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Q10.What is the major product of the following reaction sequence?

Q11.Arrange the following in order of (i) increasing acidity

(a) CH3CO2H (b) CCl3CO2H

(c) CH3CH2OH (d) CH3CH2SH

Q12.What would be the major products of the reactions of (i) butanoic acid and (ii) benzoic acid with each of the following:

(a) SOCl2, Et3N (b) LiAlH4 / THF then acidic work-up

(c) (CH3)2CHOH / H+ / heat (d) NaOH

Q13.How could you use 1-bromobutane to prepare each of the

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following carboxylic acids ?

(a) propanoic acid (b) butanoic acid

(c) pentanoic acid (d) hexanoic acid

Q14 . Why don't 3o alkyl aromatic substituents get oxidized? Q15.Write the structural formula (stereo formula when necessary) for the major organic product or for the organic starting material, or give the required stepwise sequence of reactants/catalysts, for each of the following reactions:

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Lecture 9

عضوية / الفصل األول / السنة الثانية / قسم الصيدلة الكيمياء

ORGANIC CHEMISTRY –II PHENOL

Phenol are the aromatic compounds having hydroxyl group (-OH) directly attached to benzene ring.

ELECTRONIC STRUCTURE OF PHENOL:

In phenols the –OH group is attached to sp2 hybrid carbon of an aromatic ring and the oxygen atom of the hydroxyl group has two lone pairs of electrons and the bond angle in phenol is 109o. The C-O bond length in phenol is slightly less than in methanol due to resonance in aromatic ring of phenol CLASSIFICATION OF PHENOL: Phenols are classified as mono, di and trihydric phenols according to the number of hydroxyl groups attached to the aromatic ring.

1. Monohydric phenols

2. Dihydric phenols

Mazayah University College ORGANIC CHEMISTRY –II Dep. Of Pharmacy Academic year:2015-2016

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3. Trihydric phenols

GENERAL METHODS OF PREPARATION OF PHENOLS: 1. Alkali fusion of sulphonates: Sodium salt of aryl sulphonic acids on fusion with sodium hydroxide at 300-350oC yield phenol.

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The above reaction is laboratory method for preparation of phenol. 2. Hydrolysis of diazonium salt :

3. Hydrolysis of aryl halides ( Dow’s process):

Aryl halides on hydrolysis yield phenol but the process is not so simple because halogen atom attached to benzene ring does not undergo SN2 reaction since C-X bond is resonance stabilized. Hence reaction takes place at high pressure and elevated pressure.

However if some electron withdrawing group is attached to benzene ring then reaction conditions get relaxed

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4. Decarboxylation of salicylic acid :

5. Oxidation of Grignard reagent :

6. Oxidation of aromatic hydrocarbons :

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Catalyst used in this reaction is cupric salt.

7.Oxidation of iso-propyl benzene (Cumene) : Cumene is prepared by Friedel Crafts alkylation of benzene with 2- Chloropropane.

PHYSICAL PROPERTIES OF PHENOL: 1. Physical state - Phenols are colorless liquids or low melting point solids, but they reddish brown due to auto oxidation on exposure to air and light. -Phenols are poisonous in nature but act as disinfectant and antiseptic. 2. Solubility Phenols form H-Bonds with water molecule and hence soluble in water, but their solubility is lower than that of alcohols because of large hydrocarbon part.

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Intermolecular H-bonding among water and phenol molecules. 3. Boiling point - Phenols have much higher boiling point than there corresponding hydrocarbons due to intermolecular hydrogen bonding -Amongst the isomeric nitrophenols, O-nitrophenol has much lower melting point and solubility than meta and para isomers of nitrophenol because of intramolecular H-bonding. Thus it does not undergo association with other molecules. In fact ortho-nitrophenol is steam volatile.

