Chemistry: CIX Organic Chemistry -III Lesson: Nitrogen Containing Functional Groups Unit-1: Amines-Preparation and Properties Lesson Developer: Dr. S.P Bhutani College/Dept: Formerly Associate Professor Department of Chemistry Rajdhani College, University of Delhi Lesson Editor:Dr.N.K Gautam Advisor (Sciences) Institute of Lifelong Learning, University of Delhi
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Contents: 1.Amines– Introduction 2. Classification Of Amines 3.Nomenclature Of Amines A. Common Names B. Iupac Names 4.Physical Properties Of Amines 5. Basicity Of Amines A. Pkb And Pka Values B. Effects On Amine Basicity C. Basicity Of Aromatic Amines 6. Preparation Of Amines A.Direct Alkylation Of Ammonia-Ammolysis Of Halides B. Indirect Alkylation—The Gabriel Synthesis C. Reduction Of Nitro Compounds D. Reduction Of Amides, Oximes And Nitriles (I) Reduction Of Nitriles (Ii) Reduction Of Oximes (Iii) Reduction Of Amides E. Reductive Amination F. Preparation Of Amines Through The Hofmann, Curtius And Schmidt Rearrangements (I) The Hofmann Rearrangement (Ii) Curtius Rearrangement (Iii) Schmidt Reaction 7. References
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1.AMINES - INTRODUCTION Amines are compounds in which one or more alkyl or aryl groups are attached to nitrogen. They may be considered to be the organic derivatives of ammonia
Aromatic and heterocyclic amines are generally known by historical names. Phenylamine is called aniline and its derivatives are named as derivatives of aniline.
The names and structures of some common heterocyclic amines are shown below:
Amines serve many functions in living organisms. Because of their high degree of biological activity, many amines are used as drugs and medicines. The structures and uses of some important biologically active amines are given below:
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The alkaloids are an important group of biologically active amines. The chemistry of some typical alkaloids has been discussed in chapter 5 of this book.
2. CLASSIFICATION OF AMINES Amines are classified as primary (1°), secondary (2°) or tertiary (3°) corresponding to one, two or three alkyl groups attached to nitrogen. In secondary and tertiary amines, the alkyl or aryl groups may be the same or different.
Quaternary ammonium salts have four alkyl or aryl groups attached to nitrogen atom. Thus, the nitrogen atom bears a positive charge. The four groups joined to nitrogen in the ammonium ion may be same or different. For example,
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3.NOMENCLATURE OF AMINES A. Common Names Simple amines are usually referred to by their common names. In common nomenclature, most primary aliphatic amines are named by using the alkyl group or groups attached to nitrogen followed by the suffix-amine. The names are written as one word. Some examples are, Primary Amines
Secondary and tertiary aliphatic amines are named in a similar way. We either designate the alkyl/aryl groups individually if they are different or use prefixes dior tri- if they are same. Some examples are given below: Secondary Amines
Tertiary Amines
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Aromatic amines are named as derivatives of the simplest aromatic amine, aniline. Amino toluene is named as toluidine.
