Nitrogen-containing compounds

(1)

Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework**

Consortium leader

PETER PAZMANY CATHOLIC UNIVERSITY

Consortium members

SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER

The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund ***

**Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben

***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg.

PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS

UNIVERSITY

(2)

Nitrogen-containing compounds

(Nitrogéntartalmú vegyületek)

Organic and Biochemistry

(Szerves és Biokémia )

semmelweis-egyetem.hu

Compiled by dr. Péter Mátyus

with contribution by dr. Gábor Krajsovszky

(3)

Nitrocompounds

- containing NO₂ group Nomenclature

nitromethane 2-nitropropane nitrobenzene

Structure:

C

H₃ NO₂ CH NO₂ C

H₃

C H₃

NO₂

N O O

N O

O

N O

δ⁺ O

δ⁻ N

O O

(5)

Preparation:

1. Aliphatic nitrocompounds

Nitration of hydrocarbons (R-H) → cracking of the chain 2. Aromatic nitrocompounds

NO₂ H₂SO₄

HNO R I

+

^NO²

R NO₂

R ONO

nitroalkane

alkyl nitrite

S_N2

S_N1

(6)

Their properties 1. Physical: high boiling point; good solvents 2. Chemical:

Reduction Acidity

H₃C NO₂ base

H2C N

O

pK_a=about 10

HO

nitrocompound R CH N

O O H

R CH N O O

R CH N OH O

-H +H

aci form

(nitronic acid)

(7)

generally toxic, some drugs Biological porperties

NH OH

OH O₂N

O

Cl Cl

Chloramphenicol

O₂N N

N

CH₃ OH

Metronidazol

N H

NO₂ O O

O O

CH₃ C

H₃ C

H₃ CH₃

O₂N N

N

H O

Nitrazepam

(8)

Amines

Classification:

1. According to their order (it is different from that of alcohols!!)

R NH₂

R¹

NH R²

R

¹

N R

²

R

³ ^R¹ ^N ^R⁴

R²

R³

primary secondary tertiary quaternary

(according to the number of alkyl or aryl groups connected to nitrogen atom)

(9)

2. According to the type of the hydrocarbon group

aliphatic, methylamine

enamine

alicyclic, cyclohexylamine

aromatic, aniline

aralkyl, benzylamine

C

H₃ NH₂

C

H₂ NH₂

NH₂

NH₂ CH CH

R N

R¹

R²

(10)

3. According to the number of the amino groups

NH₂

H₂N H₂N

N R

NH₂

ethylenediamine polyamine

Geometry: it is of trigonal pyra-

midal structure, the bond angle is ~ 108°

Configurational inversion:

(Ligands connected to the central atom rearrange in a way that

their bonds to the central atom are not cleaved). Low energy (5-7 kcal/mol) is needed for the inversion of the neutral, sp³ N, but it might be considerably higher in aziridines and in

a X

b c X

a

b c

X c a

b

sp³ sp² sp³

aziridine

(11)

For comparison:

R S R¹ O

R S R¹ R²

X RO S OR¹

O

R P R¹ R²

Sulfoxide Sulfonium salts Sulfites Phosphines

These are also of trigonal bipyramidal structures, their inversions are much slower.

Mechanism:

X

a c

b

X c

a

b

X a c

b

3

(12)

Ammonium salts and amine oxides

If substituents are different: chiral

Amine oxides: c.p., with ylides: P, S, N, connected to carbon

This is the structure (there is no d orbital)

R1 N R2

R4

R3 X

tetrahedral

R1 N R2

R3 O

tetrahedral

R₃P CR₂' R₃P CR₂'

phosphorus ylide

R₃N CR₂'

nitrogen ylide

R₂S CR₂' R₃S CR₂'

(13)

Nomenclature

Primary amines

Name for the functional group: -amine (e.g., ethylamin) According to the substitutive nomenclature (alkaneamine) Suffix as a principal group: amine; e.g., ethaneamine

Prefix for the substituent: amino-; e.g., 2-aminoethanol Secondary and tertiary amines

