Chemistry of carboxylic acid

Formic acid HCO2H 3.77 Acetic acid CH3COOH 4.76 Chloroacetic acid CH2ClCO2H 2.86 Deprotonation of a carboxylic acid gives a carboxylate anion, which is resonance stabilized because the n

First Edition, 2012

ISBN 978-81-323-3261-9

© All rights reserved

Table of Contents

Chapter 1 - Carboxylic Acid

Chapter 2 - Acetic Acid

Chapter 3 - Linoleic Acid

Chapter 4 - Amino Acid

Chapter 5 - Dicarboxylic Acid

Chapter 6 - Fatty Acid

Chapter 7 - Formic Acid

Chapter 8 - Butyric Acid

Chapter 9 - Chloroacetic Acids

Chapter 10 - Electron Paramagnetic Resonance

Chapter 11 - Acid Dissociation Constant

Chapter- 1

Carboxylic Acid

Structure of a carboxylic acid

Carboxylate ion

The 3D structure of the carboxyl group

Carboxylic acids are organic acids characterized by the presence of at least one carboxyl

group The general formula of a carboxylic acid is R-COOH, where R is some

monovalent functional group A carboxyl group (or carboxy) is a functional group

consisting of a carbonyl (RR'C=O) and a hydroxyl (ROH), which has the formula C(=O)OH, usually written as -COOH or -CO2H

-Carboxylic acids are Brønsted-Lowry acids, they are proton donors They are the most common type of organic acid Among the simplest examples are formic acid H-COOH, that occurs in ants, and acetic acid CH3-COOH, that gives vinegar its sour taste Acids

with two or more carboxyl groups are called dicarboxylic, tricarboxylic, etc The

simplest dicarboxylic example is oxalic acid (COOH)2, which is just two connected carboxyls Mellitic acid is an example of a hexacarboxylic acid Other important natural examples are citric acid (in lemons) and tartaric acid (in tamarinds)

Salts and esters of carboxylic acids are called carboxylates When a carboxyl group is deprotonated, its conjugate base, a carboxylate anion is formed Carboxylate ions are resonance stabilized and this increased stability makes carboxylic acids more acidic than alcohols Carboxylic acids can be seen as reduced or alkylated forms of the Lewis acid carbon dioxide; under some circumstances they can be decarboxylated to yield carbon dioxide

Physical properties

Solubility

Carboxylic acid dimers

Carboxylic acids are polar Because they are both hydrogen-bond acceptors (the

carbonyl) and hydrogen-bond donors (the hydroxyl), they also participate in hydrogen bonding Together the hydroxyl and carbonyl group forms the functional group carboxyl Carboxylic acids usually exist as dimeric pairs in nonpolar media due to their tendency to

“self-associate.” Smaller carboxylic acids (1 to 5 carbons) are soluble with water,

whereas higher carboxylic acids are less soluble due to the increasing hydrophobic nature

of the alkyl chain These longer chain acids tend to be rather soluble in less-polar solvents such as ethers and alcohols

Acidity

Carboxylic acids are typically weak acids, meaning that they only partially dissociate into

H+ cations and RCOO– anions in neutral aqueous solution For example, at room

temperature, only 0.02 % of all acetic acid molecules are dissociated Electronegative substituents give stronger acids

Formic acid (HCO2H) 3.77

Acetic acid (CH3COOH) 4.76

Chloroacetic acid (CH2ClCO2H) 2.86

Deprotonation of a carboxylic acid gives a carboxylate anion, which is resonance

stabilized because the negative charge is shared (delocalized) between the two oxygen atoms increasing its stability Each of the carbon-oxygen bonds in a carboxylate anion has partial double-bond character

Odor

Carboxylic acids often have strong odors, especially the volatile derivatives Most

common are acetic acid (vinegar) and butyric acid (rancid butter) On the other hand, esters of carboxylic acids tend to have pleasant odors and many are used in perfumes

Nomenclature

The simplest series of carboxylic acids are the alkanoic acids, RCOOH, where R is a hydrogen or an alkyl group Compounds may also have two or more carboxylic acid groups per molecule The mono- and dicarboxylic acids have trivial names

Characterization

Carboxylic acids are most readily identified as such by infrared spectroscopy They exhibit a sharp band associated with vibration of the C-O vibration bond (νC=O) between

1680 and 1725 cm−1 A characteristic νO-H band appears as a broad peak in the 2500 to

3000 cm−1 region By 1H NMR spectrometry, the hydroxyl hydrogen appears in the 10-13 ppm region, although it is often either broadened or not observed owing to exchange with traces of water

Occurrence and applications

Many carboxylic acids are produced industrially on a large scale They are also pervasive

in nature Esters of fatty acids are the main components of lipids and polyamides of aminocarboxylic acids are the main components of proteins

Carboxylic acids are used in the production of polymers, pharmaceuticals, solvents, and food additives Industrially important carboxylic acids include acetic acid (component of vinegar, precursor to solvents and coatings), acrylic and methacrylic acids (precursors to polymers, adhesives), adipic acid (polymers), citric acid (beverages),

ethylenediaminetetraacetic acid (chelating agent), fatty acids (coatings), maleic acid (polymers), propionic acid (food preservative), terephthalic acid (polymers)

Synthesis

Industrial routes

Industrial routes to carboxylic acids generally differ from those used on smaller scale because they require specialized equipment

 Oxidation of aldehydes with air using cobalt and manganese catalysts The

required aldehydes are readily obtained from alkenes by hydroformylation

 Oxidation of hydrocarbons using air For simple alkanes, the method is

nonselective but so inexpensive to be useful Allylic and benzylic compounds undergo more selective oxidations Alkyl groups on a benzene ring oxidized to the carboxylic acid, regardless of its chain length Benzoic acid from toluene and terephthalic acid from para-xylene, and phthalic acid from ortho-xylene are illustrative large-scale conversions Acrylic acid is generated from propene

