Oxidation of primary alcohols to carboxylic acids
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The oxidation of primary alcohols to carboxylic acids is an important
oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
reaction in
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
. When a primary alcohol is converted to a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
, the terminal carbon atom increases its
oxidation state In chemistry, the oxidation state, or oxidation number, is the hypothetical charge of an atom if all of its bonds to different atoms were fully ionic. It describes the degree of oxidation (loss of electrons) of an atom in a chemical compound. C ...
by four. Oxidants able to perform this operation in complex organic molecules, featuring other oxidation-sensitive functional groups, must possess substantial selectivity. The most common oxidants are alkaline potassium permanganate (KMnO4) or acidified potassium dichromate.
Jones reagent Jones may refer to: People *Jones (surname), a common Welsh and English surname *List of people with surname Jones *Jones (singer), a British singer-songwriter Arts and entertainment *Jones (Animal Farm), Jones (''Animal Farm''), a human charact ...
,
PCC PCC may refer to: Science and technology * Pearson correlation coefficient (''r''), in statistics * Periodic counter-current chromatography, a type of affinity chromatography * Portable C Compiler, an early compiler for the C programming language ...
in DMF, Heyns oxidation,
ruthenium tetroxide Ruthenium tetroxide is the inorganic compound with the formula RuO4. It is a yellow volatile solid that melts near room temperature. It has the odor of ozone. Samples are typically black due to impurities. The analogous OsO4 is more widely used ...
(RuO4) and
TEMPO In musical terminology, tempo (Italian, 'time'; plural ''tempos'', or ''tempi'' from the Italian plural) is the speed or pace of a given piece. In classical music, tempo is typically indicated with an instruction at the start of a piece (often ...
are also used.


Potassium permanganate

Potassium permanganate (KMnO4) is a very strong oxidant able to react with many functional groups, such as secondary alcohols, 1,2-diols, aldehydes, alkenes, oximes, sulfides and thiols. Under controlled conditions, KMnO4 oxidizes primary alcohols to carboxylic acids very efficiently. This reaction, which was first described in detail by Fournier, is typically carried out by adding KMnO4 to a solution or suspension of the alcohol in an alkaline aqueous solution. The resulting mixture is stirred until the oxidation is complete. For the reaction to proceed efficiently, the alcohol must be at least partially dissolved in the aqueous solution. This can be facilitated by the addition of an organic co-solvent such as
dioxane 1,4-Dioxane () is a heterocyclic organic compound, classified as an ether. It is a colorless liquid with a faint sweet odor similar to that of diethyl ether. The compound is often called simply dioxane because the other dioxane isomers ( 1,2- ...
,
pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a d ...
,
acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...
or ''t''-BuOH. KMnO4 will readily react with a carbon-carbon double bond before oxidizing a primary alcohol. Normally, these oxidations are performed under strong basic conditions, because this promotes a greater oxidation speed and selectivity. In substrates sensitive to strong base, the reaction can be carried out at a lower pH—or even under acidic conditions—at the cost of a greatly decreased reaction velocity. KMnO4 is decomposed in water, resulting in formation of
manganese dioxide Manganese dioxide is the inorganic compound with the formula . This blackish or brown solid occurs naturally as the mineral pyrolusite, which is the main ore of manganese and a component of manganese nodules. The principal use for is for dry-cell ...
(MnO2) and gaseous oxygen. This decomposition is catalyzed by acid, base and MnO2. As the extent of this decomposition is difficult to estimate during the oxidation of primary alcohols, the quantity of KMnO4 must be adjusted during the oxidation by adding it sequentially until the oxidation is complete.


