mw-page-title-main">Iodoform</span> Chemical compound

Iodoform is the organoiodine compound with the chemical formula CHI3. It is a pale yellow, crystalline, volatile substance, with a penetrating and distinctive odor and, analogous to chloroform, sweetish taste. It is occasionally used as a disinfectant.

In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drugs. This kind of conversion is in fact so common that a comprehensive overview is challenging. This article mainly deals with halogenation using elemental halogens. Halides are also commonly introduced using salts of the halides and halogen acids. Many specialized reagents exist for and introducing halogens into diverse substrates, e.g. thionyl chloride.

In organic chemistry, free-radical halogenation is a type of halogenation. This chemical reaction is typical of alkanes and alkyl-substituted aromatics under application of UV light. The reaction is used for the industrial synthesis of chloroform (CHCl3), dichloromethane (CH2Cl2), and hexachlorobutadiene. It proceeds by a free-radical chain mechanism.

<span class="mw-page-title-main">Bromoform</span> Chemical compound

Bromoform is an organic compound with the chemical formula CHBr3. It is a colorless liquid at room temperature, with a high refractive index and a very high density. Its sweet odor is similar to that of chloroform. It is one of the four haloforms, the others being fluoroform, chloroform, and iodoform. It is a brominated organic solvent. Currently its main use is as a laboratory reagent. It is very slightly soluble in water and is miscible with alcohol, benzene, chloroform, ether, petroleum ether, acetone and oils.

In chemistry, trihalomethanes (THMs) are chemical compounds in which three of the four hydrogen atoms of methane are replaced by halogen atoms. Trihalomethanes with all the same halogen atoms are called haloforms. Many trihalomethanes find uses in industry as solvents or refrigerants. Some THMs are also environmental pollutants, and a few are considered carcinogenic.

<span class="mw-page-title-main">Chemical test</span> Procedure for identifying or quantifying a chemical compound or group

In chemistry, a chemical test is a qualitative or quantitative procedure designed to identify, quantify, or characterise a chemical compound or chemical group.

In organic chemistry, α-keto halogenation is a special type of halogenation. The reaction may be carried out under either acidic or basic conditions in an aqueous medium with the corresponding elemental halogen. In this way, chloride, bromide, and iodide functionality can be inserted selectively in the alpha position of a ketone.

Chloral, also known as trichloroacetaldehyde or trichloroethanal, is the organic compound with the formula Cl3CCHO. This aldehyde is a colourless liquid that is soluble in a wide range of solvents. It reacts with water to form chloral hydrate, a once widely used sedative and hypnotic substance.

Fluoroform, or trifluoromethane, is the chemical compound with the formula CHF3. It is a hydrofluorocarbon as well as being a part of the haloforms, a class of compounds with the formula CHX3 with C3v symmetry. Fluoroform is used in diverse applications in organic synthesis. It is not an ozone depleter but is a greenhouse gas.

<span class="mw-page-title-main">Favorskii rearrangement</span> Chemical reaction

The Favorskii rearrangement is principally a rearrangement of cyclopropanones and α-halo ketones that leads to carboxylic acid derivatives. In the case of cyclic α-halo ketones, the Favorskii rearrangement constitutes a ring contraction. This rearrangement takes place in the presence of a base, sometimes hydroxide, to yield a carboxylic acid, but usually either an alkoxide base or an amine to yield an ester or an amide, respectively. α,α'-Dihaloketones eliminate HX under the reaction conditions to give α,β-unsaturated carbonyl compounds. Note that trihalomethyl ketone substrates will result in haloform and carboxylate formation via the haloform reaction instead.

The Hunsdiecker reaction is a name reaction in organic chemistry whereby silver salts of carboxylic acids react with a halogen to produce an organic halide. It is an example of both a decarboxylation and a halogenation reaction as the product has one fewer carbon atoms than the starting material and a halogen atom is introduced its place. A catalytic approach has been developed.

Bromine compounds are compounds containing the element bromine (Br). These compounds usually form the -1, +1, +3 and +5 oxidation states. Bromine is intermediate in reactivity between chlorine and iodine, and is one of the most reactive elements. Bond energies to bromine tend to be lower than those to chlorine but higher than those to iodine, and bromine is a weaker oxidising agent than chlorine but a stronger one than iodine. This can be seen from the standard electrode potentials of the X2/X− couples (F, +2.866 V; Cl, +1.395 V; Br, +1.087 V; I, +0.615 V; At, approximately +0.3 V). Bromination often leads to higher oxidation states than iodination but lower or equal oxidation states to chlorination. Bromine tends to react with compounds including M–M, M–H, or M–C bonds to form M–Br bonds.

Iodine compounds are compounds containing the element iodine. Iodine can form compounds using multiple oxidation states. Iodine is quite reactive, but it is much less reactive than the other halogens. For example, while chlorine gas will halogenate carbon monoxide, nitric oxide, and sulfur dioxide, iodine will not do so. Furthermore, iodination of metals tends to result in lower oxidation states than chlorination or bromination; for example, rhenium metal reacts with chlorine to form rhenium hexachloride, but with bromine it forms only rhenium pentabromide and iodine can achieve only rhenium tetraiodide. By the same token, however, since iodine has the lowest ionisation energy among the halogens and is the most easily oxidised of them, it has a more significant cationic chemistry and its higher oxidation states are rather more stable than those of bromine and chlorine, for example in iodine heptafluoride.

Organobromine chemistry is the study of the synthesis and properties of organobromine compounds, also called organobromides, which are organic compounds that contain carbon bonded to bromine. The most pervasive is the naturally produced bromomethane.