 Base-catalyzed dehydrogenation of alcohols

 Carbonylation is versatile method when coupled to the addition of water This method is effective for alkenes that generate secondary and tertiary carbocations,

e.g isobutylene to pivalic acid In the Koch reaction, the addition of water and carbon monoxide to alkenes is catalyzed by strong acids Acetic acid and formic acid are produced by the carbonylation of methanol, conducted with iodide and alkoxide promoters, respectively and often with high pressures of carbon

monoxide, usually involving additional hydrolytic steps Hydrocarboxylations involve the simultaneous addition of water and CO Such reactions are sometimes called "Reppe chemistry":

Preparative methods for small scale reactions for research or for production of fine

chemicals often employ expensive consumable reagents

 oxidation of primary alcohols or aldehydes with strong oxidants such as

potassium dichromate, Jones reagent, potassium permanganate, or sodium

chlorite The method is amenable to laboratory conditions compared to the

industrial use of air, which is “greener” since it yields less inorganic side products such as chromium or manganese oxides

 Oxidative cleavage of olefins by ozonolysis, potassium permanganate, or

RCO2Li + HCl RCO2H + LiCl

 Halogenation followed by hydrolysis of methyl ketones in the haloform reaction

 The Kolbe-Schmitt reaction provides a route to salicylic acid, precursor to aspirin

Less-common reactions

Many reactions afford carboxylic acids but are used only in specific cases or are mainly

of academic interest:

 Disproportionation of an aldehyde in the Cannizzaro reaction

 Rearrangement of diketones in the benzilic acid rearrangement involving the generation of benzoic acids are the von Richter reaction from nitrobenzenes and the Kolbe-Schmitt reaction from phenols

Reactions

The most widely practiced reactions convert carboxylic acids into esters, amides,

carboxylate salts, acid chlorides, and alcohols Carboxylic acids react with bases to form carboxylate salts, in which the hydrogen of the hydroxyl (-OH) group is replaced with a metal cation Thus, acetic acid found in vinegar reacts with sodium bicarbonate (baking soda) to form sodium acetate, carbon dioxide, and water:

CH3COOH + NaHCO3 → CH3COO−Na+ + CO2 + H2O

Carboxylic acids also react with alcohols to give esters This process is heavily used in the production of polyesters Similarly carboxylic acids are converted into amides, but this conversion typically does not occur by direct reaction of the carboxylic acid and the amine Instead esters are typical precursors to amides The conversion of amino acids into peptides is a major biochemical process that requires ATP

The hydroxyl group on carboxylic acids may be replaced with a chlorine atom using thionyl chloride to give acyl chlorides In nature, carboxylic acids are converted to

Specialized reactions

 As with all carbonyl compounds, the protons on the α-carbon are labile due to keto-enol tautomerization Thus the α-carbon is easily halogenated in the Hell-Volhard-Zelinsky halogenation

 The Schmidt reaction converts carboxylic acids to amines

 Carboxylic acids are decarboxylated in the Hunsdiecker reaction

 The Dakin-West reaction converts an amino acid to the corresponding amino ketone

 In the Barbier-Wieland degradation, the alpha-methylene group in an aliphatic

carboxylic acid is removed in a sequence of reaction steps, effectively a shortening The inverse procedure is the Arndt-Eistert synthesis, where an acid is converted into acyl halide and reacts with diazomethane to give the highest

chain-homolog

 Many acids undergo decarboxylation Enzymes that catalyze these reactions are known as carboxylases (EC 6.4.1) and decarboxylases (EC 4.1.1)

 Carboxylic acids are reduced to aldehydes via the ester and DIBAL, via the acid chloride in the Rosenmund reduction and via the thioester in the Fukuyama

reduction

Nomenclature and examples

The carboxylate anion R-COO– is usually named with the suffix -ate, so acetic acid, for example, becomes acetate ion In IUPAC nomenclature, carboxylic acids have an -oic acid suffix (e.g., octadecanoic acid) In common nomenclature, the suffix is usually -ic acid (e.g., stearic acid)

Straight-Chained, Saturated Carboxylic Acids

Common location or

use

1 Formic acid Methanoic acid HCOOH Insect stings

2 Acetic acid Ethanoic acid CH3COOH Vinegar

3 Propionic acid Propanoic acid CH3CH2COOH Preservative for stored grains

4 Butyric acid Butanoic acid CH3(CH2)2COOH Rancid butter

5 Valeric acid Pentanoic acid CH3(CH2)3COOH Valerian

6 Caproic acid Hexanoic acid CH3(CH2)4COOH Goat fat

7 Enanthic acid Heptanoic acid CH3(CH2)5COOH

8 Caprylic acid Octanoic acid CH3(CH2)6COOH Coconuts and breast

milk

9 Pelargonic

acid Nonanoic acid CH3(CH2)7COOH Pelargonium

10 Capric acid Decanoic acid CH3(CH2)8COOH

12 Lauric acid Dodecanoic acid CH3(CH2)10COOH Coconut oil and hand

wash soaps

14 Myristic acid Tetradecanoic

acid CH3(CH2)12COOH Nutmeg

16 Palmitic acid Hexadecanoic

acid CH3(CH2)14COOH Palm oil

18 Stearic acid Octadecanoic acid CH3(CH2)16COOH Chocolate, waxes, soaps, and oils

20 Arachidic acid Icosanoic acid CH3(CH2)18COOH Peanut oil

Other carboxylic acids

unsaturated

monocarboxylic

acrylic acid (2-propenoic acid) – CH2=CHCOOH, used in polymer synthesis

acids

Fatty acids

medium to long-chain saturated and unsaturated monocarboxylic acids, with even number of carbons examples docosahexaenoic acid and eicosapentaenoic acid (nutritional supplements) Amino acids the building blocks of proteins

