structure and properties nomenclature reactions (some review) synthesis (some review)

Structure and propertiesNomenclature Reactions (some review)Synthesis (some review)Spectroscopy – mass spec, IR, NMR

Unit 4 Amines

Amines-Introduction

Amines and amine derivatives are found throughout biological systems. Amino acids (proteins) Bioregulators Neurotransmission Vitamins drugs

Amines-Introduction

Amines-Introduction

Biologically active basic amines obtained from plants are called alkaloids.

N

N N

N

O

H3C

O

CH3

CH3

caffeine

Amines-Introduction

There are many man-made drug that are amines.

N

H

CH3

levomethamphetamine

N

H

H

amphetamine

methamphetamine

N

H

CH3

pseudoephedrine

N

H

CH3

OH

vasoconstrictor

Nasal decongestant

Amine- Structures

Amines are derivatives of ammonia NH3

Amines are classified based on the number of alkyl groups attached to nitrogen.

R-NH2 primary amine (1°)

R2-NH secondary amine (2°)

R3-N tertiary amine (3°)

R4-N+, X- quaternary ammonium salt(4°)

Amine- Nomenclature

Common amines are named based on the alkyl groups attached to the nitrogen.

Alkylamine ethylaminedialkylamine dimethylaminetrialkylamine butyldiethylaminetetralkylamine tetraethylammonium

chloride

Amine- Nomenclature

(CH3CH2)2NCH3NH CH3

Name and classify the following amines.

N

H

NH2

CH2NH2

Amine- Nomenclature

The amine is named as a substituent group when there is a higher priority group.

NH2CH2CH2CH2CO2HOH

NHCH3

4-aminobutanoic acid

2-methylaminophenol

O NCH3

CH2CH3

4-(ethylmethylamino)cyclohexanone

NH2

3-aminocyclohexene

N(CH3)2

OH

Amine- Nomenclature (IUPAC)

IUPAC names are based on the longest carbon chain. Drop the –e of the alkane name and add-amine. Substituents on nitrogen have N- prefix.

CH3CH2CHCH3

NH2

CH3CHCHCH3

NH2

CH3

CH3CH2CHCH3

NHCH3

CH3CH2CHCHCHCH3

CH3

N(CH3)2

CH3

Aromatic Amines

When the amino group is bonded to an aromatic ring the parent compound is called an aniline.

NH2

aniline

N(CH3)2

N,N-dimethylaniline

NH2

CH3

4-methylaniline or

P-toluidine

Heterocyclic Amines

N

HN H N H

N

N

HN

N N

N

N

N

H

aziridine

pyrrole pyrrolidine pyridine

piperidine pyrimidinepurine

N

N

H

H

piperazine

Structure of Amines

Nitrogen atoms with 3 or 4 single bonds are sp3 hybridized.

NH H

HH-N-H bond angle is about 107°

NH CH3

CH3

The steric interactions of larger substituents increases the bond angle C-N-C is about 108 °

Structure of Amines

The nitrogen atom is potentially a stereocenter. However nitrogen inversion occurs rapidly at room temperature.

Chiral Amines:Amines with a chiral carbon.Quaternary ammonium cpds with four different groups bonded to nitrogen.Amines that are unable to achieve the planar transition state (ie small rings). pp. 875

Structure of Amines

Quaternary ammonium salt with four different groups bonded to nitrogen. The counter ion can be Cl-, Br-, OH- etc.

N

H3C CH2CH3(CH3)2CH

(R) (S)N

CH3CH3CH2

CH(CH3)2

++

Physical properties of Amines

Amines (1 °,2 ° and 3 °) are highly polar materials because of the lone pair of electrons on nitrogen.

The N-H bond is less polar than the O-H bond. Weaker hydrogen bonding. Tertiary amines cannot hydrogen bond but are hydrogen bond acceptors.


The strength and number of hydrogen bonds found in an amine influence melting points, boiling points, and water solubility.

Compound bp (C)

Type MW

(CH3)3N: 3 3 amine 59

CH3OCH2CH3 8 ether 60

CH3NHCH2CH3 37 2 amine 59

CH3CH2CH2NH

2

48 1 amine 59

CH3CH2CHO 49 aldehyde 58

CH3COCH3 56 ketone 58

CH3CH2CH2OH 97 alcohol 60


type MW mp bpMethylamine 1° 31 -93 -7ethylamine 1° 45 -81 17n-propylamine 1° 59 -83 48

dimethylamine 2° 45 -96 7diethylamine 2° 73 -42 56

trimethylamine 3° 59 -117 3.5triethylamine 3° 101 -115 90


Amines up to about 6 carbons are water soluble. Amines accept hydrogen bonds from water and

alcohols. Branching increases solubility. Amines have very strong odors (rotting fish).