On the other hand meta and para nitrophenol exhibit intermolecular Hbonding with their own molecules as well as with water molecules and hence show comparatively higher melting and solubility.

i) Intermolecular H-bonding ( m –nitrophenol)

ii) H- bonding with water molecules ( m-nitrophenol)

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iii) Intermolecular H- bonding ( p –nitrophenol)

iv) H – bonding with water molecules ( p – nitrophenol)

CHEMCIAL PROPERTIES OF PHENOL: (A)Reactions involving cleavage of O-H bond 1. Acidic character of phenol (i) Reaction with active metals

(ii) Reaction with alkalies

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They do not react with carbonates and bicarbonates. Phenols are weaker acid as compared to carboxylic acid because of polar O-H group in them. The acidic nature of phenol is due to formation of stable phenoxide ion in solution to give H+ ions.

Phenol behaves as stronger acid than alcohol i. The greater acidity of phenol is due to stability of phenoxide ion is resonance stabilized . ii. Resonance structure of phenol

iii. As a result of resonance it weakens the polar O-H bond and thus facilitates the release of proton (H+) to give phenoxide ion which is also stable due to resonance. iv. Resonating structure of phenoxide ion

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v. Both phenol and phenoxide ion are stable due to resonance. But phenoxide ion is more stabilized than phenol because the resonating structure of phenoxide ion carry only negative structure of phenol involves separation of positive and negative charge. This charge delocalization is a stabilizing factor in phenoxide ion and increases acidity of phenol. vi. Effect of substituent on the acidity of phenols a. Electron withdrawing group (EWG) 1. Electron withdrawing groups NO2 , -X, -CHO, -COOH, -CN etc stabilizes the phenoxide ion more by dispersing the negative charge relative to phenol ( i.e. proton release become easy) and thus increases the acidic strength of phenols.

2. Particular effect is more when the substituent is present on O – and ppositions than in m- position. Thus acidic strength of nitrophenol decreases in the order p-nitrophenol > o-nitrophenol > m-nitrophenol > phenol 3. Further greater the number of electron withdrawing groups at o- and p – position, more acidic the phenol. b. Electron donating group (EDG) (i) Electron donating group –R, -NH2, -OR etc destabilize the phenoxide ion by donating electrons and intensify the negative

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charge relative to phenol (i.e. proton release become difficult)and thus decreases the acidic strength of phenol.

(ii) The effect is more when the substituent is present on o- and pposition than on m- position with respect to –OH group. Thus cresol are less acidic than phenol.

m – methoxy and m-amnion phenols are stronger acid than phenols because of –I effect ( of –OCH3 and –NH2 groups) and absence of +R effect. m –methoxy phenol > m-amino phenol > phenol > O-methoxy phenol > p-methoxy phenol vii) Reaction of –OH group : Reaction with FeCl3 is the test of phenol 6C6H5OH + FeCl3 [(C6H5O)6Fe ]-3+ 3HCl Ferric phenoxide ( violet complex) ii. Ester formation

Reaction with benzoyl chloride is known as benzoylation

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Benzoylation of alcohols o phenols in presence of NaOH is called Schotten-Baumann reaction. iii. Ether formation

Claisen rearrangement

(B) Electrophilic aromatic substitution reaction 1. Halogenation

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Due to steric hinderance at ortho position, para-product Predominates. 2. Sulphonation

4. Nitration

5. Mercuration

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6. Friedel crafts alkylation and acylation

7. Nitrosation

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8. Kolbe’s reaction

Mechanism

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(a) Acetyl salicylic acid ( Aspirin)

It is a white solid (m.pt. 408K) and is used for relieving pain (analgesic) and to bring down the body temperature (antipyretic during fever).

(b) Methyl salicylate

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It is an oily liquid (b.pt. 495K) with pleasant odor (oil of wintergreen) used in perfumery and flavoring agent. It is also used in medicine in the treatment of rheumatic pain.

(c)phenyl salicylate ( salol)

It is white solid (m.pt 316K) and is used as an intestinal antispeptic.

9. Reimer-Tiemann reaction :

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Mechanism The electrophile, dichloromethylene CCl2 is generated from chloroform by action of base .

OH- + CHCl3 ⇆ HOH + CCl3 → Cl- + CCl2

Attack of electrophile ( :CCl2) on phenoxide ion

Salic aldehyde

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If the reaction is carried out with carbon tetrachloride (CCl4) instead of chloroform, o-hydroxyl benzoic acid (salicylic acid) is formed.