Keto acids acids of biochemical significance that contain a ketone group e.g acetoacetic acid and pyruvic acid Aromatic carboxylic

acids

benzoic acid, the sodium salt of benzoic acid is used as a food preservative, salicylic acid – a beta hydroxy type found in many skin care products

Dicarboxylic acids containing two carboxyl groups examples adipic acid the monomer used to produce nylon and aldaric acid – a family of sugar acids Tricarboxylic acids containing three carboxyl groups example citric acid – found in citrus fruits and isocitric acid Alpha hydroxy acids

containing a hydroxy group example glyceric acid, glycolic acid and lactic acid (2-hydroxypropanoic acid) – found in sour milk tartaric acid - found in wine

IUPHAR ligand 1058

RTECS number AF1225000

ATC code G01AD02,S02AA10 Beilstein

Reference 506007

3DMet B00009

Properties

Molecular formula C2H4O2

Molar mass 60.05 g mol−1

Appearance Colourless liquid

Acetic acid, CH3COOH is an organic acid that gives vinegar its sour taste and pungent smell It is a weak acid, in that it is only a partially dissociated acid in an aqueous

solution Pure, water-free acetic acid (glacial acetic acid) is a colourless liquid that

absorbs water from the environment (hygroscopy), and freezes at 16.5 °C (62 °F) to a colourless crystalline solid The pure acid and its concentrated solutions are very

The global demand of acetic acid is around 6.5 million tonnes per year (Mt/a), of which approximately 1.5 Mt/a is met by recycling; the remainder is manufactured from

petrochemical feedstocks or from biological sources Dilute acetic acid produced by natural fermentation is called vinegar

Nomenclature

The trivial name acetic acid is the most commonly used and preferred IUPAC name The systematic name ethanoic acid may be used as a valid IUPAC name The name acetic acid derives from acetum, the Latin word for vinegar, and is related to the word acid itself The synonym ethanoic acid is constructed according to the substitutive

nomenclature of the IUPAC

Glacial acetic acid is a trivial name for water-free acetic acid Similar to the German

name Eisessig (ice-vinegar), the name comes from the ice-like crystals that form slightly

below room temperature at 16.7 °C (62 °F)

A common abbreviation for acetic acid is HOAc, where Ac stands for the acetyl group

CH3−C(=O)− In the context of acid-base reactions, the abbreviation HAc is used, where

Ac instead stands for the acetate anion (CH3COO−, abbreviated AcO − However, use of

HAc may be misleading as it is also used for acetaldehyde In either case, the Ac is not to

be confused with the abbreviation for the chemical element actinium

Acetic acid has the molecular formula C2H4O2 (empirical formula CH2O)

To emphasize the role of the active hydrogen in forming the salt sodium acetate, some people write the molecular formula as HC2H3O2 To better reflect its structure, acetic acid

is often written as CH3-CO2-H, CH3COOH, or CH3CO2H The ion resulting from loss of

H+ from acetic acid is the acetate anion The name acetate can also refer to a salt

containing this anion, or an ester of acetic acid

History

Vinegar was known early in civilization as the natural result of air exposure of beer and wine, as acetic acid-producing bacteria are present globally The use of acetic acid in alchemy extends into the third century BC, when the Greek philosopher Theophrastus

described how vinegar acted on metals to produce pigments useful in art, including white lead (lead carbonate) and verdigris, a green mixture of copper salts including copper(II)

acetate Ancient Romans boiled soured wine in lead pots to produce a highly sweet syrup

called sapa Sapa was rich in lead acetate, a sweet substance also called sugar of lead or sugar of Saturn, which contributed to lead poisoning among the Roman aristocracy

In the 8th century, Jabir Ibn Hayyan (Geber) was the first to concentrate acetic acid from vinegar through distillation In the Renaissance, glacial acetic acid was prepared through the dry distillation of certain metal acetates (the most noticeable one being copper(II) acetate) The 16th-century German alchemist Andreas Libavius described such a

procedure, and he compared the glacial acetic acid produced by this means to vinegar The presence of water in vinegar has such a profound effect on acetic acid's properties that for centuries chemists believed that glacial acetic acid and the acid found in vinegar were two different substances French chemist Pierre Adet proved them to be identical

Crystallized acetic acid

In 1847 German chemist Hermann Kolbe synthesized acetic acid from inorganic

compounds for the first time This reaction sequence consisted of chlorination of carbon disulfide to carbon tetrachloride, followed by pyrolysis to tetrachloroethylene and aqueous chlorination to trichloroacetic acid, and concluded with electrolytic reduction to acetic acid

By 1910, most glacial acetic acid was obtained from the "pyroligneous liquor" from distillation of wood The acetic acid was isolated from this by treatment with milk of lime, and the resulting calcium acetate was then acidified with sulfuric acid to recover acetic acid At that time, Germany was producing 10,000 tons of glacial acetic acid, around 30% of which was used for the manufacture of indigo dye

an acidic character Acetic acid is a weak monoprotic acid In aqueous solution, it has an

pKa value of 4.75 Its conjugate base is acetate (CH3COO−) A 1.0 M solution (about the concentration of domestic vinegar) has a pH of 2.4, indicating that merely 0.4% of the acetic acid molecules are dissociated

Cyclic dimer of acetic acid; dashed lines represent hydrogen bonds

Structure

The crystal structure of acetic acid shows that the molecules pair up into dimers

connected by hydrogen bonds The dimers can also be detected in the vapour at 120 °C They also occur in the liquid phase in dilute solutions in non-hydrogen-bonding solvents, and a certain extent in pure acetic acid, but are disrupted by hydrogen-bonding solvents The dissociation enthalpy of the dimer is estimated at 65.0–66.0 kJ/mol, and the

dissociation entropy at 154–157 J mol−1 K−1 This dimerization behaviour is shared by other lower carboxylic acids

