Alkyl Halides & Alcohols (Unit-3) || B.Pharm 1st Year 2nd Sem. || SN1 and SN2 Reactions, Quality Test For Alcohols, Structure & Uses of Alkyl Halides & Alcohols || Pharmaceutical Organic Chemistry-I

Unit-III: Alkyl Halides

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Alkyl halides are also known as haloalkanes.

Alkyl halides are compounds in which one or more hydrogen atoms in an alkane have been replaced by halogen atoms (fluorine, chlorine, bromine or iodine).

Alkyl halides are represented by R-X (Where R-alkyl group, X- F, Cl, Br or I

Types of Organic Halides:

Alkyl Halides: Have a halogen atom (X) bonded to a C-C Bond.

Vinyl Halides: Have a halogen atom (X) bonded to a C=C Bond.

Aryl Halides: Have a halogen atom (X) bonded to a Ar-C Bond.

Classification of Alkyl Halides:

The number of alkyl groups attached to the carbon to which the halogen is bonded determines whether an alkyl halide is Primary, Secondary or Tertiary. 

Primary (1°) Alkyl Halides: have one R group attached to the carbon linked to the halogen.

Secondary (2°) Alkyl Halides: have two R groups attached to the carbon linked to the halogen.

Tertiary (3°) Alkyl Halides: have three R groups attached to the carbon linked to the halogen.

Nucleophilic Substitution Reactions (SN1 and SN2)

A nucleophile, a species with an unshared electron pair (lone-pair electrons), reacts with an alkyl halide (substrate) by replacing the halogen substituent (leaving group) this is known as Nucleophilic Substitution Reaction.

In Nucleophilic substitution reactions, the C–X bond of the substrate undergoes heterolysis, and the lone-pair electrons of the nucleophile is used to form a new bond to the carbon atom.

A nucleophile (“nucleus loving”, or “positive-charge loving”) is a reactant that provides a pair of electrons to form a new covalent bond.

There are Two types of Nucleophilic substitution reactions called

1) SN1 : Unimolecular Nucleophilic Substitution

2) SN2 : Bimolecular Nucleophilic Substitution

SN1 Reaction:

Characteristics of SN1 Reaction

• Two-step reaction process: 1. carbon-halogen bond breaks, resulting in a positively charged carbon (carbocation) and 2. nucleophile attacks the carbocation, forming a new bond
• Unimolecular and follows first-order kinetics
• Rate of the reaction depends on the concentration of the substrate (alkyl halide)
• Has a racemization stereochemistry, i.e., both retention and inversion products are formed
• Polar protic solvent is used to enhance the reactivity
• Mostly occurs in tertiary and secondary alkyl halide, with the former having a higher reaction rate than the latter

SN2 Reaction:

Characteristics of SN2 Reaction

• One-step reaction process, the reaction is concerted: carbon-halogen bond breaking and carbon-nucleophile bond formation takes place at the same time.
• Bimolecular and follows second-order kinetics.
• Rate of the reaction depends on the concentrations of the substrate (alkyl halide) and the nucleophile.
• Has an inversion (Walden inversion) stereochemistry at the reaction center.
• Polar aprotic solvent is used to enhance the reactivity
• Mostly occurs in primary and secondary alkyl halides

SN1 versus SN2 reactions:

Factors affecting SN1 and SN2 reactions:

The rate of an SN1 & SN2 reaction depends upon 4 factors:

1. The nature of the substrate (the alkyl halide)

2. The power of the nucleophile

3. The ability of the leaving group to leave

4. The nature of the solvent

Nature of the substrate (the alkyl halide):

In SN1 & SN2 reaction the substrate plays the most important part in determining the rate of the reaction. Highly substituted alkyl halides (substrates) form a more stable Carbonium ion. 3° alkyl halides undergo SN1 reactions with ease. 1° alkyl halides undergo SN2 reactions with ease.

Nature of the Nucleophile :

•  A nucleophile with a negative charge is always more powerful than its conjugate acid.

Thus OH¯ is more powerful than H₂O & NH₂¯ is more powerful than NH₃ & CH₃O¯ is more powerful than CH₃OH, etc.

•  The weak nucleophile favors an SN1 mechanism

•  The strong nucleophile favors an SN2 mechanism

Nature of the leaving group:

• The nature of the leaving group has the same effect on both SN1 and SN2 reactions.

• The better the leaving group, the faster a C+ can form and hence the faster will be the SN1 reaction.

• The leaving group usually has a negative charge

Example:  Iodine (-I) is a good leaving group because iodide (I-) is non basic.

The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH-) is a strong base.