According to the radicofunctional nomenclature (di- and trialkylamines) e.g., diethylamine, triethylamine (usually symmetric amines)

According to the substitutive nomenclature (N-alkyl alkaneamine) amines as a principal group, substituted on the nitrogen (N), e.g., N,N-

dimethylpentaneamine

(14)

Nomenclature

Quaternary ammonium compounds

Salts or hydroxydes of type R₄N X might be named as substituted ammonium compounds, e.g., tetramethylam-monium bromide

(15)

Examples:

(CH₃CH₂)₂NHCH₂CH₂CH(CH₃)₂ isopentyl diethylamine

Subst.: N,N-diethyl 3-methylbutanamine

IUPAC: ethylazane

IUPAC: (diethyl)(3-methylbutyl)azane di-tert-butylazane

CH₃ CH₃

OH

HO CH₂CH₂CH₂ NH₃ Cl

(ethyl-trimethylammonium) hydroxide

(3-hydroxypropyl)ammonium chloride Subst.:

(17)

Trivial (Common) names:

aniline

toluidine

methylaniline (o, m, p)

phenylenediamine (o, m, p)

N,N-dimethylaniline

NH₂ CH₃

NH₂

N

CH₃ C

H₃

(18)

Preparations

By alkylation of amines

product is a mixture of different amines

(19)

~ 20 mol (in alcohol) Other, more selective alkylations:

Cl

+

^NH³

Cu₂O, H₂O 200-300 °C high pressure

NH₂ C

H₃ (CH₂)₃ Br

+

^NH³ ^NaOH ^H³^C ^(CH²⁾³ ^NH²

~ 10 mol 47 %

(20)

Preparations of primary amines:

by Gabriel’s synthesis

not concerted!

N O

O

H KOH

-H₂O

N^- O

O

K⁺ R X - KX

N O

O

R

N

H₂ NH₂ NH

NH O

O

+

^RNH²

(21)

Preparation of secondary amines:

S O O

N H R¹

KOH -H₂O

S O O

N R¹

K⁺

- KX R² X

S O O

N R²

R¹ H₃O⁺ or

-OH/H₂O

S O O

OH

+

^H^N

R² R¹

(22)

Reduction of nitrogen compounds with higher oxidation state.

Amines are the nitrogen compounds with the lowest oxidation state.

(23)

Reduction of nitriles and acid amides

e.g.,

(24)

Béchamp’s reduction

The electrons come from the iron, while protons come from water

Fe + 2 HCl - 2 H

FeCl₂ + H₂O

Fe(OH)₂ + 2 HCl

NO₂

+

NH₂

3 Fe

+

^{6 HCl}

+

^{3 FeCl}²

+

^{2 H}²^O

(25)

Other reducing agents: SnCl₂ + H₂O (HCl)

(NH₄)₂S: regioselective

NO₂

NH₂

NO₂ (NH₄)₂S_x

(26)

H₂N OH

N R1

OH H₂/kat

R1

H₂O

-

-H₂O

NH₃ H₂/kat.

primary amine

R³ NH₂

oxime imine

NaBH₄ R²

C

2

C N

CH NH₂ R¹

R²

C O R¹

R²

C NH R¹

R²

CH NH R³ R¹

(27)

Preparations of divalent amines

NO₂

NH₂

NO₂

NH₂

NH₂ HNO₃

H₂SO₄

Béchamp reduction

(CH₃CO)₂O pyridine

NHCOCH₃

acetic acid 0^-5 °C

HNO₃ H₂SO₄

NHCOCH₃ NO₂

NHCOCH₃ H₃O⁺

H₃O⁺

NH₂

NO₂

NH₂

reduction

NH₂

(28)

Physical properties

Structural parameters (see at the structure) Hydrogen bridges

b.p. [°C] b.p. [°C] b.p. [°C]

N H N

the hydrogen bridge in amines is weaker, than the hydrogen bridge in alcohols

(29)

Chemical properties of amines

Basicity

Characterization by pK_a, or by pK_b

Any effects, that increase electron density at the nitrogen, also increase basicity.