Solvent properties

Liquid acetic acid is a hydrophilic (polar) protic solvent, similar to ethanol and water With a moderate relative static permittivity (dielectric constant) of 6.2, it can dissolve not only polar compounds such as inorganic salts and sugars, but also non-polar compounds such as oils and elements such as sulfur and iodine It readily mixes with other polar and non-polar solvents such as water, chloroform, and hexane With higher alkanes (starting with octane) acetic acid is not completely miscible anymore, and its miscibility continues

to decline with longer n-alkanes This dissolving property and miscibility of acetic acid makes it a widely used industrial chemical

Chemical reactions

Organic chemistry

Acetic acid undergoes the typical chemical reactions of a carboxylic acid, such as

producing water and a metal acetate when reacting with alkalis, producing a metal acetate when reacted with a metal, and producing a metal acetate, water, and carbon dioxide when reacting with carbonates and hydrogencarbonates Most notable of all its reactions

is the formation of ethanol by reduction, and formation of derivatives such as acetyl chloride via nucleophilic acyl substitution Other substitution derivatives include acetic anhydride; this anhydride is produced by loss of water from two molecules of acetic acid Esters of acetic acid can likewise be formed via Fischer esterification, and amides can also be formed When heated above 440 °C, acetic acid decomposes to produce carbon dioxide and methane, or to produce ethenone and water

Reactions with inorganic compounds

Acetic acid is mildly corrosive to metals including iron, magnesium, and zinc, forming hydrogen gas and salts called acetates Aluminium, when exposed to oxygen, forms a thin layer of aluminium oxide on its surface, which is relatively resistant to the acid, allowing aluminium tanks to transport acetic acid

Mg + 2 CH3COOH → (CH3COO)2Mg + H2

Metal acetates can also be prepared from acetic acid and an appropriate base, as in the popular "baking soda + vinegar" reaction:

NaHCO3 + CH3COOH → CH3COONa + CO2 + H2O

A colour reaction for salts of acetic acid is iron(III) chloride solution, which results in a deeply red colour that disappears after acidification Acetates when heated with arsenic trioxide form cacodyl oxide, which can be detected by its malodorous vapours

additive, and is found in cosmetics and topical medicines

Acetic acid is produced and excreted by acetic acid bacteria, notable ones being the

Acetobacter genus and Clostridium acetobutylicum These bacteria are found universally

in foodstuffs, water, and soil, and acetic acid is produced naturally as fruits and other

foods spoil Acetic acid is also a component of the vaginal lubrication of humans and other primates, where it appears to serve as a mild antibacterial agent

Production

Purification and concentration plant for acetic acid in 1884 Acetic acid is produced industrially both synthetically and by bacterial fermentation Today, the biological route accounts for only about 10% of world production, but it remains important for the production of vinegar, as many nations' food purity laws

stipulate that vinegar used in foods must be of biological origin About 75% of acetic acid made for use in the chemical industry is made by methanol carbonylation, explained below Alternative methods account for the rest Total worldwide production of virgin acetic acid is estimated at 5 Mt/a (million tonnes per year), approximately half of which

is produced in the United States European production stands at approximately 1 Mt/a and

is declining, and 0.7 Mt/a is produced in Japan Another 1.5 Mt are recycled each year, bringing the total world market to 6.5 Mt/a The two biggest producers of virgin acetic acid are Celanese and BP Chemicals Other major producers include Millennium

Chemicals, Sterling Chemicals, Samsung, Eastman, and Svensk Etanolkemi

Methanol carbonylation

Most acetic acid is produced by methanol carbonylation In this process, methanol and carbon monoxide react to produce acetic acid according to the chemical equation:

CH3OH + CO → CH3COOH

The process involves iodomethane as an intermediate, and occurs in three steps A

catalyst, usually a metal complex, is needed for the carbonylation (step 2)

methanol carbonylation long appeared to be an attractive method for acetic acid

production Henry Dreyfus at British Celanese developed a methanol carbonylation pilot plant as early as 1925 However, a lack of practical materials that could contain the corrosive reaction mixture at the high pressures needed (200 atm or more) discouraged commercialization of these routes The first commercial methanol carbonylation process, which used a cobalt catalyst, was developed by German chemical company BASF in

1963 In 1968, a rhodium-based catalyst (cis−[Rh(CO)2I2]−) was discovered that could operate efficiently at lower pressure with almost no by-products The first plant using this catalyst was built by US chemical company Monsanto Company in 1970, and rhodium-catalysed methanol carbonylation became the dominant method of acetic acid production

In the late 1990s, the chemicals company BP Chemicals commercialized the Cativa catalyst ([Ir(CO)2I2]−), which is promoted by ruthenium This iridium-catalysed Cativa process is greener and more efficient and has largely supplanted the Monsanto process, often in the same production plants

Acetaldehyde oxidation

Prior to the commercialization of the Monsanto process, most acetic acid was produced

by oxidation of acetaldehyde This remains the second-most-important manufacturing method, although it is usually uncompetitive with the carbonylation of methanol

The acetaldehyde may be produced via oxidation of butane or light naphtha, or by

hydration of ethylene When butane or light naphtha is heated with air in the presence of

various metal ions, including those of manganese, cobalt, and chromium, peroxides form and then decompose to produce acetic acid according to the chemical equation

2 C4H10 + 5 O2 → 4 CH3COOH + 2 H2O

The typical reaction is conducted at temperatures and pressures designed to be as hot as possible while still keeping the butane a liquid Typical reaction conditions are 150 °C and 55 atm Side-products may also form, including butanone, ethyl acetate, formic acid, and propionic acid These side-products are also commercially valuable, and the reaction conditions may be altered to produce more of them where needed However, the

separation of acetic acid from these by-products adds to the cost of the process

Under similar conditions and using similar catalysts as are used for butane oxidation, acetaldehyde can be oxidized by the oxygen in air to produce acetic acid