The nature solvent :

There are 3 classes of organic solvents:

Protic solvents: which contain –OH or –NH2 groups.

Polar aprotic solvents: which contain strong dipoles but no –OH or –NH2 groups.

Non polar solvents: e.g., hydrocarbons.

Polar protic solvents like H₂O and ROH favor SN1 reactions because the ionic intermediates (both cations and anions) are stabilized by solvation.

Polar aprotic solvents favor SN2 reactions because nucleophiles are not well solvated, and therefore, are more nucleophilic.

Structures & Uses of Alkyl Halides:

Ethylchloride:

Chloroethane or monochloroethane, commonly known by its old name ethylchloride, is a chemical compound with chemical formula C₂H₅Cl, once widely used in producing tetraethyllead, a gasoline additive.

Chloroethane is produced by hydro chlorination of ethene:

C₂H₄ + HCl → C₂H₅Cl

Uses: 

- The major use of chloroethane was to produce tetraethyllead (TEL), an anti-knock additive for gasoline.

- It is used in the production of cellulose, dyes, medicinal drugs, and other commercial products, and as a solvent and refrigerant.

Chloroform:

Chloroform or trichloromethane is an organic compound with formula CHCl₃. It is a colorless, sweet-smelling, dense liquid.

Uses:

- It is used as a solvent for lacquers, floor polishes, resins, adhesives, alkaloids, fats, oils and rubber.

- Chloroform is used in making Fluorocarbon- 22, a refrigerant.

- Chloroform is also used to extract and purify penicillin.

- Chloroform used for extraction and purification of Alkaloids.

Trichloroethylene:

The chemical compound trichloroethylene is a halocarbon commonly used as an industrial solvent. It is a clear non-flammable liquid with a sweet smell.

When1, 2-dichloroethane heated with chlorine at 400°C is produced to trichloroethylene.

ClCH₂CH₂Cl + 2Cl₂ → ClCH=CCl₂ + 3HCl

Uses:

- The main use of trichloroethylene is in the vapor degreasing of metal parts.

- Trichloroethylene is also used as an extraction solvent for greases, oils, fats, waxes, and tars, a chemical intermediate in the production of other chemicals, and as a refrigerant.

Tetrachloromethane:

- Tetrachloromethane also known by many other names Carbon tetrachloride (CCl₄).It is a colourless liquid with a "sweet" smell that can be detected at low levels.

It is mainly produced from methane: 

CH₄ + 4 Cl₂ → CCl₄ + 4 HCl

Uses:

- Carbon tetrachloride was used to produce the chlorofluorocarbon refrigerants R-11 (trichlorofluoromethane) and R-12 (dichlorodifluoromethane).

- Carbon tetrachloride has also been used in the detection of neutrinos.

- It is a useful solvent for halogenations.

- Carbon tetrachloride was widely used as a dry cleaning solvent, and metal degreasing solvent.

Tetrachloroethylene:

Tetrachloroethylene is a volatile chlorinated organic hydrocarbon that is widely used as a solvent with the chemical formula C₂Cl₄. It is non-flammable liquid at room temperature, evaporates easily into the air and has a sharp sweet odour.

It is prepared by thermal decomposition of hexachloroethane.

C₂Cl₆ → C₂Cl₄ + Cl₂

Uses:

- Tetrachloroethylene is an excellent solvent for organic materials.

- It is widely used in dry cleaning.

- It is also used to degrease metal parts in the automotive and other metalworking industries, usually as a mixture with other chlorocarbons.

Dichloromethane:

Dichloromethane (DCM or methylene chloride) is an organic compound with the formula CH₂Cl₂. This colorless, volatile liquid with a moderately sweet aroma. 

DCM is produced by treating chloromethane with chlorine gas at 400–500 °C.

CH₃Cl + Cl₂ → CH₂Cl₂ + HCl

Uses:

- DCM is a useful solvent for many chemical processes.

- It is widely used as a paint stripper and a degreaser.

- In the food industry, it has been used to decaffeinate coffee and tea as well as to prepare extracts of hops and other flavorings.

Iodoform:

It is also known as tri-iodomethane, carbon triiodide, and methyl triiodide.

Iodoform is the organoiodine compound with the formula CHI₃. A pale yellow, crystalline, volatile substance, it has a penetrating and distinctive odor and, analogous to chloroform, sweetish taste.

CH₃CH₂OH + 6NaOH+4I₂ → CHI₃ +HCOONa +5H₂O +5NaI

CH₃COCH₃ + 4NaOH+3I₂ → CHI₃ +CH₃COONa +3H₂O +3NaI

Uses:

It is occasionally used as a disinfectant.