TESTS TO DISTINGUISH BETWEEN ALCOHOLS AND PHENOLS: 1. Litmus test Phenol turns blue litmus red being acidic in nature but alcohol do not. 2. Ferric chloride test Phenol react with neutral ferric chloride solution to form violet or green colored solution whereas alcohol do not undergo such reactions. 3. Bromine water test Aqueous solution of phenol forms white precipitate of 2,4,6-tribromo phenol, when treated with bromine water. However alcohol so not give such precipitation.

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Practical problems

Q.1. Choose the incorrect statement about the benzyl chloride:

(a) It is less reactive than alkyl halides.

(b) It can be oxidized to benzaldehyde by boiling with copper nitrate

solution.

(c) It gives a white precipitate with alcoholic silver nitrate

Q.2. The reaction RX + 2Na + RX _______________? R-R + 2NaX

is called

(a) Sandmeyer’ reaction

(b) Fittig reaction

(c) Wurtz reaction

(d) Williamson’s synthesis

Q.3. (CH3)3CMgBr on reaction with D2O gives:

(a) (CH3)3CD

(b) (CH3)3COD

(c) (CD3)3CD

(d) (CD3)3OD

Q.4. which of the following is the most reactive towards nucleophilic

substitution reaction?

(a) C6H5Cl

(b) CH2=CHCl

(c) ClCH2CH=CH2

(d) CH3CH=CHCl

Q.5. which of the following is the correct:

(a) RF>RCl>RBr>RI

(b) RF>RBr>RCl>RI

(c) RCl>RBr>RF>RI

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(d) RI>RBr>RCl>RF

(Q.6. which of the following is the most reactive towards the SN2

reaction:

(a) MeX

(b) RCH2X

(c) R2CHX

(d) R3CX

Q.7. the correct order of Nucleophlicity is:

(a) CH3- < NH2- < HO- < F-

(b) NH2- > CH3- > HO- > F-

(c) CH3- > NH2- > HO- > F-

(d) NH2- > F- > HO- > CH3-

Q. 8. 2-Phenyl-2-chloropropane on treatment with alcoholic KOH gives

mainly:

(a) 2-Phenylpropene

(b) 3-Phenylpropene

(c) 1-Phenylpropan-2-ol

(d) 1-Phenylpropan-3-ol

Q.9. The IUPAC name of CH3-CH=CHCH2Br is: ( 1 mark )

(a) 1-Bromo-2-butene (c) 2-Butene-1-bromide

(b) 1-Bromo-3-butene (d) 4-Bromo-2-butene

Q.10. Write the IUPAC name of the following compound.

ClCH2CHClCH3

Q.11. which is a better nucleophile, a bromide ion or iodide ion? Why?

Q.12. Write the structure of 2-Chloro-3-methylpentane.

Q.13. what is the nature of C-X bond of haloalkanes?

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Q.14. Arrange the compounds of each set in order of reactivity

towards SN2 displacement:

2-Bromo-2-methylbutane, 1-Bromopentane, 2-Bromopentane.

Q.15. what is an asymmetric carbon?

Q.16. which haloalkane has the maximum density and why?

Q.17. Write a chemical reaction to illustrate Saytzeff’s rule.

Q.18. Write the IUPAC name of the following structure.

CH2BrCH=CHCH2CHCl2

Q.19. Arrange the following in increasing order of boiling point.

CH3CH2CH2CH2Br, (CH3)3CBr, (CH3)2CHCH2Br.

Q.20. Arrange the following in order of their decreasing reactivity in

nucleophile substitution reactions:

CH3F, CH3I, CH3Br, CH3Cl.

(Q.21) Define optical activity?

Q. 22. What are enantiomers? Give an example.

Q.23. What is racemic mixture? Give an example.

Q.24. Define retention? Give an example.