2 CH3CHO + O2 → 2 CH3COOH

Using modern catalysts, this reaction can have an acetic acid yield greater than 95% The major side-products are ethyl acetate, formic acid, and formaldehyde, all of which have lower boiling points than acetic acid and are readily separated by distillation

Ethylene oxidation

Acetaldehyde may be prepared from ethylene via the Wacker process, and then oxidized

as above In more recent times, a cheaper, single-stage conversion of ethylene to acetic acid was commercialized by chemical company Showa Denko, which opened an ethylene oxidation plant in Ōita, Japan, in 1997 The process is catalysed by a palladium metal catalyst supported on a heteropoly acid such as tungstosilicic acid It is thought to be competitive with methanol carbonylation for smaller plants (100–250 kt/a), depending on the local price of ethylene

Oxidative fermentation

For most of human history, acetic acid, in the form of vinegar, has been made by acetic

acid bacteria of the genus Acetobacter Given sufficient oxygen, these bacteria can

produce vinegar from a variety of alcoholic foodstuffs Commonly used feeds include apple cider, wine, and fermented grain, malt, rice, or potato mashes The overall chemical reaction facilitated by these bacteria is:

C2H5OH + O2 → CH3COOH + H2O

A dilute alcohol solution inoculated with Acetobacter and kept in a warm, airy place will

become vinegar over the course of a few months Industrial vinegar-making methods accelerate this process by improving the supply of oxygen to the bacteria

The first batches of vinegar produced by fermentation probably followed errors in the winemaking process If must is fermented at too high a temperature, acetobacter will overwhelm the yeast naturally occurring on the grapes As the demand for vinegar for culinary, medical, and sanitary purposes increased, vintners quickly learned to use other organic materials to produce vinegar in the hot summer months before the grapes were ripe and ready for processing into wine This method was slow, however, and not always successful, as the vintners did not understand the process

One of the first modern commercial processes was the "fast method" or "German

method", first practised in Germany in 1823 In this process, fermentation takes place in a tower packed with wood shavings or charcoal The alcohol-containing feed is trickled into the top of the tower, and fresh air supplied from the bottom by either natural or forced convection The improved air supply in this process cut the time to prepare

vinegar from months to weeks

Nowadays, most vinegar is made in submerged tank culture, first described in 1949 by Otto Hromatka and Heinrich Ebner In this method, alcohol is fermented to vinegar in a continuously stirred tank, and oxygen is supplied by bubbling air through the solution Using modern applications of this method, vinegar of 15% acetic acid can be prepared in only 24 hours in batch process, even 20% in 60-hour fed-batch process

Anaerobic fermentation

Species of anaerobic bacteria, including members of the genus Clostridium, can convert

sugars to acetic acid directly, without using ethanol as an intermediate The overall chemical reaction conducted by these bacteria may be represented as:

C6H12O6 → 3 CH3COOH

It is interesting to note that, from the point of view of an industrial chemist, these

acetogenic bacteria can produce acetic acid from one-carbon compounds, including methanol, carbon monoxide, or a mixture of carbon dioxide and hydrogen:

2 CO2 + 4 H2 → CH3COOH + 2 H2O

This ability of Clostridium to utilize sugars directly, or to produce acetic acid from less

costly inputs, means that these bacteria could potentially produce acetic acid more

efficiently than ethanol-oxidizers like Acetobacter However, Clostridium bacteria are less acid-tolerant than Acetobacter Even the most acid-tolerant Clostridium strains can produce vinegar of only a few per cent acetic acid, compared to Acetobacter strains that

can produce vinegar of up to 20% acetic acid At present, it remains more cost-effective

to produce vinegar using Acetobacter than to produce it using Clostridium and then

concentrate it As a result, although acetogenic bacteria have been known since 1940, their industrial use remains confined to a few niche applications

Applications

2.5-litre bottle of acetic acid in a laboratory The bottle is made out of amber glass

Acetic acid is a chemical reagent for the production of chemical compounds The largest single use of acetic acid is in the production of vinyl acetate monomer, closely followed

by acetic anhydride and ester production The volume of acetic acid used in vinegar is comparatively small

Vinyl acetate monomer

The major use of acetic acid is for the production of vinyl acetate monomer (VAM) This application consumes approximately 40% to 45% of the world's production of acetic acid The reaction is of ethylene and acetic acid with oxygen over a palladium catalyst

2 H3C-COOH + 2 C2H4 + O2 → 2 H3C-CO-O-CH=CH2 + 2 H2O

Vinyl acetate can be polymerized to polyvinyl acetate or to other polymers, which are applied in paints and adhesives

Ester production

The major esters of acetic acid are commonly used solvents for inks, paints and coatings The esters include ethyl acetate, n-butyl acetate, isobutyl acetate, and propyl acetate They are typically produced by catalysed reaction from acetic acid and the corresponding alcohol:

H3C-COOH + HO-R → H3C-CO-O-R + H2O, (R = a general alkyl group)

Most acetate esters, however, are produced from acetaldehyde using the Tishchenko reaction In addition, ether acetates are used as solvents for nitrocellulose, acrylic

lacquers, varnish removers, and wood stains First, glycol monoethers are produced from ethylene oxide or propylene oxide with alcohol, which are then esterified with acetic acid The three major products are ethylene glycol monoethyl ether acetate (EEA), ethylene glycol monobutyl ether acetate (EBA), and propylene glycol monomethyl ether acetate (PMA, more commonly known as PGMEA in semiconductor manufacturing processes, where it is used as a resist solvent) This application consumes about 15% to 20% of worldwide acetic acid Ether acetates, for example EEA, have been shown to be harmful to human reproduction