Jones oxidation

The so-called
Jones reagent Jones may refer to: People *Jones (surname), a common Welsh and English surname *List of people with surname Jones *Jones (singer), a British singer-songwriter Arts and entertainment *Jones (Animal Farm), Jones (''Animal Farm''), a human charact ...
is prepared by dissolving
chromium trioxide Chromium trioxide (also known as chromium(VI) oxide or chromic anhydride) is an inorganic compound with the formula CrO3. It is the acidic anhydride of chromic acid, and is sometimes marketed under the same name. This compound is a dark-purple ...
(CrO3) in aqueous
sulfuric acid Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular formu ...
, which results in formation of a reddish solution containing chromic acid (H2CrO4) and oligomers thereof. Addition of Jones reagent to a solution of a primary alcohol in
acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...
(as first described by Jones ) results in oxidation of the alcohol to a carboxylic acid. This classical protocol, involving a ''direct addition'', is used very often regardless of the fact that it frequently leads to the formation of substantial amounts of
ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
s (possessing the structure R-CO-O-CH2-R) derived from oxidative dimerization of primary alcohols. Holland and Gilman proved that this side reaction can be greatly suppressed by following the ''inverse addition'' protocol whereby a solution of the primary alcohol in acetone is slowly added to Jones reagent under conditions as dilute as practical. Jones reagent interacts with secondary alcohols resulting in oxidation to ketones. Treatment of compounds, containing both primary and secondary alcohols, with Jones reagent leads to formation of ketoacids. Problems encountered with the use of large quantities of chromium trioxide, which is toxic and dangerous for the environment, prompted the development by Zhao of a catalytic procedure, involving treatment with excess of periodic acid (H5IO6) in presence of about 1.2 mol% of CrO3. Zhao's procedure for the use of catalytic CrO3 is very well-suited for reactions on a large scale.


PDC in DMF (Corey and Schmidt)

Pyridinium dichromate The pyridinium dichromate (PDC) or Cornforth reagent is a pyridinium salt of dichromate with the chemical formula 5H5NHsub>2 r2O7 This compound is named after the Australian-British chemist Sir John Warcup Cornforth (b. 1917) who introduced it ...
(PDC) is a bright-orange solid with the formulas (C5H5NH)2Cr2O7 that is very often used for the oxidation of primary and secondary alcohols to aldehydes and ketones respectively. On the other hand, in 1979, Corey and Schmidt reported that reaction of ''saturated'' primary alcohols with PDC, ''using dimethylformamide'' (Me2NCHO, DMF) as solvent, results in oxidation to carboxylic acids rather than aldehydes. No oxidation to carboxylic acids occurs on allylic and benzylic primary alcohols. The procedure of Corey and Schmidt for the oxidation of saturated primary alcohols to carboxylic acids is run under essentially neutral conditions.


Heyns oxidation

In the heyns oxidation the oxidizing reagent is a combination of oxygen and
platinum Platinum is a chemical element with the symbol Pt and atomic number 78. It is a dense, malleable, ductile, highly unreactive, precious, silverish-white transition metal. Its name originates from Spanish , a diminutive of "silver". Platinu ...
.


Ruthenium tetroxide

Ruthenium tetroxide has many uses in organic chemistry as an oxidizing agent. It is an aggressive agent allowing mild reaction conditions.


Two-step oxidation of alcohols to acids via isolated aldehydes

As a lot of the aforementioned conditions for the oxidations of primary alcohols to acids are harsh and not compatible with common protection groups, organic chemists often use a two-step procedure for the oxidation to acids. The primary alcohol is oxidized to an
aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
using one of the many existing procedures (e.g.
IBX 2-Iodoxybenzoic acid (IBX) is an organic compound used in organic synthesis as an oxidizing agent. This periodinane is especially suited to oxidize alcohols to aldehydes. IBX is prepared from 2-iodobenzoic acid, potassium bromate, and sulfur ...
oxidation,
Dess–Martin periodinane Dess–Martin periodinane (DMP) is a chemical reagent used in the Dess–Martin oxidation, oxidizing primary alcohols to aldehydes and secondary alcohols to ketones. This periodinane has several advantages over chromium- and DMSO-based oxidants ...
). The aldehyde can then be subjected to the conditions of the Pinnick oxidation using
sodium chlorite Sodium chlorite (NaClO2) is a chemical compound used in the manufacturing of paper and as a disinfectant. Use The main application of sodium chlorite is the generation of chlorine dioxide for bleaching and stripping of textiles, pulp, and pape ...
. This sequence is often used in natural product synthesis, Nicolaou et al. applied it in their synthesis of Platencin.


References


Further reading

* {{cite book , author1=Marcos Fernández , author2=Gabriel Tojo , title=Oxidation of Primary Alcohols to Carboxylic Acids: A Guide to Current Common Practice (Basic Reactions in Organic Synthesis) , publisher=Springer , location=Berlin , year=2006 , isbn=0-387-35431-X Organic oxidation reactions Primary alcohols Carboxylic acids