Q.25. The most suitable reaction for the preparation of n-propylphenol

is:

(a) Friedel-crafts reaction

(b) Wurtz reaction

(c) Grignard reaction

Q.26. Most reactive halide towards SN1 reaction is

(a) n-Butyl chloride (c) tert-Butyl chloride

(b) sec-Butyl chloride (d) Allyl chloride

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األول / السنة الثانية / قسم الصيدلةالكيمياء عضوية / الفصل Lecture 10

Amines and its derivatives Classification of Amines : Amines are derivatives of ammonia, the same way that alcohols are derivatives of water Amines can be classified as 1º, 2º or 3º based on how many alkyl groups are attached to the nitrogen

Nomenclature of Amines:

Most simple amines are named by their common names (which are accepted by IUPAC)

For common names, the alkyl groups attached to the N are named alphabetically, and amine is added to the end, Lower amines are named with the suffix -amine.

methylamine

NH2

HN N

H

N

H

H

Ammonia Primary Amine Secondary Amine Tertiary Amine

Mazayah University College ORGANIC CHEMISTRY –II

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Higher amines have the prefix amino as a functional group. IUPAC however does not recommend this convention, but prefers the alkanamine form, e.g. pentan-2-amine.

2-aminopentane

(IUPAC Name / pentan-2-amine )

IUPAC rules are more often used for more complicated amines

- find the longest chain bonded to N, and replace -e in alkane name with amine

- number at end nearest N and give number for position of N

- the prefixes di, tri etc. are used for multiple amines

- when amines are with other functional groups they are called amino groups.

Naming Aromatic and Heterocyclic Amines:

• Aromatic amines are named as anilines. • When alkyl groups are attached to the aromatic N, they are

written as N-alkyl at the beginning of the name • As substituents on the ring they are named as amino groups • Heterocyclic amines have one or more nitrogen as part of

the ring and are usually named by their common names

- know those that are boxed

NHN

NH2

H

ONH2

H2N

NH2

trimethylamine ethylmethylamine 2-butanamine 3-aminobutanal 1,2-ethanediamine

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Physical Properties of Amines: 1.Boiling point :

Primary and secondary amines form H-bond with themselves, so have

relatively high boiling points.

However, because the N-H bond is less polar than the O-H bond,

amines have lower boiling points than alcohols

Primary and secondary amines have boiling points similar to

aldehydes and ketones

Tertiary amines can’t form H-bond with themselves, and so have

boiling points near those of ethers and hydrocarbons.

2.Solubility :

primary and secondary amines are more soluble than tertiary because

they have more H-bonding with water:

Ethylamine when added to water forms intermolecular H−bonds with water. Hence, it is soluble in water.

NH2

HN

NH2

OH

O

analine N-methylanaline ortho-aminobenzoic acid

NH

N

NH

NH

NH N

N

N

N

N NH

N

pyrrolidine pyrrole imidazole piperidine pyridine pyrimidine purine

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But aniline does not undergo H−bonding with water to a very large extent due to the presence of a large hydrophobic −C6H5 group. Hence, aniline is insoluble in water and forms intermolecular H-bonding.

Solubility decreases with the increase in the number of carbon atoms. Smaller amines (less than 5 carbons) are soluble in water. The aromatic amines, such as aniline, their solubility in water is low their their lone pair electrons conjugated into the benzene ring, thus their tendency to form hydrogen bonding is disappeared. Basicity of Amines and Amine Salts:

• Amines are weak bases that partially ionize in water to form ammonium ions and hydroxide ions

• When treated with acids, amines form salts, without the formation of water

• Quaternary ammonium ions have 4 alkyl groups attached to the nitrogen, and have a permanent positive charge on the N (no H attached to N, so can’t react with bases)

• Amine salts are solids at room temperature and are soluble in water, making them much more useful as medicines

NH2+ H2O NH3

+ OH

N+ HCl

N

H

Cl

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• Alkaloids are naturally occurring compounds that contain nitrogen and have basic properties • They have a wide variety of structures, including simple

amines, aromatic amines, and heterocyclic amines • Some examples of alkaloids are caffeine Heroin , Morphine

and Codeine

Preparation of Amines : 1. Alkylation The most industrially significant amines are prepared from ammonia by alkylation with alcohols:

ROH + NH3 → RNH2 + H2O These reactions require catalysts, specialized apparatus, and additional purification measures. The same amines can be prepared by treatment of haloalkanes with ammonia and amines: RX + 2 R′NH2 → RR′NH + [RR′NH2]X

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Such reactions, which are most useful for alkyl iodides and bromides, are rarely employed because the degree of alkylation is difficult to control.