Acetic anhydride

The product of the condensation of two molecules of acetic acid is acetic anhydride The worldwide production of acetic anhydride is a major application, and uses approximately 25% to 30% of the global production of acetic acid The main process involves

dehydration of acetic acid to give ketene, which condenses with acetic acid to give the anhydride:

CH3CO2H → CH2=C=O + H2O

CH3CO2H + CH2=C=O → (CH3CO)2O

Acetic anhydride is an acetylation agent As such, its major application is for cellulose acetate, a synthetic textile also used for photographic film Acetic anhydride is also a reagent for the production of aspirin, heroin, and other compounds

Vinegar

Acetic acid comprises typically 4 to 18% of vinegar, with the percentage usually

calculated by mass Vinegar is used directly as a condiment, and also in the pickling of vegetables and other foods Table vinegar tends to be more diluted (4% to 8% acetic acid), while commercial food pickling, in general, employs more concentrated solutions The amount of acetic acid used as vinegar on a worldwide scale is not large, but is by far the oldest and best-known application

Acetic acid is often used as a solvent for reactions involving carbocations, such as

Friedel-Crafts alkylation For example, one stage in the commercial manufacture of synthetic camphor involves a Wagner-Meerwein rearrangement of camphene to isobornyl acetate; here acetic acid acts both as a solvent and as a nucleophile to trap the rearranged carbocation Acetic acid is the solvent of choice when reducing an aryl nitro-group to aniline using palladium-on-carbon

Glacial acetic acid is used in analytical chemistry for the estimation of weakly alkaline substances such as organic amides Glacial acetic acid is a much weaker base than water,

so the amide behaves as a strong base in this medium It then can be titrated using a solution in glacial acetic acid of a very strong acid, such as perchloric acid

Niche applications

Dilute solutions of acetic acids are also used as a stop bath during the development of photographic films, and in descaling agents to remove limescale from taps and kettles In the clinical laboratory dilute acetic acid lyse red blood cells in order to facilitate

microscopic examination

The acidity is also used for treating the sting of the box jellyfish by disabling the stinging cells of the jellyfish, preventing serious injury or death if applied immediately, and for treating outer ear infections in people in preparations such as Vosol In this manner, acetic acid is used as a spray-on preservative for livestock silage, to discourage bacterial and fungal growth Glacial acetic acid is also used as a wart and verruca remover

Organic or inorganic salts are produced from acetic acid, including:

 Sodium acetate, used in the textile industry and as a food preservative (E262)

 Copper(II) acetate, used as a pigment and a fungicide

 Aluminium acetate and iron(II) acetate—used as mordants for dyes

 Palladium(II) acetate, used as a catalyst for organic coupling reactions such as the Heck reaction

 Silver acetate, used as a pesticide

Substituted acetic acids produced include:

 Monochloroacetic acid (MCA), dichloroacetic acid (considered a by-product), and trichloroacetic acid MCA is used in the manufacture of indigo dye

 Bromoacetic acid, which is esterified to produce the reagent ethyl bromoacetate

 Trifluoroacetic acid, which is a common reagent in organic synthesis

Amounts of acetic acid used in these other applications together (apart from TPA)

account for another 5–10% of acetic acid use worldwide These applications are,

however, not expected to grow as much as TPA production Diluted acetic acid is also used in physical therapy to break up nodules of scar tissue via iontophoresis

Safety

Concentrated acetic acid is corrosive and must, therefore, be handled with appropriate care, since it can cause skin burns, permanent eye damage, and irritation to the mucous membranes These burns or blisters may not appear until hours after exposure Latex gloves offer no protection, so specially resistant gloves, such as those made of nitrile rubber, are worn when handling the compound Concentrated acetic acid can be ignited with difficulty in the laboratory It becomes a flammable risk if the ambient temperature exceeds 39 °C (102 °F), and can form explosive mixtures with air above this temperature (explosive limits: 5.4–16%)

The hazards of solutions of acetic acid depend on the concentration The following table lists the EU classification of acetic acid solutions:

Safety symbol

Concentration

>90% >14.99 mol/L Corrosive (C) Flammable (F) R10, R35

Solutions at more than 25% acetic acid are handled in a fume hood because of the

pungent, corrosive vapour Dilute acetic acid, in the form of vinegar, is harmless

However, ingestion of stronger solutions is dangerous to human and animal life It can cause severe damage to the digestive system, and a potentially lethal change in the acidity

of the blood

Due to incompatibilities, it is recommended to keep acetic acid away from chromic acid, ethylene glycol, nitric acid, perchloric acid, permanganates, peroxides and hydroxyls

Linoleic acid (LA) is an unsaturated n-6 fatty acid It is a colorless liquid at room

temperature In physiological literature, it has a lipid number of 18:2(n-6) Chemically,

linoleic acid is a carboxylic acid with an 18-carbon chain and two cis double bonds; the

first double bond is located at the sixth carbon from the methyl end

Linoleic acid is one of two essential fatty acids that humans and other animals must ingest for good health because the body requires them for various biological processes, but can not synthesize them from other food components

The word linoleic comes from the Greek word linon (flax) Oleic means of, relating to, or derived from oil or olive or of or relating to oleic acid because saturating the n-6 double

bond produces oleic acid

In physiology

Linoleic acid (LA) is a polyunsaturated fatty acid used in the biosynthesis of arachidonic acid (AA) and thus some prostaglandins It is found in the lipids of cell membranes It is abundant in many vegetable oils, comprising over half (by weight) of poppy seed,

safflower, sunflower, and corn oils

Linoleic acid is an essential fatty acid that must be consumed for proper health A lack of linoleic acid and other n-6 fatty acids in the diet causes dry hair, hair loss, and poor wound healing