It was used in medicine as a healing and antiseptic dressing for wounds and sores.

Alcohols:

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Alcohols is any organic compound in which the hydroxyl functional group (-OH) is bound to a saturated carbon atom. 

The organic compound which has -OH functional group are called alcohols.

The general formula for alcohol is C_nH_2n+1OH / R-OH.

Classification of Alcohol:

On the basis of -OH group attached to the carbon atom, alcohols are divided into three categories:

Primary alcohol: When the carbon atom attached to the hydroxyl group is bonded to only one carbon atom such type of alcohol is known as primary alcohol.

Secondary alcohol: When it is bonded to two carbon atoms such type of alcohol is known as secondary alcohol.

Tertiary alcohol: When it is bonded to three carbon atoms such type of alcohol is known as tertiary alcohol.

Quality Test for Alcohols:

The following tests may be used to detect the presence of an –OH group in organic compounds.

For these tests, take the liquid compound or a solution of solid compound in an inert solvent such as dry ether or benzene.

A) Esterification Test:

B) Sodium metal test

C) Ceric ammonium nitrate test

D) Acetyl chloride test

E) Iodoform test

A) Esterification Test:

Carboxylic acid reacts with alcohols forming a fruit smelling ester. The reaction between an alcohol and a carboxylic acid is called Esterification.

This reaction is a slow reaction catalysed by concentrated sulfuric acid.

The chemical reaction is given below.

R-OH + R-COOH → R-COOR + H₂O

CH₃OH + CH₃-COOH → CH₃-COOCH₃ + H₂O

Note: A sweet smell indicates the presence of alcoholic group.

B) Sodium Metal Test:

It is based on the appearance of brisk effervescence due to the liberation of hydrogen gas when alcohol reacts with active metals like sodium.

The chemical reaction is given below.

2R-OH + 2Na → 2R-O-Na + H₂↑

2CH₃-OH + 2Na → 2CH₃-O-Na + H₂↑

The alcohol to be tested should be dry because water also reacts with sodium. Sodium should be handled carefully, unreacted sodium should be destroyed by adding excess alcohol. This test is favorable if phenyl or carboxyl groups are absent.

Note: Evolution of hydrogen gas cause a brisk effervescence indicates an alcoholic group.

C) Phosphorus Pentachloride Test:

Alcohol reacts with PCl₅ results in the mixture becomes warm with evolution of HCl Gas, the given compound contains an –OH group.

The chemical equation is given below.

R-OH + PCl₅ → R-Cl + POCl₃ + HCl

Note:  Evolution of HCl gas indicates an alcoholic group.

D) Ceric Ammonium Nitrate Test:

Alcohol or reaction with Ceric ammonium nitrate forms a pink or red colour precipitate due to the formation of a complex compound and ammonium nitrate.

The chemical reaction is given below.

(NH₄)₂ [Ce(NO₃)₆] + 3ROH → [Ce(NO₃)₄(ROH)₃] + 2NH₄NO₃

(NH₄)₂ [Ce(NO₃)₆] + 3CH₃OH → [Ce(NO₃)₄(CH₃OH)₃] + 2NH₄NO₃

Note: The appearance of red colour precipitate shows the presence of alcoholic group.

E) Acetyl Chloride Test:

Alcohol reacts with acetyl chloride results in the formation of ester and hydrogen chloride. The resulting hydrogen chloride on contact with ammonium hydroxide forms a white fumes of ammonium chloride and water.

The chemical equation is given below.

R-OH + CH₃-CO-Cl → CH₃-COOR + HCl

HCl + NH₄OH → NH₄Cl + H₂O

Note: The formation of white fumes indicates the presence of alcohol.

Distinction between Primary, Secondary and Tertiary Alcohols:

1) Lucas Test:  (Lucas reagent - ZnCl₂ + Conc. HCl)

The mixture of zinc chloride and concentrated hydrochloric acid is called Lucas reagent.

It reacts with primary, secondary and tertiary alcohols at different rates. This reagent forms a cloudiness on reacting with alcohols.

Tertiary alcohols reacts immediately and give cloudiness, secondary alcohols reacts slowly and gives cloudiness after 5 to 10 minutes and there is no reaction with primary alcohols, this because primary alcohols do not react with Lucas Reagent at room temp. High temperatures are needed.

2) Oxidation Test (Dichromate Test)

In the oxidation test, the alcohols are treated with sodium dichromate (Na₂Cr₂O₇) in sulphuric Acid (orange solution). The rate of oxidation varies between primary, secondary and tertiary alcohol. On the basis of their oxidation rates, alcohols can be distinguished as:

Primary alcohol gets easily oxidized to an aldehyde and can further be oxidized to carboxylic acids too. There will be a change in colour of the solution from orange to green.

