PETER PAZMANY CATHOLIC UNIVERSITY · The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund * Molekuláris bionika

2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 1

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

Consortium leader

PETER PAZMANY CATHOLIC UNIVERSITYConsortium 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 UNIVERSITYSEMMELWEIS

UNIVERSITY

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Nitrogen-containing compounds(Nitrogéntartalmú vegyületek)

Organic and Biochemistry(Szerves és Biokémia )

semmelweis-egyetem.hu

Compiled by dr. Péter Mátyuswith contribution by dr. Gábor Krajsovszky

Formatted by dr. Balázs Balogh

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Table of Contentssemmelweis-egyetem.hu

Organic and Biochemistry: Nitrogen-containing compounds

1. Nitrocompounds 4 – 72. Amines 8 – 11

3. Ammonium salts and amine oxides 12 – 124. Nomenclature 13 – 175. Preparation 18 – 27

6. Physical properties 28 – 28

7. Chemical properties 29 – 44

8. Most important amines 45 – 49

9. Aromatic diazonium compounds 50 – 55

10. Azodyes 56 – 58

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Nitrocompounds

- containing NO2 group

Nomenclature

nitromethane 2-nitropropane nitrobenzene

Structure:



CH3 NO2 CH NO2

CH3

CH3

NO2

N

O

O

N

O

O

N

O

Oδ+

δ− N

O

O

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Preparation:

1. Aliphatic nitrocompounds

Nitration of hydrocarbons (R-H) → cracking of the chain

2. Aromatic nitrocompounds



NO2H2SO4

HNO3

R I + NO2

R NO2

R ONO

nitroalkane

alkyl nitrite

SN2

SN1

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Their properties

1. Physical: high boiling point; good solvents2. Chemical:

Reduction

Acidity



H3C NO2base H2C N

O

O

pKa=about 10

HO

nitrocompound

R CH NO

O

R CH NO

O

HR CH N

O

OR CH N

OH

O

-H +H

aci form(nitronic acid)

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generally toxic, some drugs

Biological porpertiessemmelweis-egyetem.hu


NH

OH

OHO2NO

Cl

Cl

Chloramphenicol

NO2N

N

CH3

OH

Metronidazol

NH

NO2

OO

OO

CH3CH3

CH3 CH3

Nifedipine

NO2N

NH O

Nitrazepam

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Amines

Classification:

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

R NH2

R1

NHR2

R1

NR2

R3 R1 N R4

R2

R3primary secondary tertiary quaternary

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



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2. According to the type of the hydrocarbon group

aliphatic, methylamine

enamine

alicyclic,cyclohexylamine

aromatic,aniline

aralkyl,benzylamine



CH3 NH2

CH2 NH2

NH2

NH2CH CHR N

R1

R2

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3. According to the number of the amino groupsNH2H2N H2N

NR

NH2

ethylenediamine polyamine

Geometry: it is of trigonal pyra-midal structure, thebond angle is ~ 108°

Configurationalinversion:

(Ligands connected to the central atom rearrange in a way thattheir bonds to the central atom are not cleaved). Low energy (5-7 kcal/mol) is needed for theinversion of the neutral, sp3 N, but it might be considerably higher in aziridines and incompounds with N connected to other atoms with lone electron pair.

Xa

b c X

ab cX c

a

b

sp3 sp2 sp3

aziridine



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For comparison:

R S R1

O

R S R1

R2

X RO S OR1

O

R P R1

R2Sulfoxide Sulfonium salts Sulfites Phosphines

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

Mechanism:

Xa c

b

X ca

b

Xc

ab

sp3 sp2 sp3



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Ammonium salts and amine oxides

If substituents aredifferent: 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

R4R3 X

tetrahedral

R1 N

R2

R3O

tetrahedral

R3P CR2' R3P CR2'phosphorus ylide

R3N CR2'nitrogen ylide

sulfur ylideR2S CR2'R3S CR2'

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NomenclaturePrimary amines

Name for the functional group: -amine (e.g., ethylamin)

According to the substitutive nomenclature (alkaneamine)Suffix as a principal group: amine; e.g., ethaneaminePrefix 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



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Nomenclaturesemmelweis-egyetem.hu


Quaternary ammonium compounds

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

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Examples:

H3C CH2 NH2

(H3C)3C NH C(CH3)3

H2N (CH2)5 NH2

ethylamine

di-tert-butylamine

pentamethylene-diamine

Subst.: ethanamine pentan-1,5-diamine

(CH3CH2)2NHCH2CH2CH(CH3)2

isopentyl diethylamine

Subst.: N,N-diethyl 3-methylbutanamine

IUPAC: ethylazane

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



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H2N CH2CH2CH2 OH

3-aminopropan-1-ol

H5C2 N

CH3

CH3

CH3

OH

HO CH2CH2CH2 NH3 Cl

(ethyl-trimethylammonium) hydroxide

(3-hydroxypropyl)ammonium chloride

Subst.:



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Trivial (Common) names:

anilinetoluidine

methylaniline (o, m, p)

phenylenediamine(o, m, p)

N,N-dimethylaniline



NH2 CH3

NH2

NH2

NH2

NCH3CH3

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Preparations

By alkylation of amines

product is a mixture of different amines



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~ 20 mol(in alcohol)

Other, more selective alkylations:



Cl

+ NH3

Cu2O, H2O

200-300 °Chigh pressure

NH2

CH3 (CH2)3 Br + NH3

NaOHCH3 (CH2)3 NH2

~ 10 mol 47 %

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Preparations of primary amines:

by Gabriel’s synthesis

not concerted!



N

O

O

HKOH

-H2ON

-

O

O

K+ R X

- KX

N

O

O

RNH2 NH2 NH

NH

O

O

+ RNH2

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Preparation of secondary amines:



S

O

O

N

H

R1

KOH

-H2OS

O

O

N

R1

K+

- KX

R2

X

S

O

O

N

R2

R1 H3O

+

or

-OH/H2OS

O

O

OH + NH

R2

R1

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Reduction of nitrogen compounds with higher oxidation state.Amines are the nitrogen compounds with the lowest oxidation state.



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Reduction of nitriles and acid amides

e.g.,



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Béchamp’s reduction

The electrons come from the iron, while protons come from water(it is enough to use 1/20 mol of hydrochloric acid).

Fe + 2 HCl - 2 H FeCl2+ H2O

Fe(OH)2 + 2 HCl



NO2

+

NH2

3 Fe + 6 HCl + 3 FeCl2 + 2 H2O

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Other reducing agents: SnCl2 + H2O (HCl)

(NH4)2S: regioselective



NO2

NO2

NH2

NO2

(NH4)2Sx

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H2N OHN

1ROH H2/kat

1R

H2O-

-H2ONH3 H2/kat.

primary amine

R NH23

H2O-

oxime

imine

NaBH4

R2C

R2C N

R3

CH NH2

R1

R2

C OR1

R2

C NHR1

R2

CH NH R3R1

R2secundary amineSchiff’s base



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Preparations of divalent aminessemmelweis-egyetem.hu


NO2

NH2

NO2

NO2

NH2

NH2

HNO3

H2SO4

Béchampreduction

Béchampreduction

(CH3CO)2O

pyridine

NHCOCH3

aceticacid

0-5 °C

HNO3

H2SO4

NHCOCH3

NO2

NHCOCH3

NO2

H3O+

H3O+

NH2

NO2

NH2

NO2

reduction

reduction

NH2

NH2

NH2

NH2

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Physical propertiesStructural parameters (see at the structure)

Hydrogen bridges

b.p. [°C] b.p. [°C] b.p. [°C]CH4 -161 CH3CH2CH2CH3 -1

NH3 -33 CH3CH2CH2NH2 +49 (CH3)3N +3

H2O +100 CH3CH2CH2OH +97 CH3CH2OCH3 +8

O H O

N H N the hydrogen bridge in amines is weaker, than the hydrogen bridge inalcohols



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Chemical properties of amines

Basicity

Characterization by pKa, or by pKbAny 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: + H2O BH + OHsolvated ions

The less H-s are attached to the nitrogen, the poorer the solvation is.



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Basicity - acidic strength

pKb - pKa

For any conjugate acid / base pair, in water, at temperature of 298oK: pKa + pKb = 14



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NH

H

Interaction of N with the ring

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



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pKb 3.43.2 4.2 4.7

pKb 9.4 14.2 13.0 9.5 8.7



NH2 NH2

NO2

NH2

NO2

NH2

OCH3

NH2

OCH3

NH CH3CH3 NH2CH3 N CH3CH3

CH3

NH3

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RNH

RR NH2 R N

R

R

NH3 NH2 >>> > >

9,24

4,60

pKa (vizes oldatban) ammóniumionamin

NH3

10,78(CH3)2NH

9,80 (CH3)3N

10,63

PhNH2

CH3NH2 CH3NH3

PhNH3

NH4

(CH3)2NH2

(CH3)3NH



amine ammonium ion pKa (in aqueous solution)

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pKa:

NH2

NO2

1,11

NH2

OCH3

5,30

NH2

OCH3

4,51

NH2

NO2

- 0,26

enamin

H2C CH NH2 H2C CH NH2



enamine

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Reactions at the amine nitrogenR1, R2, R3 might be either H or alkyl group

formation of salt:

ammonium salt

alkylation:

see at the reactions of halogene compounds



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from oxocompounds:



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Protecting groups for amines

-Amino groupR1 N

R2

R3

a.) it might be protonatedb.) it might react with electrophiles

Protection: it decreases reactivity of the lone electron pairby acyl group amidesby alkoxycarbonyl group carbamate



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Acylation:semmelweis-egyetem.hu


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Mannich reaction

C-H acids:



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Preparation of isonitrile from primary aminessemmelweis-egyetem.hu


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Reaction with nitrous acid:semmelweis-egyetem.hu


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Reactions of aromatic amines

Reaction with halogenesNH2 X2

diluted acid

NH2

X X

X(CH3CO)2O

NH

O

CH3

Br2

NH

O

CH3

Br

NH2 I2NaHCO3

NH2

I



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Nitration

NH2

NH

O

CH3

(CH3CO)2O

HNO3H2SO4

NH

O

CH3

NO2

NH

O

CH3

NO2

+

H2SO4

NH3

HNO3H2SO4

NH3

NO2

Na2CO3

NH2

NO2

o- and p-nitroanilines could beprepared by their hydrolysis

m-nitroaniline



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Nitrosation

Sulfonation



NHAc

2 ClSO3H

NHAc

SO2ClN-acetylsulfa-nyl chloride

NH4OH or(NH4)2CO3heating

NHAc

SO2NH2N-acetylsulfa-nylamide

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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



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Amino compoundsAromatic aminesFor syntheses of intermediates, drugs or dyes:

aniline acetanilide o-toluidine p-phenylene-diamine

phenacetine paracetamol



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procaine (Novocain®)

procainamide (Novocamid®)

lidocaine (Xylocaine®)



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1-phenylethylaminefor resolution of

racemic acids

amphetamine(central stimulator)



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NH

COO-

N-OOC COO-

O O

CH3

N-OOC COO-

5 K+

INDO-1

binding

fluorescence



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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



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Preparation: diazotization

Mechanism:

Ar NH2 + NaNO2 + 2 HClH2O

0 - 5 oC Ar N N Cl + NaCl + H2O

2,5 equivalent of acid is necessary to avoid coupling



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Reactions of diazonium groupSandmeyer reactionCatalyst: Cu(I) salt



Ar N NAr N N ClBF4

HBF4 KSCN

Cu2(SCN)2

Ar SCN

Ar F + N2 + BF3

Ar Cl + N2

HClCu2Cl2

HBrCu2Br2

Ar Br + N2

KI

Ar I + N2

NaCN Cu2(CN)2

Ar C N + N2

+ N2

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Reactions of diazonium group

Introduction of other groups:



Ar N N ClKNCO

CuAr N C OAr OH + N2

Ar H + N2

H3PO2

Ar SH + N2

Ar NO2 + N2

+ N2

H2OH2SO4

CuSO4

1. KSH

2. H3O

NaNO2CuO

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Azocoupling

G = -NR2 or -O H

Possible side reaction:

slightly acidicmedium

slightly basicmedium

diazotate ion

(reacting) (do not take place in the coupling)



N N X + G N N XGH

- HX

N N G

azocompound

diazonium hydroxidediazonium ion

Ar N N N OAr NN OHAr N+OH

+H

+OH

+H

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AzodyesCondition 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 selectiveabsorption:

Absorbed lightwavelength [nm] Absorbed color Color of compound

400425450490510530550590640730

violetindigo blue

bluebluish green

greenyellowish green

yelloworange

redpurple (deep red)

yellowish greenyelloworange

redpurpleviolet

indigo blueblue

bluish greengreen



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Metilorange

sárga (lúgban)pH > 4,0

λmax = 454 nm

NS N

O

O

O

NCH3

CH3

S N N

O

O

O NCH3

CH3

NS N

O

O

O

NCH3

CH3

H

- H+ H

piros (savban)pH < 3,1

λmax = 504 nm

S N N

O

O

O NCH3

CH3

H



yellow (in basics)pH > 4.0

λmax = 454 nm

red (in acids)pH < 3.1

λmax = 504 nm

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Other important nitrogen containing compounds

Diazomethane: it has resonance structures:

Its preparation:



Documents

PETER PAZMANY CATHOLIC UNIVERSITY · The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika

PETER PAZMANY CATHOLIC UNIVERSITY · The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund * Molekuláris bionika