Metabolism and eicosanoids

The first step in the metabolism of Linoleic Acid (LA) is performed by Δ6desaturase, which converts LA into gamma-linolenic acid (GLA)

There is evidence suggesting that infants lack Δ6desaturase of their own, and must

acquire it through breast milk Studies show that breast-milk fed babies have higher concentrations of GLA than formula-fed babies, while formula-fed babies have elevated concentrations of LA

GLA is converted to Dihomo-gamma-linolenic acid (DGLA), which in turn is converted

to Arachidonic acid (AA) One of the possible fates of AA is to be transformed into a group of metabolites called eicosanoids, a class of paracrine hormones The three types of eicosanoids are prostaglandins, thromboxanes, and leukotrienes Eicosanoids produced from AA tend to be inflammatory For example, both AA-derived Thrombaxane and LeukotrieneB4 are proaggretory and vasoconstrictive eicosanoids Another important clinical effect is that the oxidized metabolic products of linolenic acid such as 9-

hydroxyoctadecanoic acid and 13-hydroxyoctadecanoic acid have also been shown to activate TRPV1, the capsaicin receptor and through this might play a major role in

hyperalgesia and allodynia

An increased intake of n–3 fatty acids with a decrease in n-6 fatty acids has been shown

to attenuate (diminish) inflammation due to reduced production of these eicosanoids One study monitoring two groups of survivors of myocardial infarction concluded that

“the concentration of alpha-linolenic acid was increased by 68%, in the experimental group, and that of linoleic acid reduced by 7% the survivors of a first myocardial

infarction, assigned to a Mediterranean alpha-linolenic acid rich diet, had a markedly reduced rate of recurrence, other cardiac events and overall mortality.”

Possible roles in curing or preventing disease

Cystic fibrosis

Since children with cystic fibrosis suffer from Essential Fatty Acid Deficiency due to malabsorption, it was hypothesized that high doses of LA might aid in their growth The study looked at two groups of infants with cystic fibrosis on diets with two different levels of LA It was shown that supplementary LA, indeed, has a positive effect on the growth of infants with cystic fibrosis, especially between 6 and 9 months of age

Dermatitis

Dermatitis is one of the first signs of an Essential Fatty Acid deficiency in both humans and animals Until 1955, one of the most widely applied treatments for atopic eczema was a high dose of GLA

Diabetes

A number of studies have shown that diabetics require higher than normal intakes of LA Because diabetics have consistently been shown to have above normal levels of LA while having lower than normal levels of GLA, it is believed that diabetics have impaired

Δ6desaturase activity Increased intakes of LA have been shown to attenuate diabetic complications in numerous studies

Industrial uses

Linoleic acid is used in making soaps, emulsifiers, and quick-drying oils Reduction of linoleic acid yields linoleyl alcohol Linoleic acid has become increasingly popular in the beauty products industry because of its beneficial properties on the skin Research points

to linoleic acid's anti-inflammatory, acne reductive, and moisture retentive properties when applied topically on the skin

Chapter- 4

Amino Acid

The generic structure of an alpha amino acid

The 21 amino acids found in eukaryotes, grouped according to their side chains' pKa's and charge at physiological pH 7.4

Amino acids are molecules containing an amine group, a carboxylic acid group and a

side chain that varies between different amino acids The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen They are particularly important in

biochemistry, where the term usually refers to alpha-amino acids

An alpha-amino acid has the generic formula H2NCHRCOOH, where R is an organic substituent; the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (the α–carbon) Other types of amino acid exist when the amino group

is attached to a different carbon atom; for example, in gamma-amino acids (such as gamma-amino-butyric acid) the carbon atom to which the amino group attaches is

separated from the carboxylate group by two other carbon atoms The various amino acids differ in which side chain (R-group) is attached to their alpha carbon, and can vary in size from just one hydrogen atom in glycine to a large heterocyclic group in tryptophan

alpha-Amino acids are critical to life, and have many functions in metabolism One particularly important function is to serve as the building blocks of proteins, which are linear chains

of amino acids Amino acids can be linked together in varying sequences to form a vast variety of proteins Twenty-two amino acids are naturally incorporated into polypeptides and are called proteinogenic or standard amino acids Of these, 20 are encoded by the universal genetic code Eight standard amino acids are called "essential" for humans because they cannot be created from other compounds by the human body, and so must

be taken in as food

Due to their central role in biochemistry, amino acids are important in nutrition and are commonly used in food technology and industry In industry, applications include the production of biodegradable plastics, drugs, and chiral catalysts

History

The first few amino acids were discovered in the early 19th century In 1806, the French chemists Louis-Nicolas Vauquelin and Pierre Jean Robiquet isolated a compound in asparagus that proved to be asparagine, the first amino acid to be discovered Another amino acid that was discovered in the early 19th century was cystine, in 1810, although its monomer, cysteine, was discovered much later, in 1884 Glycine and leucine were

also discovered around this time, in 1820 Usage of the term amino acid in the English

language is from 1898

General structure

Lysine with the carbon atoms in the side chain labeled

In the structure shown at the top of the page, R represents a side chain specific to each

amino acid The carbon atom next to the carboxyl group is called the α–carbon and amino

acids with a side chain bonded to this carbon are referred to as alpha amino acids These

are the most common form found in nature In the alpha amino acids, the α–carbon is a chiral carbon atom, with the exception of glycine In amino acids that have a carbon chain attached to the α–carbon (such as lysine, shown to the right) the carbons are labeled

in order as α, β, γ, δ, and so on In some amino acids, the amine group is attached to the β

or γ-carbon, and these are therefore referred to as beta or gamma amino acids

Amino acids are usually classified by the properties of their side chain into four groups The side chain can make an amino acid a weak acid or a weak base, and a hydrophile if the side chain is polar or a hydrophobe if it is nonpolar