Secondary alcohol gets easily oxidized to ketone but further oxidation is not possible. There will be a change in colour of the solution from orange to green.

Tertiary alcohol doesn’t get oxidized in the presence of sodium dichromate. Solution will remain orange.

3) Victor Meyer test:

Victor Mayer method is one of the most important methods of identification of alcohols.

In this methods primary, secondary and tertiary alcohols are subjected to a series of chemical analysis and the colour of resulting solution is observed.

The different steps involved in Victor Meyer methods are as below 1. The alcohol is treated with iodine in presence of red phosphorous to obtain iodol alkane.

2. Iodoalkane so formed is allowed to react with alcoholic silver nitrate in order to obtained nitroalkane.

3. The nitroalkane is treated with nitrous acid (the mixture of NaNO₂ +HCl) and the resulting solution is made alkaline.

4. The colour of resulting solution is observed in which following observations are observed.

a. A primary alcohol gives blood red colour.

b. A secondary alcohol gives the blue colour.

c. A tertiary alcohol does not produce any colour.

Structure and Uses of Alcohols:

Ethyl alcohol:

It is also known as alcohol, Ethanol and drinking alcohol, is a chemical compound, a simple alcohol with the chemical formula C₂H₅OH or CH₃−CH₂−OH.

Ethanol in alcoholic beverages and fuel is produced by fermentation. Certain species of yeast metabolize sugar, producing ethanol and carbon dioxide.

C₆H₁₂O₆ → 2 CH₃CH₂OH + 2 CO₂

Uses:

- Ethanol is used in medical wipes and most common antibacterial hand sanitizer gels as an antiseptic. Ethanol kills organisms by denaturing their proteins and is effective against most bacteria, fungi, and many viruses.

- Ethanol may be administered as an antidote to methanol and ethylene glycol poisoning.

Chlorobutanol:

Chlorobutanol (trichloro-2-methyl-2-propanol), is commonly used as a chemical preservative in a wide range of cosmetic and pharmaceutical products.

Chlorobutanol is formed by the simple Nucleophilic addition of chloroform and acetone in presence of KOH / NaOH.

Uses:

- Topically along with clove oil as dental analgesic.

- Chlorobutanol has been employed as sedative and hypnotic.

- Chlorobutanol used as pharmaceutical aid (antimicrobial) antiseptic and local anesthetic.

Cetostearyl alcohol:

It is also known as cetearyl alcohol or cetylstearyl alcohol is a mixture of fatty alcohols, consisting predominantly of CETYL and STEARYL ALCOHOLS and is classified as a fatty alcohol.

Uses:  

- Used in the cosmetic industry as an opacifier in shampoos, or as an emollient, emulsifier or thickening agent in the manufacture of skin creams and lotions.

- It is also employed as a lubricant for nuts and bolts, and is the active ingredient in some "liquid pool covers" (forming a surface layer to reduce evaporation and retain heat).

Benzyl alcohol:

Benzyl alcohol is an aromatic alcohol with the formula C₆H₅CH₂OH. 

Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor.

Benzyl alcohol is prepared by the hydrolysis of benzyl chloride using KOH / NaOH:

Uses:

Benzyl alcohol is used as a general solvent for inks, waxes, shellacs, paints, lacquers, and epoxy resin coatings.

It is also used in e-liquid for e-cigarettes to enhance the flavors used.

Glycerol:

It is also called glycerine or glycerin.

It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in those lipids known as glycerides.

Uses:

- Glycerol having antimicrobial and antiviral properties it is widely used in FDA approved wound and burn treatments.

- It can also be used as an effective marker to measure liver disease.

- It is also widely used as a sweetener in the food industry

Propylene glycol:

Propylene glycol (propane-1,2-diol) is an organic compound with the chemical formula CH₃CH(OH)CH₂OH.

It is a viscous, colorless liquid, which is nearly odorless but possesses a faintly sweet taste. 

Uses:

- Propylene glycol is a synthetic liquid substance that absorbs water. 

- Propylene glycol is also used to make polyester compounds, and as a base for deicing solutions. 

- Propylene glycol is used by the chemical, food, and pharmaceutical industries as antifreeze when leakage might lead to contact with food.

Note: All information copyright @ www.pharmawisdom.co.in

Prepared By:

S.Seetaramswamy

Assoc. Prof.

Dept. Pharmaceutical Chemistry

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