In vapor phase: R₃N > R₂NH > RNH₂ > NH₃

In water: R₂NH > RNH₂ > R₃N > NH₃ >> PhNH₂

B: + H

₂

O BH + OH

solvated ions The less H-s are attached to the nitrogen,

(30)

Basicity - acidic strength pK_b - pK_a

For any conjugate acid / base pair, in water,

(31)

N

H H

Interaction of N with the ring

It is more difficult to protonate it, and protonation decreases size of the delocalised system.

(32)

pK_b 3.2 3.4 4.2 4.7

pK_b 9.4 14.2 13.0 9.5 8.7

NH₂ NH₂

NO₂

NH₂

NO₂

NH₂

OCH₃

NH₂

OCH₃ NH CH₃

C

H₃ H₃C NH₂ H₃C N CH₃

CH₃

NH₃

(33)

R

NH R

R NH₂ R N

R

NH₃ >> NH₂

> > >

9,24 4,60

pK_a (vizes oldatban) ammóniumion

amin

NH₃

10,78 (CH₃)₂NH

(CH₃)₃N 9,80

10,63 PhNH₂

CH₃NH₂ CH₃NH₃ PhNH₃

NH₄ (CH₃)₂NH₂

(CH₃)₃NH

amine ammonium ion pK_a (in aqueous solution)

(34)

pK_a:

NH₂

NO₂ 1,11

NH₂

OCH₃ 5,30 NH₂

OCH₃

4,51 NH₂

NO₂

- 0,26

enamin

H₂C CH NH₂ H₂C CH NH₂

enamine

(35)

Reactions at the amine nitrogen

R¹, R², R³ might be either H or alkyl group formation of salt:

ammonium salt alkylation:

(36)

from oxocompounds:

(37)

Protecting groups for amines

-Amino group

R¹ N R² R³

a.) it might be protonated

b.) it might react with electrophiles Protection: it decreases reactivity of the lone electron pair

by acyl group amides

by alkoxycarbonyl group carbamate

(38)

Acylation:

(39)

Mannich reaction

C-H acids:

(40)

Preparation of isonitrile from primary amines

(41)

Reaction with nitrous acid:

(42)

Reactions of aromatic amines

Reaction with halogenes

NH₂

X₂ diluted acid

NH₂

X X

X (CH₃CO)₂O

NH O

CH₃

Br₂

NH O

CH₃

NH₂

I₂ NaHCO₃

NH₂

I

(43)

Reactions of aromatic amines

Nitration

NH₂

NH O

CH₃

(CH₃CO)₂O

HNO₃ H₂SO₄

NH O

CH₃ NO₂

NH O

CH₃

NO₂

+

H₂SO₄

NH₃

HNO₃ H₂SO₄

NH₃

NO₂

Na₂CO₃

NH₂

NO₂ o- and p-nitroanilines could be prepared by their hydrolysis

(44)

Reactions of aromatic amines

Nitrosation

Sulfonation

NHAc

2 ClSO₃H

NHAc

SO₂Cl N-acetylsulfa-

NH₄OH or (NH₄)₂CO₃

heating

NHAc

SO₂NH₂ N-acetylsulfa-

(45)

Most important amines

These could be prepared by

alkylation of ammonia, using the following industrial alkylating agents: CH₃OH or CH₃CH₂OH

hexamethylene diamine: plastic industry Most important quaternary ammonium compounds:

- have ganglion blocking and muscle relaxant effect - phase transfer catalysts

(46)

Amino compounds

Aromatic amines

For syntheses of intermediates, drugs or dyes:

aniline acetanilide o-toluidine p-phenylene- diamine

(47)

procaine (Novocain^®)

procainamide (Novocamid^®)

lidocaine (Xylocaine^®)

(48)

1-phenylethylamine for resolution of

racemic acids

amphetamine (central stimulator)

(49)

NH

COO^-

-OOC N COO^-

O O

CH₃

-OOC N COO^-

5 K⁺

INDO-1

binding

fluorescence

(50)