The phrase "branched-chain amino acids" or BCAA refers to the amino acids having aliphatic side chains that are non-linear; these are leucine, isoleucine, and valine Proline

is the only proteinogenic amino acid whose side group links to the α-amino group and, thus, is also the only proteinogenic amino acid containing a secondary amine at this position Chemically, proline is therefore an imino acid since it lacks a primary amino group, although it is still classed as an amino acid in the current biochemical

nomenclature, and may also be called an "N-alkylated alpha-amino acid"

The two optical isomers of alanine, D-Alanine and L-Alanine

Isomerism

Of the standard α-amino acids, all but glycine can exist in either of two optical isomers, called L or D amino acids, which are mirror images of each other While L-amino acids represent all of the amino acids found in proteins during translation in the ribosome, D-amino acids are found in some proteins produced by enzyme posttranslational

modifications after translation and translocation to the endoplasmic reticulum, as in exotic sea-dwelling organisms such as cone snails They are also abundant components of the peptidoglycan cell walls of bacteria, and D-serine may act as a neurotransmitter in the brain The L and D convention for amino acid configuration refers not to the optical

activity of the amino acid itself, but rather to the optical activity of the isomer of

glyceraldehyde from which that amino acid can theoretically be synthesized (D

-glyceraldehyde is dextrorotary; L-glyceraldehyde is levorotary) Alternatively, the (S) and (R) designators are used to indicate the absolute stereochemistry Almost all of the amino acids in proteins are (S) at the α carbon, with cysteine being (R) and glycine non-chiral

Cysteine is unusual since it has a sulfur atom at the second position in its side-chain, which has a larger atomic mass than the groups attached to the first carbon which is

attached to the α-carbon in the other standard amino acids, thus the (R) instead of (S)

An amino acid in its (1) unionized and (2) zwitterionic forms

and negative charges and are known as a zwitterion, which comes from the German word Zwitter meaning "hermaphrodite" or "hybrid" Amino acids can exist as zwitterions in

solids and in polar solutions such as water, but not in the gas phase Zwitterions have minimal solubility at their isolectric point and an amino acid can be isolated by

precipitating it from water by adjusting the pH to its particular isoelectric point

Occurrence and functions in biochemistry

A polypeptide is an unbranched chain of amino acids

Standard amino acids

Amino acids are the structural units that make up proteins They join together to form short polymer chains called peptides or longer chains called either polypeptides or

proteins These polymers are linear and unbranched, with each amino acid within the chain attached to two neighboring amino acids The process of making proteins is called

translation and involves the step-by-step addition of amino acids to a growing protein

chain by a ribozyme that is called a ribosome The order in which the amino acids are added is read through the genetic code from an mRNA template, which is a RNA copy of one of the organism's genes

Twenty-two amino acids are naturally incorporated into polypeptides and are called proteinogenic or standard amino acids Of these, 20 are encoded by the universal genetic code The remaining 2, selenocysteine and pyrrolysine, are incorporated into proteins by unique synthetic mechanisms Selenocysteine is incorporated when the mRNA being translated includes a SECIS element, which causes the UGA codon to encode

selenocysteine instead of a stop codon Pyrrolysine is used by some methanogenic

archaea in enzymes that they use to produce methane It is coded for with the codon UAG, which is normally a stop codon in other organisms

The amino acid selenocysteine

Non-standard amino acids

Aside from the 22 standard amino acids, there are a vast number of other amino acids that

are called non-proteinogenic or non-standard Those are either not found in proteins (for

example carnitine, GABA, or L-DOPA), or are not produced directly and in isolation by standard cellular machinery (for example hydroxyproline and selenomethionine)

Non-standard amino acids that are found in proteins are formed by post-translational modification, which is modification after translation during protein synthesis These modifications are often essential for the function or regulation of a protein; for example, the carboxylation of glutamate allows for better binding of calcium cations, and the hydroxylation of proline is critical for maintaining connective tissues Another example is the formation of hypusine in the translation initiation factor EIF5A, through modification

of a lysine residue Such modifications can also determine the localization of the protein, e.g., the addition of long hydrophobic groups can cause a protein to bind to a

phospholipid membrane

β-alanine and its α-alanine isomer Some nonstandard amino acids are not found in proteins Examples include lanthionine, 2-aminoisobutyric acid, dehydroalanine and the neurotransmitter gamma-aminobutyric acid Nonstandard amino acids often occur as intermediates in the metabolic pathways for standard amino acids — for example ornithine and citrulline occur in the urea cycle, part

of amino acid catabolism (see below) A rare exception to the dominance of α-amino acids in biology is the β-amino acid beta alanine (3-aminopropanoic acid), which is used

in plants and microorganisms in the synthesis of pantothenic acid (vitamin B5), a

component of coenzyme A

In human nutrition

When taken up into the human body from the diet, the 22 standard amino acids are either used to synthesize proteins and other biomolecules, or are oxidized to urea and carbon dioxide as a source of energy The oxidation pathway starts with the removal of the amino group by a transaminase, the amino group is then fed into the urea cycle The other product of transamidation is a keto acid that enters the citric acid cycle Glucogenic amino acids can also be converted into glucose, through gluconeogenesis

Pyrrolysine trait is restricted to several microbes, and only one organism has both Pyl and Sec Of the 22 standard amino acids, 8 are called essential amino acids because the

human body cannot synthesize them from other compounds at the level needed for

normal growth, so they must be obtained from food In addition, cysteine, taurine,

tyrosine, histidine and arginine are semiessential amino-acids in children, because the metabolic pathways that synthesize these amino acids are not fully developed The

amounts required also depend on the age and health of the individual, so it is hard to make general statements about the dietary requirement for some amino acids