1,5-pentanediamine (cadaverine). 1,4-butanediamine (putrescine).

Pure amine are clear (liq. or solids) but oxidation from atmospheric oxygen often results in the materials being dark colored.


Amines are bases, in the presence of acids the lone pair of electrons act as a proton acceptor (Bronsted-Lowry bases).

The lone pair of electrons on nitrogen can also act as a nucleophile (Lewis base).

NH2R + HCl R NH3 + Cl-

NH2R + R N

H

H

H

HH

+ Cl-CH

Cl

HH


R N

H

H

+ H OH

R N

H

H

H

+ OH -Kb

Kb = ______________[RNH3

+] [OH - ]

[RNH2 ]

ammonium ionhydroxide ion

Amines are weak bases:

Kb = 10-3 - 10-10 Larger Kb is stronger base.

pKb = 3 - 10 Smaller pKb is stronger base.


type pKb

ammonia 4.74methylamine 1° 3.36ethylamine 1° 3.36n-propylamine 1° 3.32

dimethylamine 2° 3.28diethylamine 2° 3.01

trimethylamine 3° 4.26triethylamine 3° 3.24

aniline 1° 9.4pyridine heterocyclic 8.75

see page 878


Amines are converted to the water soluble ammonium salt by treatment with an acid. Examples: HCl, HBr, H2SO4 and organic acids.

The salt can be converted back to the free amine by treatment with a strong base. Examples: NaOH, KOH, Na2CO3 and bicarbonate.

Amines are often isolated and purified using acid/base extraction. page 881

Amine salts are more stable to air oxidation than the free amine and have little or no odor.

Spectroscopy of Amines


propylamine


piperidine


Benzylamine


N-methylaniline

Reactions of Amines (review)

Primary amines react with ketones and aldehydes to give imines. Analogous products are obtained for hydroxylamine, hydrazine, semicarbazide and carbazide. Write the mechanism for this reaction. (Note: The acid conditions.)

Formation of Imines

The formation of an imine involves an initial nucleophilic attack by ammonia or a primary amine on the carbonyl carbon. Followed by subsequent loss of a water molecule.

The C=O becomes a C=N-R group where R= H, alkyl or aryl

C OH3C

Ph

H+

C OH3C

Ph

H H2N R

R N C

CH3

OH

Ph

H

H

H2OR N C

CH3

OH

PhH

+ H3O+

H+

R N C

CH3

PhH

R N C

CH3

OH

PhH

R N C

CH3

O

PhH

H

HR N C

CH3

PhH

H2OR N C

CH3

Ph


The aromatic ring of aniline derivatives are highly activated for electrophilic aromatic substitution reactions. As shown above the sigma complex is stabilized at the ortho and para positions by the non-bonding electron on the nitrogen. Is the ring activated in the presents of an acid?


What function does the sodium bicarbonate serve in the above reaction?

Give two reasons why anilines can not be nitrated directly using HNO3/H2SO4?

NH2

NO2

NH2

NO2

Cl

Clxs Cl2

NaHCO3

+ 2 HCl

Reactions of Pyridine

The pyridine ring is deactivated towards electrophilic aromatic substitution because of the electronegative nitrogen in the ring.Additionally the non-bonding electron on the nitrogen would react with the electrophile. Reaction only occurs under extreme conditions. Note: That substitution is in the 3-position.

Reactions of Pyridine

The pyridine ring is activated towards nucleophilic aromatic substitution. With substitution occurring at either the 2- or 4- position. The sigma complex is stabilized by the negative charge being on nitrogen.

Alkylation of Amines

Amines are good nucleophiles that react with alkyl halides via a Sn2 mechanism.

Reaction with primary halides give alkylated ammonium halides.

Secondary halides are less reactive than primary halides andoften give poor yields or elimination products.

Tertiary halides do not react because of steric hindrance. Note: The that °3 halides can still under go elimination.


The above reaction gives an incomplete picture of the chemistry involved in the alkylation of an amine with an alkyl halide.


The reaction of one mole of primary amine with one mole of alkyl halide will give a mixture of starting primary amine, secondary amine, tertiary amine and quaternary ammonium salts.

There two methods that can be used to avoid obtaining mixtures of products when alkylating amines with alkyl halides.


Exhaustive alkylation (methylation) involves reacting the amine with an excess of alkyl halide in the presence of an acid scavenger.

(> 90%)

R N (CH3)3 Cl -NaHCO3

3 CH3 Cl+R NH2


The use of a large excess of ammonia results in monoalkylation. The excess ammonia is simply allowed to boil of at the end of the reaction. This synthetic approach is useful in many situations but is often limited by the cost of the alkyl halide.