2. Alkylation of Phthalimide (Gabriel synthesis of Primary Alkyl Amines)

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using phthalimide with base (KOH) and followed by hydrazine. The reaction begins with the deprotonating of the phthalimide which then attacks the alkyl halide in an SN2 reaction to give an N-alkylphthalimide intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation of the final primary amine product and phthalhydrazide by-product.

Aromatic primary amines can't be prepared by this method because aryl halides do not undergo nueleophilic substitution with potassium phthalimide.

3.Hofmann degradation of amides

This reaction is used for preparation of primary amines only, and it gives good yields of primary amines uncontaminated with other amines.

The mechanism of reaction is as following :

1. Base abstracts an acidic N-H proton, yielding an anion. 2. The anion reacts with bromine in an α-substitution reaction to

give an N-bromoamide.

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3. Base abstraction of the remaining amide proton gives a bromoamide anion.

4. The bromoamide anion rearranges as the R group attached to the carbonyl carbon migrates to nitrogen at the same time the bromide ion leaves, giving an isocyanate.

5. The isocyanate adds water in a nucleophilic addition step to yield a carbamic acid .

6. The carbamic acid spontaneously loses CO2, yielding the amine product.

4. Hofmann elimination of quaternary ammonium salts:

All of the eliminations that we have described so far have involved electrically neutral substrates. However, eliminations are known in which the substrate bears a positive charge. One of the most important of these is the E2-type elimination that takes place when a quaternary ammonium hydroxide is heated. The products are an alkene, water, and a tertiary amine:

5. Reduction of nitriles and amides:

Nitriles are reduced to amines using hydrogen in the presence of a palladium catalyst

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R–C≡N + H2

catalyst

RCH=NH imine

H2

RCH2NH2

Although acidic or alkaline conditions should be avoided to avoid the possible hydrolysis of the -CN group. LiAlH4 is more commonly employed for the reduction of nitriles on the laboratory scale.

Amides can be reduced to the amine by conversion of the C=O to -CH2- using reducing agent LiAlH4 and Et2O or THF followed by H3O+

Reaction of Amines:

1. Alkylation

Alkylation of amine is a type of organic reaction between an alkyl halide and ammonia or an amine. The reaction is called nucleophilic aliphatic substitution (of the halide), and the reaction product is a higher substituted amine. The method is widely used in the laboratory, but is less important industrially, where alkyl halides are not preferred alkylating agents.

When the amine is a tertiary amine the reaction product is a quaternary ammonium salt :

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Amine also reacts with aryl halides (ArX) but reaction usually requires "activated" aryl halides, such as those with strong electron-withdrawing groups such as nitro groups ortho or para to the halogen atom. For the arylation of amines with unactivated aryl halides palladium complexes must be used as catalysts.

2.Acylation Both aliphatic and aromatic primary and secondary amines undergo N-acetylation. This acetylation can be effected using acid halides or anhydrides in acetone , under weakly basic conditions in the presence of sodium acetate and/or triethyl amine and the product obtained is an amide. Base remove HCl and prevent protonation of amine.

For example reaction of methyl methanamine with acetylchloride in basic medium gives N,N-dimethylethanamide as shown in the following mechanism below :

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3. Sulfonation

Benzenesulfonyl chloride, reacts with amines to give sulfonamide derivatives.This reaction is a useful test for distinguishing primary, secondary and tertiary amines (the Hinsberg test). As shown in the following equations, 1º and 2º-amines react to give sulfonamide derivatives with loss of HCl, whereas 3º-amines do not give any isolable products other than the starting amine. In the latter case a quaternary "onium" salt may be formed as an intermediate, but this rapidly breaks down in water to liberate the original 3º-amine (lower right equation).