Aromatic diazonium compounds

Structure:

Nomenclature:

Diazonium group is a principal group

its stability is much higher, than that of an aliphatic diazo-

nium compound

benzenediazonium chloride

(51)

Preparation: diazotization

Mechanism:

Ar NH₂ + NaNO₂ + 2 HCl H₂O

0 - 5 ^oC Ar N N Cl + NaCl + H₂O 2,5 equivalent of acid is necessary to avoid coupling

(52)

Reactions of diazonium group

Sandmeyer reaction Catalyst: Cu(I) salt

Ar N N

Ar N N BF₄ Cl

HBF₄ KSCN

Cu₂(SCN)₂

Ar SCN

Ar F + N₂ + BF₃

Ar Cl + N₂ HCl Cu₂Cl₂

HBr Cu₂Br₂

Ar Br + N

KI

Ar I + N₂ NaCN Cu₂(CN)₂

Ar C N + N₂

+ N₂

(53)

Reactions of diazonium group

Introduction of other groups:

Ar N N Cl

KNCO Cu

Ar N C O Ar OH + N₂

Ar H + N₂ H₃PO₂

Ar SH + N₂

Ar NO₂ + N₂

+ N₂ H₂O

H₂SO₄ CuSO₄

1. KSH 2. H₃O

NaNO₂ CuO

(54)

Azocoupling

G = -N R

2 or -O H

Possible side reaction:

slightly acidic medium

slightly basic medium

diazotate ion

N N X + G N N G X

H

- HX

N N G

azocompound

diazonium hydroxide diazonium ion

Ar N N Ar N N OH Ar N N O

+OH

+H

+OH

+H

(55)

(56)

Azodyes

Condition of color:

Easy excitement of the π electron system, resulting in selective absorption. We see the material in the complementary color.

Relationship between the color of compounds and the selective absorption:

Absorbed light

wavelength [nm] Absorbed color Color of compound

400 425 450 490 510 530 550 590 640

violet indigo blue

blue bluish green

green yellowish green

yellow orange

red

yellowish green yellow orange

red purple

violet indigo blue

blue bluish green

(57)

Metilorange

sárga (lúgban) pH > 4,0 λ_max = 454 nm

N

S N

O O

O

N CH₃ CH₃

S N N

O

O N

CH₃ CH₃

N

S N

O O

O

N CH₃

CH₃ H

- H + H

piros (savban) pH < 3,1 λ_max = 504 nm

S N N

O

O N

CH₃ CH₃ H

yellow (in basics) pH > 4.0 λ_max = 454 nm

red (in acids) pH < 3.1 λ_max = 504 nm

(58)

Other important nitrogen containing compounds Diazomethane: it has resonance structures:

Its preparation:

Nitrogen-containing compounds

Nitrogen-containing compounds

Organic and Biochemistry

Compiled by dr. Péter Mátyus

with contribution by dr. Gábor Krajsovszky

Table of Contents

Nitrocompounds

Preparation:

+

Amines

R

N R

R

Ammonium salts and amine oxides

Nomenclature

Nomenclature

Examples:

H

C CH

NH

(H

C)

C NH C(CH

)

H

N CH

CH

CH

OH

Preparations

+

+

+

+

+

+

+

+

Preparations of divalent amines

Physical properties

b.p. [°C] b.p. [°C] b.p. [°C]

CH

-161 CH

CH

CH

CH

-1

NH

-33 CH

CH

CH

NH

+49 (CH

)

N +3 H

O +100 CH

CH

CH

OH +97 CH

CH

OCH

+8

N H N

Chemical properties of amines

B: + H

O BH + OH

N

H H

Reactions at the amine nitrogen

Protecting groups for amines

Mannich reaction

Preparation of isonitrile from primary amines

Reaction with nitrous acid:

Reactions of aromatic amines

Reactions of aromatic amines

Reactions of aromatic amines

Most important amines

Amino compounds

INDO-1

Aromatic diazonium compounds