CH2 XR'NH3 + CH2 N+H3R' X -

10 moles 1 mole

Acylation of Amines

Amides are produced by the treatment of primary and secondary amines with acid halides in the presents of a non-nucleophilic acid scavenger.

The reaction involves the nucleophilic attack of the amine on the carbonyl carbon (the electrophilic center) of the acid halide followed by loss HX.

Amides are far less basic and nucleophilic than amines. As a result mono-acylation product is normally produced.

Why is the amide less basic and nucleophilic than the amine?

Acylation of Amines

+ R NH2R' C

O

Cl R'

O -

NH2

Cl

R

R' C

O

NHR

H

+ Cl - R' C

O

NHRBase

+ H Base + Cl -

Cl -+R' C

O

NHR

H

R'

O

NH2

Cl

R

The base is typically pyridine, a tertiary amine or bicarbonate.The yields are generally very good ( > 90 %).

Acylation of Amines

The acyl group in an amide can be easily removed by hydrolysis with aqueous acid. As a result acylation can be used as a means of temporary protecting the amine group as the amide while conducting other reactions that would produce undesired change in the amine. The acyl group acts as a Masking agent.

Many reactions can not be done directly on the aromatic ring of aniline either because the amine will react with the reagents or multiple substitution occur.

Acylation of Amines

The Friedel-Crafts acylation of the ring fails in the above reaction. However, if the amine of the aniline is acylation first then the ring can be acylated.

NH2

Cl

O

+ CH3CCl

O NHCCH3

O

AlCl3

NHCCH3

O

O

Base

aluminum complexs+N

O

H

+

AlCl3Cl

O

NH2

Acylation of Amines

Why do we need to do a final pH adjustment?

NHCCH3

O

O

NH2

O

H+ / heat

pH adjust

Sulfonylation of Amines

The reaction of amines with sulfonyl chlorides is analogous to that of acyl halides.

R' S

O

O

NHRR' S

O

Cl

O

R NH2+

NaOH

The sulfa drugs are antibacterial agents that contain the sulfonamide group.

Elimination Reactions involving Amines

Amines can under go two different types of elimination reactions that give alkenes.

Hofmann elimination: An amine is exhaustively methylated to the quaternary ammonium salt. The halide salt is converted to the hydroxide salt by treatment with silver oxide. The quaternary ammonium hydroxide is then thermally decomposed via a conserted E2 mechanism to give the alkene.

Cope Elimination: A tertiary amine is converted to the amine oxide by treatment with hydrogen peroxide or a peroxyacid. The amine oxide is then thermally decomposed to give an alkene.

Both reactions generally give the least-substituted alkene.

Elimination Reactions involving Amines

Hofmann elimination:

R NH2 + CH3 I3acid scavenger

R N(CH3)3 I - + 2 HI

trimethyl amine a good leaving group

I -R N(CH3)3 + 1/2 Ag2O OH -R N(CH3)3

For R = 2-butyl the product is 95 % 1-butene, the least substituted alkene. Onle 5% of the product is the Saytzeff product.

OH -CH3CH2CH N(CH3)3

CH3

CH3CH2CH CH2 + H2O + N(CH3)3

heat


Requirements an anti coplanar stereochemistry.


Predict the products of the following reactions.

N

CH3

CH3

CH3

1) CH3I

2) Ag2O

3) heat

NH2

3) heat

2) Ag2O

1) CH3I

NHCH2CH3

1) CH3I

2) Ag2O

3) heat

Cope elimination:

The oxidation of amines can lead to a number of different products depending on the type of starting amine.

Oxidation of °1 amines results in the formation of hydroxyl amines which are oxidized to nitroso cpds which are then oxidized to nitro cpds.

°2 amines are oxidized to hydroxyl amines.

°3 amines are oxidized to amine oxides. The Cope elimination involves the thermal decomposition of these amine oxides.

Cope elimination:

The oxidation of the °3 amine is easily done using either 30% or 50% hydrogen peroxide. The reaction is very exothermic and the addition of the peroxide must be carefully regulated to avoid over heating the reaction.

R N

R

R

+ H2O2 R N

R

R

O

°3 amine oxide°3 amine

+ H2O

Cope elimination:

Heating the amine oxide results in the elimination of a dialkyl hydroxylamine. The reaction occurs via a concerted E2 mechanism that requires syn stereochemistry to occur. The reaction occurs under milder conditions than the Hofmann elimination.

HO N(CH3)2+CH3CH2CH CH2

heatCH3CH2CH N

CH3

CH3

O

CH3

Cope elimination:

Predict the products of the following reactions.

N

1) H2O2

2) heat

N

1) H2O2

2) heat

1) H2O2

2) heat

(CH3)2N

Reactions with Nitrous Acid

Treatment of primary aromatic amines with sodium nitrite under acidic conditions arenediazonium salt. This process is called diazotization of an amine. Once the diazonium salt is made the diazonium group can be replace by many different groups.