Unlike its lighter congeners, the halogen iodine forms a number of stable organic compounds, in which iodine exhibits higher formal oxidation states than -1 or coordination number exceeding 1. These are the hypervalent organoiodines, often called iodanes after the IUPAC rule used to name them.

Radical theory is an obsolete scientific theory in chemistry describing the structure of organic compounds. The theory was pioneered by Justus von Liebig, Friedrich Wöhler and Auguste Laurent around 1830 and is not related to the modern understanding of free radicals. In this theory, organic compounds were thought to exist as combinations of radicals that could be exchanged in chemical reactions just as chemical elements could be interchanged in inorganic compounds.

<span class="mw-page-title-main">Georges-Simon Serullas</span>

Georges-Simon Serullas was a French pharmacist. He was a professor of pharmacy notable for being the first to publish a work on Iodoform, an early antiseptic and disinfectant.

References

  1. ↑ March, Jerry; Smith, Michael B. (2007). Knipe, A.C. (ed.). March's Advanced Organic Chemistry Reactions, Mechanisms, and Structure (6th ed.). Hoboken: John Wiley & Sons. p. 484. ISBN   9780470084946.
  2. 1 2 Reynold C. Fuson and Benton A. Bull (1934). "The Haloform Reaction". Chemical Reviews. 15 (3): 275–309. doi:10.1021/cr60052a001.
  3. ↑ Chakrabartty, in Trahanovsky, Oxidation in Organic Chemistry, pp. 343–370, Academic Press, New York, 1978
  4. ↑ Bain, Ryan M.; Pulliam, Christopher J.; Raab, Shannon A.; Cooks, R. Graham (2016). "Chemical Synthesis Accelerated by Paper Spray: The Haloform Reaction". Journal of Chemical Education. 93 (2): 340–344. Bibcode:2016JChEd..93..340B. doi:10.1021/acs.jchemed.5b00263. ISSN   0021-9584.
  5. ↑ Paulsen, P. J.; Cooke, W. D. (1 September 1963). "Preparation of Deuterated Solvents for Nuclear Magnetic Resonance Spectrometry". Analytical Chemistry. 35 (10): 1560. doi:10.1021/ac60203a072.
  6. ↑ Zaharani, Lia; Johan, Mohd Rafie Bin; Khaligh, Nader Ghaffari (2022). "Cost and Energy Saving Process for the Laboratory-Scale Production of Chloroform-d". Organic Process Research & Development. 26 (11): 3126–3129. doi:10.1021/acs.oprd.2c00260. S2CID   253071632.
  7. ↑ Earing, Mason H.; Cloke, John B. (1951). "A New Synthesis of Chloroform-d1". Journal of the American Chemical Society. 73 (2): 769–770. doi:10.1021/ja01146a080.
  8. ↑ Rook, Johannes J. (1977). "Chlorination reactions of fulvic acids in natural waters". Environmental Science & Technology. 11 (5): 478–482. Bibcode:1977EnST...11..478R. doi:10.1021/es60128a014. ISSN   0013-936X.
  9. ↑ Reckhow, David A.; Singer, Philip C.; Malcolm, Ronald L. (1990). "Chlorination of humic materials: byproduct formation and chemical interpretations". Environmental Science & Technology. 24 (11): 1655–1664. Bibcode:1990EnST...24.1655R. doi:10.1021/es00081a005. ISSN   0013-936X.
  10. ↑ Boorman, GA (February 1999). "Drinking water disinfection byproducts: review and approach to toxicity evaluation". Environmental Health Perspectives. 107 (Suppl 1): 207–17. doi:10.1289/ehp.99107s1207. PMC   1566350 . PMID   10229719.
  11. ↑ László Kürti and Barbara Czakó (2005). Strategic Applications of Named Reactions in Organic Synthesis. Amsterdam: Elsevier. ISBN   0-12-429785-4.
  12. ↑ Surellas, Georges-Simon (May 1822). Notes sur l'Hydriodate de potasse et l'Acide hydriodique. – Hydriodure de carbone; moyen d'obtenir, à l'instant, ce composé triple [Notes on the hydroiodide of potassium and on hydroiodic acid – hydroiodide of carbon; means of obtaining instantly this compound of three elements] (in French). Metz, France: Antoine. On pages 17–20, Surellas produced iodoform by passing a mixture of iodine vapor and steam over red-hot coals. However, later, on pages 28–29, he produced iodoform by adding potassium metal to a solution of iodine in ethanol (which also contained some water).
  13. ↑ Liebig, Justus von (1832). "Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen" [On the compounds which arise by the reaction of chlorine with base [ethanol], ether [diethyl ether], oil-forming gas [ethylene], and spirit of vinegar [acetone]]. Annalen der Physik und Chemie. 2nd series. 100 (2): 243–295. Bibcode:1832AnP...100..243L. doi:10.1002/andp.18321000206.
    On pages 259–265, Liebig describes Chlorkohlenstoff ("carbon chloride", chloroform), but on p. 264, Liebig incorrectly states that the empirical formula of chloroform is C2Cl5. From p. 259: "Chlorkohlenstoff. Man erhält diese neue Verbindung, wenn man Chloral mit ätzenden Alkalien, Kalkmilch oder Barytwasser in Ueberschuss vermischt und das Gemenge destillirt." (Chloroform. One obtains this new compound when one mixes chloral with an excess of caustic alkalies, milk of lime [solution of calcium hydroxide] or barite water [solution of barium hydroxide], and [then] distills the mixture.)
  14. ↑ See:
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