When it is necessary to name a compound containing the amino group as a derivative of some other function, the prefix -amino is used. For example,
B. IUPAC Names Under the IUPAC nomenclature, amines are named by adding the suffix -amine to the name of the chain or ring system to which the amino group is attached with removal of the final ‘e’. Primary Amines
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Secondary Amines
Tertliary Amines
4.PHYSICAL PROPERTIES OF AMINES Amines are strongly polar compounds because the large dipole moment of the lone pair of electrons adds to the dipole moments of C N and H N bonds. Primary and secondary amines have N—H bonds, therefore they form hydrogen bonds. Tertiary amines cannot engage in hydrogen bonding because they do not have N—H bonds. Amines have higher boiling points than non-polar compounds of the same molecular weight but lower boiling points than alcohols or carboxylic acids. Because nitrogen is less electronegative than oxygen, the N—H bond is less polar than the O—H bond. Therefore, amines form weaker hydrogen bonds than do alcohols of similar molecular weights. Primary and secondary amines have boiling points that are lower than those of alcohols but higher than those of ethers of similar molecular weights. Hydrogen bonding is more important with 1° than with 2° amines. Therefore, primary amines have higher boiling points than those of secondary amines. Tertiary amines have no hydrogen bonding, they have lower boiling points than primary and secondary amines of similar molecular weights. Table 1. gives melting points, boiling points and water solubilities of some simple aliphatic and aromatic amines. All these properties increase with increasing molecular weight as a result of the greater intermolecular attraction with the larger members in the series. Thus, we observe a primary amine always boils higher than a secondary amine of the same molecular weight. All amines, even tertiary ones, form hydrogen bonds with hydroxylic solvents such as water and alcohols. Therefore, amines tend to be soluble in alcohols and lower molecular weight amines (up to about six carbon atoms) are relatively soluble in water. Institute of Lifelong Learning, University of Delhi
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TABLE 1.Physical Properties of Amines Amine
Molecular
Melting
Boiling
Water
weight
point °C
point °C
solubility
Primary Amines Methylamine
31
–93
–7
Very soluble
Ethylamine
45
–81
17
Very soluble
n-Propylamine
59
–83
48
Very soluble
n-Butylamine
73
–50
77
Very soluble
Aniline
93
–6
184
Less soluble
Cyclohexylamine
99
—
134
Slightly soluble
107
—
53
Very soluble
Dimethylamine
45
–96
7
Very soluble
Ethylmethylamine
59
—
37
Very soluble
Diethylamine
73
–42
56
Very soluble
Di-n-propylamine
101
–40
111
Slightly soluble
N-Methylaniline
107
–57
196
Slightly soluble
Diphenylamine
169
54
302
Insoluble
59
–117
3.5
Soluble
Triethylamine
101
–115
90
N, N-Dimethylaniline
121
2
194
Low solubility
Triphenylamine
251
126
365
Insoluble
Benzylamine Secondary Amines
Tertiary Amines Trimethylamine
Less soluble
The most important property of amines is their characteristic odour of rotting fish. Some of the diamines are particularly pungent. However, the methylamines and ethylamines smell like ammonia. Aromatic amines are generally very toxic. They are readily absorbed through the skin often with fatal results. Aromatic amines are very easily oxidised by air. Most are colourless when pure, they are often discoloured due to the presence of oxidation products.
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5. BASICITY OF AMINES A. pKb and pKa Values Amines are Lewis bases (nucleophiles) because of the presence of a nonbinding electrons on nitrogen, which can form a bond with an electrophile. An amine can also act as a Bronsted-Lowry base accepting a proton from a proton acid. Reaction of an amine as a nucleophile
Reaction of an amine as a base
As nitrogen is less electronegative than oxygen, amines are more basic than alcohols.
However, amines are stronger bases than water, but are far weaker bases than hydroxide ions, alkoxide ions and carbanions. Since amines are much more basic than water, aqueous solutions of amines have basic properties. An amine can abstract a proton from water giving an ammonium ion and a hydroxide ion.
The equilibrium constant for this reaction is called the base-dissociation constant (basicity constant) and is denoted by Kb . Kb is given by the expression +
[R - NH3 ][OH- ] Kb = [R - NH2 ] water being in large excess, concentration of water is not included in the above expression. This gives us a convenient method of comparing the relative basicities of amines. Values of Kb for most amines are fairly small and the equilibrium for this dissociation constant lies Institute of Lifelong Learning, University of Delhi
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toward the left, we use its negative logarithm, pK b values to compare the relative strengths of amines as polar bases. pKb = –log Kb The values of Kb, pKb and pKafor some amines are listed in Table 2. The larger the value of Kb (or smaller the value of pKb), the greater is the tendency of the amine to accept a proton from water and thus the greater will be theconcentrations of +
R - NH3 and OH– in the solution. Larger values of Kb are associated with those amines that are stronger bases and smaller values of Kb are associated with those amines that are weaker bases. Just the opposite is true for values of pK b. The basicity constant for ammonia at 25°C is 1.8 × 10 –5, we can have its pKb as given below:
K b=
[NH4+ ][OH- ] = 1.8 × 10–5 [NH2 ]
pKb = –log (1.8 × 10–5) = 4.74 Another way to compare the basic strengths of amines is to compare the acidity constants or pKa values of their conjugate acids, the alkylammonium ions. We have the equilibrium as
Kb =
[R - NH2 ][H3O+ ] [R - NH3+ ]
pKa = –log Ka Multiplying Kawith Kb, we get Ka × Kb = [H3O+] [OH–] = Kw = 1.0 × 10–14 pKa + pKb = 14
∴
pKb = 14 – pKa
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Thus, it is possible to convert values of K a (or pKa) for the ammonium ion into Kb (or pKb) for the amine. If the amine is strongly basic, the ammonium ion will hold the proton tightly, it will have larger pKai.e., it will not be very acidic. On the otherhand, if the amine is weakly basic the ammonium ion will not hold the proton tightly and will be much more acidic (it will have a small pKa). TABLE 2. Values of Kb, pKb and pKa of some Amines Amine
Kb
pKb
pKa
1.8 × 10–5
4.75
9.25
4.3 × 10–4
3.36
10.64
Ethylamine
4.4 × 10
–4
3.33
10.67
n-Propylamine
4.7 × 10–4
3.32
10.68
Cyclohexylamine
4.7 × 10–4
3.32
10.68
–5
4.67
9.33
Ammonia Primary Amines Methylamine
Benzylamine
2.0 × 10
Aniline
4.0 × 10–10
9.38
4.62
p-Toluidine
1.2 × 10–9
8.90
5.10
–9
8.71
5.29
p-Methoxyaniline
2.0 × 10
p-Nitroaniline
1.0 × 10–13
13.0
1.0
Secondary Amines Dimethylamine
5.3 × 10–4
3.23
10.77
Diethylamine
9.8 × 10–4
3.67
10.93
3.0
11.0
Di-n-propylamine N-Methylaniline
10.0 × 10–4 6.1 × 10
–10
9.16
4.84
Tertiary Amines Trimethylamine
5.5 × 10–5
4.20
9.80
Triethylamine
5.7 × 10–4
3.12
10.88
–4
3.35
10.65
8.85
5.15
Tri-n-propylamine N, N-Dimethylaniline
4.5 × 10
11.6 × 10–10
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B. Effects on Amine Basicity When we examine the pKb values of the amines given in Table 2, we see that most primary amines are stronger bases than ammonia.
We can explain this on the basis of electron-releasing ability (+I effect) of an alkyl group. An alkyl group has +I effect, it releases electrons and stabilises the alkyl ammonium ion that results from the acid-base reaction.
This explanation is supported by measurements in the gas phase. The basicities of the following amines increase with increasing methyl substitution.
We might expect secondary amines to be stronger than primary amines and tertiary amines to be the strongest of all. This is not the order of basicity of these amines in aqueous solution. In aqueous solution the order is—
It is observed that the introduction of an alkyl group into ammonia increases the basic strength markedly as expected. The introduction of second alkyl group further increases the basic strength but the effect of introducing the second alkyl group is much less marked. The introducing of a third alkyl group to yield a tertiary amine, however, decreases the basic strength. It becomes even less basic than a primary amine. This is due to solvation effects. The basicity of an amine in water is determined not only by the availability of electrons on the nitrogen atom but also by the extent to which cation, formed by uptake of a proton, stabilises by solvation. The more the number of hydrogen atoms attached to nitrogen in the cation the greater is the possibility of solvation via. hydrogen bonding between these and hydrogen.
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As we go along the series NH3 R—NH2 R2—NH R3—N, the inductive effect will tend to increase the basicity but less stabilisation of the cation by hydrogen bonding will occur, which will tend to decrease the basicity. The net effect of introducing alkyl groups becomes smaller and actual change over takes place on going from secondary to tertiary amine. We observe that order of basicity of the butyl amines in chlorobenzene as solvent is BuNH2 > Bu2NH > Bu3N
Whereas their related pKa values in water are 10.61, 11.27 and 9.87. There is no solvation of butylamines in chlorobenzene. The effect of introducing electron-withdrawing groups e.g., Cl, NO2, close to the basic centre ¾ NH 2 is to decrease the basicity due to their –I effect. Thus, we observe the amine
is found to be virtually non basic due to the three powerful electron-withdrawing CF3 groups. Amides are found to be very weakly basic in water. Thus, acetamide pK a ~ 0.5 is very weak in comparison to ammonia pKa = 9.25. This is due to electronwithdrawing mesomeric effect of C = O group.
The lone pair of electrons on the nitrogen are withdrawn by the adjacent C = O group. If two C = O groups are present, the resultant imides are often sufficiently acidic to form alkali metal salts, e.g., phthalimide is so acidic that on treatment with potassium hydroxide it forms potassium phthalimide because the conjugate base can stabilise by resonance.
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The resonance effect in increasing the basic strength of an amine is seen in guanidine, HN = C (NH2)2, which is a very strong organic nitrogenous base withpK a of ~ 13.6. Both Å
the neutral molecule and the cation H2N = C(NH2)2 resulting from its protonation are stabilised by delocalisation.
The cation is greatly stabilised with respect to the neutral molecule because the structures are equivalent and there is no charge separation. Thus, protonation of guanidine makes it energetically favourable and guanidine becomes an extremely strong base. Urea has two amino groups joined to aC=O group. On protonation we get two equivalent resonating structures. Therefore, it acts as a monoacidic base.
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C. Basicity of Aromatic Amines Aromatic amines are much weaker bases than the corresponding non aromatic amine, cyclohexylamine. For example, aniline is a very weak base (pK a = 4.62) compared to ammonia (pKa = 9.25) or cyclohexylamine (pKa = 10.68). We attribute this due to the resonance contributions to overall hybrid of aniline. In aniline, the nitrogen is bonded to sp2 hybridised carbon atom, the lone pair of electrons on nitrogen conjugate with electrons of the benzene nucleus and we get various resonating structures. This delocalisation of the electron pair stabilses aniline. Moreover, there is –I effect of the phenyl group. Electrons are withdrawn and less available for protonation. Hence, aniline becomes a weaker base than ammonia itself.
When anilne is protonated, it become anilinium ion,
Anilinium ion has got only two resonating structures and consequently resonance does not stabilise the anilinium ion to as extent as it does aniline itself. The aniline is thus stabilised to a greater extent with respect to the anilinium cation and it is energetically unfavourable for aniline to take a proton. Therefore, aniline acts as a weaker base (pKa = 4.62) compared to cyclohexylamine, pKa = 10.68.
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The base wreaking effect is more pronounced when further phenyl groups are introduced on the nitrogen atom. Thus, diphenylamine is an extremely weak base (pK a = 0.8) whereas triphenylamine is not basic at all.
Electrons on nitrogen atom are withdrawn by phenyl groups and are not available for protonation. Introduction of alkyl e.g., —CH3 groups on to the nitrogen of aniline results in increase in basic strength. Thus, dimethyl aniline is a stronger base than methylaniline which is stronger than aniline.
Irregular effects of introduction of methyl group into o-, m-, and p-positions in aniline have been observed. When a methyl group is attached to the benzene nucleus in aniline, the basicity increases only if the group is at para position. Thus, we have
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A group with a more powerful inductive effect is found to have more influence. For example, electron withdrawl is intensified when the —NO2 group is in the o-, or p-position due to extended conjugation of the lone pair of electrons with electrons of the benzene nucleus. Thus, nitroanilines are found to have low pK a values.
We observe that o-nitrotoluene is a much weaker base than other nitroanilines.This is due to the fact that inductive effect is more powerful in o-nitroaniline dueto short distance. Moreover, there is streric interaction and hydrogen bonding ino-nitroaniline as shown below:
o-Nitroaniline is such a weak base that its salts are largely hydrolysed in aqueous solution, while 2,4-dinitroaniline is insolube in aqueous acid and 2,4,6trinitroaniline behaves as an amide, called picramide. It readily undergoes hydrolysis to picric acid.
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When electron-donating groups such as —OH and —OCH3 are present at o-, mor p-positions, the mesomeric effect can be exerted from the o- and p-and not from the m-position. The m-substituted compound is a weaker base than aniline itself due to electron-withdrawing inductive effect exerted by the oxygen atom in each case. However, effect is more pronounced in the p-substituted aniline. In case of o-substituted aniline, the pKa values do not change appreciably due to steric and polar effects as is evident from the pKa values given below:
We show below the conjugation of lone pair of electrons of —OCH3 group with the π electrons of the benzene nucleus. This results in increasing basicity when —OCH3 group is there at the p-position.
We have seen difference between the basicities of dimethylaniline and aniline is very little. However, the basicity of 2,4,6-trinitro-N,N-dimethyl aniline is about40,000times than that of 2,6-trinitroaniline. This is due to the fact
thatgroup issufficiently large to inter-
feresterically with the large —NO2 groups in both the o-positions. As a result of this the extended conjugation of the lone pair of electrons with —NO2 groups is inhibited because the p-orbitals on the N atoms are no longer parallel to the p-orbitals of the ring carbon atoms. Thus the expected base weakening by mesomeric electron withdrawl does not take
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place. Therefore,2,4,6-trinitrodimethylaniline becomes a very strong base than 2,4,6trinitroaniline.
6. PREPARATION OF AMINES A.Direct alkylation of Ammonia-Ammolysis of Halides We know that alkyl halides undergo nucleophilic substitution reactions. Salts of primary amines can be prepared by the reaction of alkyl halides with ammonia by nucleophilic substitution reactions. Subsequent treatment of the resulting aminium salts with base gives primary amines
For example,
In practice, this type of displacement reaction might be used as a method of synthesising primary amines. But the method is of very limited synthetic application because multiple alkylations occur. When ethyl bromide reacts with ammonia, the ethylaminium bromide that is produced initially can react with ammonia to liberate ethylamine. Since the primary amine is also nucleophilic, it may undergo further reaction to give the secondary amine. Repetition of acid-base and alkylation reactions ultimately produce some tertiary amine and even some quaternary ammonium salt if the alkyl halide is present in excess.
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Multiple alkylations can be minimized by using a large excess of ammonia or the amine being alkylated. This method is only practical in cases where the amine is relatively inexpensive and sufficiently volatile that the unreacted excess may be easily removed. An example is the preparation of n-butylamine by the reaction of n-butylbromide with ammonia.
We give the general scheme of reactions where overalkylations may give a mixture of products even when equivalent molar amounts of ammonia and alkyl halide are used.
B. Indirect Alkylation—The Gabriel Synthesis Pure primary amines can be prepared in good yield by a method known as Gabriel Synthesis. This method involves the alkylation of a protected form of ammonia. Phthalimide, prepared from ammonia and phthalic acid, is converted into potassium phthalimide. Alkylation of potassium phthalimide with any alkyl halide results in the formation of N- alkyl phthalimide. Alkaline hydrolysis produces the desired primary amine and phthalic acid, obtained as a byproduct is recycled again. The scheme of Gabriel Synthesis is given below:
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Phthalimide has one acidic N—H proton ( pKa = 8.3) that is abstracted by potassium hydroxide to give the phthalimide anion, which stabilises by resonance.
The phthalimide anion is a strong nucleophile and can enter into displacement reactions with alkyl halides. It reacts with alkyl halides by SN2 mechanism displacing a halide ion.
C. Reduction of Nitro Compounds Nitro compounds undergo ready reduction to yield primary amines. The method gives the most general synthesis of aromatic amines because aromatic nitro compounds of a wide Institute of Lifelong Learning, University of Delhi
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variety are available from nitration of aromatic compounds. Nitro compounds can be reduced in two general ways:
(i)
By catalytic hydrogenation using molecular hydrogen or
(ii)
By use of chemical reducing agents in acidic media using a metal and acid.
Catalytic hydrogenation of a nitro compound to a primary amine takes place smoothly. A solution of the nitro compound in alcohol is heated with finely divided nickel or platinum under hydrogen. For example,
This method cannot be used when some easily hydrogenated group is present in the molecule. Among the most common chemical reducing agents are metals and acid, usually, iron, zinc or tin and dilute hydrochloric acid. In the laboratory, reduction of nitrobenzene to aniline is generally carried out by using dilute hydrochloric acid and granulated tin. In the acidic solution aniline is obtained as its salt. The free amine is liberated from the solution by the addition of base and is steamdistilled from the reaction mixture.
Stannous chloride, SnCl2, and hydrochloric acid are especially useful combination when other reducible groups, such as carbonyl groups are present. For example,
Selective reduction of one nitro group of a dinitro compound can be achieved by using sodium hydrogen sulphide in alcoholic solution. Institute of Lifelong Learning, University of Delhi
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This reduction can also be achieved through the use of hydrogen sulphide in aqueous or alcoholic ammonia. When this method is used, the amount of H 2S must be carefully measured, because the use of an excess may result in the reduction of more than one nitro group. It is not always possible to predict which nitro group will be reduced. However, treating 2,4-dinitrotoluene with H2S and ammonia results in reduction of the 4-nitro group.
On the other hand reduction of 2,4-dinitroaniline causes reduction of the 2-nitro group.
D. Reduction of Amides, Oximes and Nitriles Amides, oximes and nitriles can be reduced to amines. Reduction of a nitrile or an oxime yields a primary amine whereas reduction of an amide can yield a primary, secondary or tertiary amine. Nitriles can be prepared from alkyl halides and CN – or from aldehydes and ketones as cyanohydrins. Oximes can be prepared from aldehydes and ketones by the reaction with hydroxylamine. Amides can be prepared from acid chlorides, acid anhydrides or esters. (i) Reduction of Nitriles Nitriles are reduced by hydrogen and a catalyst or by lithium aluminium hydride in an ether solvent to give primary amines.
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Example,
In the catalytic hydrogenation, secondary amines are often produced as by products. The initially formed imine may react with some primary amine already produced in the reduction to give a new imine. Hydrogenation of the imine gives the secondary amine
The side reaction may be suppressed by carrying out the hydrogenation in the presence of excess ammonia.
Secondary amine formation may also be minimized by carrying out the reaction in acetic anhydride as solvent. The primary amine produced is rapidly converted into the amide. The amine may then be obtained by hydrolysis of the amide.
Since nitriles are easily available by several methods, many primary amines may be synthesised by this procedure. (ii) Reduction of Oximes Oximes can be reduced to primary amines. Since oximes are easily generated in high yield, this is a useful synthetic method. Reduction can be carried out with hydrogen and a catalyst or with LiAlH4. Institute of Lifelong Learning, University of Delhi
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For example,
Oximes are also easily reduced with sodium in alcohol, which is a safer method than the use of LiAlH4.
(iii) Reduction of Amides Amides are reduced by lithium aluminium hydride in refluxing ether. We can get primary, secondary or tertiary amine depending upon the nature of the amide.
The reduction is unusual because a C=O group is reduced to CH2. Yields are generally good. Examples,
Diboranl, B2H6, may also be used as the reducing agent. Institute of Lifelong Learning, University of Delhi
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E. Reductive Amination Aldehydes and ketones can be converted into amines by reduction in the presence of ammonia or an amine. Ammonia and primary amines condense with aldehydes and ketones to give imines. In the case of ammonia, the imines are unstable and cannot be isolated. However, if a mixture of carbonyl compound and ammonia is treated with hydrogen and a suitable catalyst, the C=N bond of the imine is reduced and an amine results. The process is often called ‘reductive amination’. The reducing agents generally used are hydrogen and a catalyst (such as nickel) or sodium cyanohydridoborate (NaBH3CN) or LiBH3CN. The reaction involves reduction of the intermediate imine obtained from aldehyde or a ketone.
Some examples are as follows:
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Primary amine obtained in the above reaction may condense with the starting aldehyde to give a different imine. Reduction of this imine gives a secondary amine.
This side reaction may be minimized by using a large excess of ammonia in the reaction medium. However, reductive amination may also be used as a method for the synthesis of secondary amines as shown by the following example:
Reductive amination appears to proceed through the following general mechanism:
When ammonia or a primary amine is used there are two possible pathways for the formation of the product-via. an amino alcohol which is called hemiaminal or via. an imine. When secondary amines are used, an imine cannot form and therefore, the pathway is through the hemiaminal or through an iminium ion
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F. Preparation of Amines Through the Hofmann, Curtius and Schmidt Rearrangements (i) Hofmann Rearrangement In the Hofmann rearrangement, an acid amide is converted to a primary amine on treatment with aqueous solution of sodium hypobromite (or sodium hydroxide and bromine). Thus, it results in shortening of the carbon chain by one atom and a change in the functional group from an amide to an amine. The actual product is the formation of the isocyanate. The isocyanate is generally not isolated since it is hydrolysed under the reaction conditions to give the corresponding amine.
Here R may be an alkyl oraryl group. If the alkyl group is of six or seven carbon atoms low yields of the product are obtained. When bromine and sodium methoxide are used instead of bromine and sodium hydroxide, the product of addition to the isocyanate is the formation of a carbamate,which is easily isolated and can be hydrolysed to the anime.
Mechanism The mechanism of the reaction follows the following pattern:
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Water addition to the isocyanate results in the whichdecarboxylates to give an amine and carbon dioxide.
formation
of
carbamic
acid
The first step in the above reaction sequence is the formation of the N- bromoamide. A proton is removed from the nitrogen atom. The deprotonated intermediate undergoes simultaneous rearrangement with the migration of the alkyl group to give the formation of the isocyanate. N-Bromoamide is quite acidic and loses a proton to the base because of the presence of two electron withdrawing groups — acyl and bromine atom. The process of migration is intramolecular. This has been established by isotopic labelling. When two amides are rearranged, together no cross products are obtained. The isocyanate produced may be isolated in anhydrous conditions but the reaction is generally carried out in aqueous or alcoholic solution in which the isocyanate is converted into an amine or a urethane respectively.
In this case it is the nucleophilicity of the migrating group that facilitates the reaction. Hofmann rearrangement provides an efficient route for making both aliphatic and aromatic amines. Thus, we have
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(ii) Curtius Rearrangement The Curtius rearrangement involves pyrolysis of acyl azides to yield isocyanates. The reaction gives good yields of isocyanates since no water is present to hydrolyse them to amines. However, they can be subsequently hydrolysed in the presence of water or alcohol. The addition of water to isocyanate initially results in the formation of carbamic acid, which is unstable and decarboxylates to give amines. With alcohols the corresponding carbamates are obtained, which can be hydrolysed to give amines. The azides may be prepared by nucleophilic substitution on an acyl chloride by sodium azide or by the reaction of acyl hydrazides with nitrous acid.
Azides may be treated with caution as they may decompose explosively. The isocyanate may be isolated by carrying out the reaction in an aprotic solvent such as chloroform. Generally, an alcoholic solvent is used with which the isocyanate reacts to form a urethane. The amines formed contain one carbon atom less than the original acyl azide. It is due to this reason that the reaction is sometimes referred to as Curtius degradation rather than Curtius rearrangement. Mechanism Here the azide undergoes rearrangement to give an isocyanate when a molecule of nitrogen is expelled.
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The Curtius rearrangement is a very general reaction and can be applied to almost any carboxylic acid — aliphatic, aromatic, alicyclic, heterocyclic, unsaturated and containing many functional groups. For example,
(iii) Schmidt Reaction In the Schmidt reaction, carboxylic acids react with hydrazoic acid in the presence of sulphuric acid to give isocyanates directly. The acid azide is normally not isolated, but allowed to rearrange to give the product. Hydrolysis of isocyanate results in the formation of primary amine. Sulphuric acid is the most common catalyst, but Lewis acids have also been used. Good results are obtained for aliphatic R groups. When R is aryl, the yields are variable. It is almost a direct method of converting carboxylic acids into primary amines, but conditions are more drastic. Under the acid conditions employed, the isocyanate is virtually never isolated. However, Schmidt reaction is applicable if the acid does not contain other groups that are sensitive to concentrated sulphuric acid.
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Mechanism The mechanism of Schmidt reaction follows the same pattern as seen in case of Curtius rearrangement.
REFERENCES: 1.Organic Chemistry by Morrison, R.T. and Boyd, R.N. Darling Kindersley (India) Pvt. Ltd. (Pearson Education). 2. Organic Chemistry by Graham Solomons, T.W. John Wiley and Sons. 3. Introduction to organic chemistry by Andrew Streitwieser, Jr. and Claylon H. Heathcock Macmillan Publishing Company. 4. Organic Chemistry by Seyhan Ege A.I.T.B.S. Publishers and Distributers J5/6, Krishan Nagar, Delhi- 110051. 5. Advanced Organic Chemistry by Jerry March John Wiley and Sons. 6. Organic Chemistry by L.G. Wade, Jr. Pearson Education. 7. A Guide Book to Mechanism in Organic Chemistry by Peter Sykes – Pearson Education.
Institute of Lifelong Learning, University of Delhi
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