NH2 NaNO2

HCl

N2 Cl -

What about diazonium salts made from alkylamines?


R N N OH R N N O

H

H

H3O +

R N N + H2O

diazonium ion


Reactions of diazonium salts.

Synthesis via diazonium salts

Devise a synthetic pathway for the following reactions.

NO2 CN

O

H2N

O

HO

N2

NO2

O2N N N OH

Cl -

Synthesis of Amines via reduction

Reductive amination is a two step process that adds an alkyl group to ammonia, a primary or secondary amine.

1. The first step is the formation of the imine or oxime

derivative of an aldehyde or ketone.

2. The imine/oxime is then reduced to give the amine.

The reaction is done on an industrial scale using H2

over a Ni catalyst. Laboratory scale process generally rely on hydride reducing agents such

as LAH.


Primary amines via reductive amination:

R R'

O

R=R'= alkyl, aryl and hydrogenR=R'

H2NOH

R R'

NOH

H+

reduction

R R'

NH2

The hydrogenation can be done with 15-60 psig of H2 at 140-60°C over 0.2% supported Ni catalyst.


Secondary amines via reductive amination:

N-substituted imine

a primary amine

R" NH2

R R'

NR"H

reduction

H+ R R'

NR"


R R'

O


Tertiary amines via reductive amination:

Since many iminium salts are unstable they are generally not isolate. As a result the reducing agent is added to the reaction mixture so that the iminium salt can be reduced as it is formed. Only very weak reducing agents can be used in this reaction to avoid reduction of the starting aldehyde or ketone. Sodium triacetoxyborohydride and sodium cyanoborohydride will reduce the iminium salt without reducing the carbonyl compound.Industrially, the reaction is done using hydrogen and a Ni catalyst.

R R'

O


R R'

NR"R"

H+

reduction

R R'

NR"R"

R" NH

R"

a secondary amine

iminium salt


Propose a synthetic route for the following.

NH N

C18H37NH2 C18H37N(CH3)2

C18H37NH2 C18H37NCH2CH(CH2CH3)CH2CH2CH2CH3

H

NH2O

NH2Br

Ncpd with no more than 5 carbons

Synthesis of Amines via acylation reduction

Amines are mono acylated by treatment with with an acid chloride. Since the resulting amide is a poor nucleophile multiply acylations are not likely. The amide is then converted to the amine by treatment with LAH. The type of amine produced depends on the type of starting amine used.

Starting amine product Ammonia 1° amines 1° amines 2° amines 2° amines 3° amines

Synthesis of Amines via acylation reduction

NH CH2CH2CH2CH3

from aniline

Synthesis of of primary Amines

Direct alkylation:

Primary amines can be prepared from alkyl halide by using a large excess of ammonia to avoid / minimize multiply alkylations on nitrogen.

Gabriel synthesis:

This synthetic method allows for the selective preparation of primary amines with out the use of a large excess of amine. The synthesis involved the alkylation of the phthalimide anion, which is simply a protected ammonia that can only be alkylated once.

Synthesis of primary Amines (Gabriel Synthesis)

R CH2 X R CH2 NH2

excess NH3

X= Cl, Br and I

Synthesis from azides and nitriles

The azide and nitrile groups can be reduced to primary amines using either LAH or catalytic hydrogenation.

The azide ion N3- and cyanide ion CN- are both

very good nucleophiles that will react readily with primary and secondary halides.


Reaction of an alkyl halide with azide ion produces an alkyl azide. Reduction of the azide gives corresponding the 1° amine. The main drawback to the synthetic method is that alkyl azides are explosive. The net reaction is the replacement of the halide with NH2.


Reaction of an alkyl halide with cyanide ion produces an a nitrile. Nitriles are very stable and are easily handled. Reduction of the nitrile gives a primary amine that is one carbon (CH2) longer then the initial alkyl halide.

CH2BrCN -

CH2C N CH2CH2NH2

1) LAH

2) H2O

Synthesis from nitro compounds

The nitro group can be reduced to the amine by:

1) catalytic hydrogenation2) active metal and H+

NO2

CH3

NH2

CH3

H2

Ni

90%

Hofmann rearrangement

The Hofmann rearrangement allows for the preparation of primary amines that have 1°, 2° and 3° alkyl groups, or aryl amines. The reaction involves the treatment of an amide with a halogen under strongly basic conditions. This results in a rearrangement of the amide to an amine in which the carbonyl of the starting amide has been lost.

C C

O

NH2

CH3

CH3

Cl2 / OH -

C

CH3

CH3

NH2

H2O

Hofmann rearrangement

structure and properties nomenclature reactions (some review) synthesis (some review)

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