4.Diazotization

Amines react with nitrous acid to give diazonium salts. The alkyl diazonium salts are of little synthetic importance because they are too

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unstable. The most important members are derivatives of aromatic amines such as aniline ("phenyl amine") (A = aryl or naphthyl):

ANH2 + HNO2 + HX → AN2+X− + 2 H2O

Anilines and naphthylamines form more stable aryl diazonium salts, which can be isolated in the crystalline form. They are prepared in cold (0 º to 5 ºC) aqueous solution,

Diazonium salts undergo two reactions:

1. Replacement reaction :

The N2 group is easily replaced by anions.

AN2+ + Y− → AY + N2

Examples of replacement of the N2 group with anions is shown below

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2.Coupling reaction :

Aryldiazonium couple with electron-rich aromatic compounds such as a phenol to form azo compounds (dyes) in which two benzene rings are linked by a nitrogen bridge. Coupling occurs para to hydroxyl or amino group. All azo compounds are strongly coloured and are used as dyes.

OR

Aniline is also coupled with diazonium salt to give a yellow solid azo compound .

Methyl orange is an important dye obtained by coupling the diazonium salt of sulphanilic acid with N, N-dimethylaniline

5. Conversion to imines :

Imine formation is an important reaction. Primary amines react with ketones and aldehydes to form imines. In the case of formaldehyde (R′ = H), these products typically exist as cyclic trimers.

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RNH2 + R′2C=O → R′2C=NR + H2O

Reduction of these imines gives secondary amines:

R′2C=NR + H2 → R′2CH–NHR

Similarly, secondary amines react with ketones and aldehydes to form enamines:

R2NH + R′(R″CH2)C=O → R″CH=C(NR2)R′ + H2O Derivatives of Amines: Amides: Structure and Naming of Amides :

• Amides are considered derivatives of carboxylic acids • They have an amino group attached to the carbonyl • Most simple amides are known by their common names • For common names the -ic acid is changed to -amide • For IUPAC names the -oic acid is changed to -amide • Alkyl groups attached to the amide nitrogen are indicated by

writing N-alkyl or N,N-dialkyl before the amide name

Physical Properties and Stability of Amides: Primary and secondary amides form H-bond with themselves, and so have high melting and boiling points Tertiary amides can’t form H-bond with themselves, so have lower melting and boiling points than primary or secondary amides. Amides have higher melting and boiling points than carboxylic acids because they are more flat (due to delocalization of electrons), so they stack better.

H NH2

O

NH2

O

NH

O

OH

NH2

O

Br

methanamide(formamide)

ethanamide(acetamide) N-methyl-2-hydroxybutanamide para-bromobenzamide

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Amides (except formamide) are solids at room temperature Smaller amides (5 carbons or less) are soluble in water Unlike amines, amides are not basic. They are also very stable (unreactive) compared to esters. This is due to the delocalization of the nonbonded pair of electrons (through resonance)

Preparation of Amides: Amides can be synthesized by the condensation reaction of a carboxylic acid with ammonia or a primary or secondary amine

NH2

O

NH2

O

NH

O

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Reactions of Amides :

1. Action of NaOH:

Amides are decomposed by NaOH to evolve ammonia. The gas can be tested by a moist red litmus paper which is then turned blue.

Amide Sodium salt of carboxylic acid

2. Alkaline hydrolysis of aromatic amides to aromatic acid:

The soluble sodium salt of aromatic acid formed from aromatic amides upon hydrolysis is regenerated as white precipitate in acidic medium.

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Aromatic amide Sodium salt of Aromatic Acid

3. Biuret Reaction for aliphatic diamide:

When aliphatic diamide is heated at a temperature above its melting point, ammonia is evolved and crystalline biuret is formed. This biuret in alkaline medium gives a violet color with a drop of copper sulphate solution.

Biuret

4. Hydroxamic acid test for aromatic primary amides:

Hydrogen peroxide reacts with aromatic primary amides to form the hydroxamic acid, which then reacts with ferric chloride to form ferric hydroxamate complex having a violet color.

Aromatic amide

Ferric hydroxamate Complex

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Practical problems

Q .Give the structures of A, B and C in the following reactions: