amines grouping and characterization of binding systems

Amines grouping and characterization of binding systems.

Physical properties. Basicity of amines, basicity dependence of the structural factors. The nature of

the amino nucleophile reactions, alkylation, acylation, sulfonamide formation reaction with

nitrous acid. Amine oxidation.

Reactions of aromatic rings of anilines. Amine, aliphatic and aromatic industrial methods.

Grouping of compounds containing C-N bondsExtremely wide range of nitrogen-containing compounds, high biological and practicalsignificance!

1. Amines – only C-N and C-R single bonds2. Nitroso (x=1) and nitro (x=2) compounds typical: C-NOx N=O bonds also!3. Azo compounds typical: C-N=N-C N=N bonds also!4. Diazo compounds typical: C-N2 N=N bond,description only with resonance structures! No Lewis Langmuir structural formula.5. Diazonium salts typical: C-N2

N=N bond,description only with resonance structures! No Lewis Langmuir structural formula.6. Azides typical: C-N3 N=N bond,description only with resonance structures! No Lewis Langmuir structural formula.

1. AminesClassification and nomenclature

Formally: alkylated/arylated derivatives of NH3

Amines are classified according to their degree of substitution at nitrogen. According to the number of the attached hydrocarbon chains:primary (1o) one alkyl/aryl group, R1 = R2 = H secondary (2o) two alkyl/aryl group, R2 = Htertiary (3o) three alkyl/aryl group, no N-H bond

quaternary ammonium salts and ammonium bases (X = OH)

Difference to oxygen analogues - stable compounds

An amine with one carbon attached tonitrogen is a primary amine, an aminewith two is a secondary amine, and anamine with three is a tertiary amine.

Classification of amines 2.According to the joined groups

symmetric and non-symmetric amines- aliphatic amines (only N-alkyl bonds)- aromatic amines (at least one N-aryl/hetaryl bonds)

Except! Amines that has aromatic group in the side chain are NOT aromatic amines(Ar-(CH2)xNR2, n ≥ 1), these are aralkyl amines

- mixed aliphatic-aromatic amines noncyclic and cyclic amines – in latter case N is the part of the ring

According to the number of the attached hydrocarbylgroups – order (differences to alcohols!!)

According to the number of the attached amino groups –(like in case of alcohols)

Nomenclature of amines- Substitutive ~: -amine suffix or amino- prefix (at higher priority substituent) + main chain (+ location, multiplier)- Functional class ~: name of the hydrocarbyl group (alkyl or aryl) + amine suffix

- Common names – Among the aromatic amines, and (naturally occurring) cyclic compounds common names are particularly frequent

Non-symmetric di- and trisubstituted amines: main chain + groups attached to the N

Naming of ammonium salts:

Amines are named in two main ways, in the IUPAC system: either as alkylamines (functionalclass n.) or as alkanamines (substitutive n.). When primary amines are named as alkylamines (functional class n.), the ending – amine is added to the name of the alkyl group that bears the nitrogen. When named as alkanamines (substitutive n.), the alkyl group is named as an alkane and the -e ending replaced by -amine.

Aniline is the parent IUPAC name for amino-substituted derivatives of benzene.Substituted derivatives of aniline are numbered beginning at the carbon that bears theamino group. Substituents are listed in alphabetical order, and the direction of numbering is governed by the usual “first point of difference” rule.

Nomenclature of amines

Compounds with two amino groups are named by adding the suffix -diamine to the name of the corresponding alkane or arene. The final -e of the parent hydrocarbon is retained.

Amino groups rank rather low in seniority when the parent compound is identified for naming purposes. Hydroxyl groups and carbonyl groups outrank amino groups. In these cases, the amino group is named as a substituent.


Secondary and tertiary amines are named as N-substituted derivatives of primary amines. The parent primary amine is taken to be the one with the longest carbon chain. The prefix N- is added as a locant to identify substituents on the amino nitrogen as needed.

A nitrogen that bears four substituents is positively charged and is named as an ammonium ion. The anion that is associated with it is also identified in the name. Ammonium salts that have four alkyl groups bonded to nitrogen are called quaternary ammonium salts.


Bonding systems of aminesThe structure of ammonia – sp3 hybrid state for N (h1

2h21h3

1h41)

Tetrahedral (trigonal pyramidal) structure

H-N-H bond angle is greater than that of water -- larger space requirements of non-bonding electron pair

Amines: heteronuclear C-N (and N-H) σ bonds

Bond anglesIts H-N-H angles (106°) are slightly smaller thanthe tetrahedral value of 109.5°, whereas the C-N-H angle (112°) is slightly larger. Slightly distorted tetrahedron - the groups have dominant space requirements.

Due to the tetrahedral structure chirality is possible but not stable enantiomers (pyramidal inversion)

Bond distances and bond energies

C-N and N-H bonds are weaker compare toC-C and C-H or C-O and O-H bonds

The C-N bond distance of 147 pm lies between typical C-C bond distances in alkanes (153 pm) and C-O bond distances in alcohols (143 pm).

Bonding systems of aromatic amines – aniline Similar to phenols +M effect shorter, stronger bond, bond order: > 1!LCAO-MO theory: 7 centered bond with 8 electronVB-theory: according to the resonance structures the N is electron deficient and the e-density of the C is increased

NH2, NHR and NR2 groups│-I│ < │+M│ I. order, activating substituents

Bond polarityElectron negativity e- density is greater on N than C, nucleophile character. Permanent dipole moment – even for NH3 is ( = 1.46 D, evidence for tetrahedral structure)

Physical properties of aminesH-bonds – for primary and secondary amines,

tertiary amines: dipole-dipole interactions (weaker)

Melting points: homologous series, after a minimum drop continuous rise Mp. < the corresponding alcohol (Mw approx. the same), > corresponding alkyl halide

Physical properties of amines 2.

Boiling points of amines

Gradually increases for the same MW1o> 2o> 3o. Reason: hydrogen bonds, strength: 1o> 2o amines3o amines: only dipole-dipole and van der Waals: weak interactions

Boiling points of alcohols and amines containing the same hydrocarbon group

MeOH: 65 oC, MeNH2: -7 oC!! Reason: EN of N is smaller so it is abetter nonbonding e-pair donor, however weaker H+ acceptor weaker association

SolubilityGood solubility in organic solvent (especially polar, eg. alcohol). Solubility in water: in case of smaller MW unlimited (limit: C5-NH2, C4-NH-C4, Et3N), other are good. Reason: N excellent nonbonding e-pair donor, water is a H-donor!!3o amines solubility in water ~ similar to 1o amines with the same MW

Ammonium salts/ammonium bases: ion pairs, ionic compounds solids, high mp, good solubility in water

Low density (d < 1), strong characteristic smell (low MW: characteristic ammonia smell; milder MW: a distinctive "fishy" smell”; high MW: reduction of volatility weakening odour).

Aromatic amines – generally strong toxicity („ blood poison”, be absorbed through the skin).

bp bp bp MW

Chemical properties of aminesSimilarity to alcohols - resulting from bonding system, BUT!ENN < ENO smaller polarizability, smaller anion stability.

Amines: weaker acid, stronger base better nucleophile (weaklybonded nonbonding e-pair)

1. Acid-base properties1.1. Acidity – Brönsted acidity onlyDeprotonation with strong bases (weak acidity, less than alcohols!!), pKa = 33-36 (alcohols: 15-17)

Electron density of methylamine

(red: high, blue: low)

acidity

• Basicity,• nucleophile character, • activation of the

electrophilic C-N bondor

1.2. Basicity – Brönsted and Lewis basicity

Two conventions are used to measure the basicity of amines. One of them defines a basicity constant Kb for the amine acting as a proton acceptor from water.

Amines are weak bases, but as a class, amines are the strongest bases of all neutral molecules.

Basicity of amines 2.

pKb values of amines

The differences in basicity between ammonia, and primary, secondary, and tertiaryalkylamines result from the interplay between steric and electronic effects on the molecules themselves and on the solvation of their conjugate acids. In total, the effects are small, and most alkylamines are very similar in basicity.

Decisive: stability of the cationElectron donating groups are beneficial NH3 < RNH2 < R2NH < R3N (+I effect)

it is true in gaseous phase!In aqueous/polar solutions: solvation has certain stabilization effectbut it is get decreased by the growing of alkyl substitution (hydrophobic character)

NH3 > RNH2 > R2NH > R3N (solvation)Summary (basicity in aqueous solution): R2NH > RNH2 > R3N > NH3

Structural factors which controll the basicity of amines

Ammonium base – hydroxide ion is responsible for basicity (like alkali hydroxide)

Electrostatic potential map of methyl ammonium cation

(red: high, blue: small)

Lewis-basicity – non-bonding e-pair e-pair donor

Basicity of amines 3.

Basicity of aromatic aminesArylamines are a different story, however; most are about a million times weaker as bases than ammonia and alkylamines.

reason: due to + M effect the electron density of non-bonding electron pair is reducedworse proton and Lewis acid acceptor than alkylamines

Substituens effect: electron-donating group increases, the electron-withdrawing groups decreases the basicity

In general, electron-donating substituents on the aromatic ring increase the basicity of arylamines slightly. Electron-withdrawing groups are base-weakening and exert largereffects.

pKb value of aniline: 9.42

Just as aniline is much less basic than alkylamines because the unshared electron pair ofnitrogen is delocalized into the system of the ring, p-nitroaniline is even less basicbecause the extent of this delocalization is greater and involves the oxygens of the nitrogroup.

2. Alkylation

SN: consecutive alkylation, mixture of products – poor control, small synthetic significance

SN mechanism: alkyl-, allyl-, benzyl-, aralkyl halides

Peptide synthesis: N terminal determination (Sanger’s method)

The nucleophile substitution of simple aryl halides (e.g. bromobenzene) requires harshreaction conditions – low yields, highly polluting technologies.

Chemical properties of amines 3.

Leaving group

SN reaction

Result:

Secondary amine is also a nucleophile

Aryl halides: generally no reaction (due to the reduced reactivity of Ar-Hlg).Exception: aryl halides with electron withdrawing groups – Ad + E mechanism(Meisenheimer-complex)

3. Acylation

Reaction with tertiary amines – no chance for proton loss, no reaction. BUT! A reactive intermediate…


Nucleophile acyl substitution: AdN + E = SN

Base (eg. Py) used for bind the formed HX.Acylating agents:X = Hlg, OCOR or active esters or stronger conditions

If X = OH only salt formation in the first

step!!!

amide

Ammonium salt of carboxylic acid

1o amine → 2o amide2o amine → 3o amide

3o Amines can be used to bind HX during acylation (e.g. alcohols, amines) if acid halides or acid anhydrides used as acylating agents.

Acylium ion

Acilezés klórhangyasav észterekkel

4. Sulphonylation

Practical significance of acylation Reducing the nuclephilicity of amino group- protecting groupindustry - production of polyamide (polycondensation plastic)identification of amines (crystallizing, well-characterized compounds - reduced importance)

Chemical properties of amines 5.Acylation 2.

Acylation with chloroformate esters

ester of chloroformic acid carbamate

Peptide synthesis

Cbz: CarboxybenzylBoc: N-tert-butyloxycarbonylEasier to cleave than amides (use: H+, H2/ cat.) → protecting groups

Hinsberg’s test:It is an excellent test for distinguishing primary, secondary and tertiary amines.

Reagent: excess PhSO2Cl / NaOH-solution

Mechanism similar to that of theacylation:B = K2CO3, TEA, py

sulfonamide

precipitate

precipitateNo H, No deprotonation

Acidic H

Delocalized charge, stable anion

nC= up to 8 it is water soluble

No reaction (no precipitate)

5. Reaction with oxo compounds

6. Reaction with nitrous acid --- Generation of electrophile - NO


Primary amines can attack on sp2 electrophilic C

Schiff base: imine

Nitrosyl cation

Reaction with different amines →


N-nitroso amineyellow oil or crystal

Diazonium cation (diazonium salt)

tautomerism

in the case of secondaryamines it is the product

N-nitrosation

transformation of diazonium salts

Reaction of primary and secondary amines with nitrous acid

diazoacid

if

Mechanism

Primary amines (Properties of diazonium salts)▪ Aliphatic primary amines – yield aliphatic diazonium salts. Alkyl diazonium salts are very

unstable and yield carbocation-derived products (rapid spontaneous decomposition evenat low temperature carbocations are formed by losing nitrogen) generally little practical importance

▪ Aromatic primary amines – arenediazonium salts are stable at low temperature (0-5 ° C) in aqueous solutions, they are of considerable synthetic importance because thediazonium group can be replaced by a variety of other functional groups (syntheticapplications of aromatic diazonium salts see later) BUT! In solid, dry form it is unstable!

Secondary amines – stable N-nitroso compounds

Tertiary amines – tertiary aliphatic amines: possibility of proton loss is missing, there is no effective reaction. Actually very slow C-N bond cleavage

Reaction of primary, secondary and tertiary amines with nitrous acid

– tertiary arylamines react with nitrous acid to form C-nitroso aromaticcompounds. Nitrosation takes place almost exclusively at the para position if it is open and,if not, at the ortho position. The reaction is an example of electrophilic aromaticsubstitution:

NN

NN

NN

NN

NN

Resonance structures

8 centred, 10

electrons:

delocalized

system

7. Reaction of aromatic ring of aniline derivatives – ArSE

The amino group can be protonated --- changed directing effect!!!

product ratio of nitration: o- : m- : p- = 2 : 47 : 51)

Similarity to phenols:• Reaction with weak electrophiles• Reaction without catalyst• Polysubstituion

Oxidation of aromatic amines: similar to phenols


I. orderactivating

II. orderdesactivating

I. order, activating agent

In CHCl3 solution too!

quinone-imin 1,4-benzoquinone

To avoid protonation and oxidation – protecting groups needed (eg. acylation, acetylation)

Similar + M effect as amino group RCONH I. order (o/p) activation effect

About amide nitrogen: it is not basic so no protonation and no sensitivity toward oxidation

8. Oxidation of anilines

General characteristics: due to the high electron density easy oxidizability (oxidation = electron release !!), but a wide variety of concurrent reaction little synthetic value

Exception: tertiary amines See the oxidation of aromatic amines

(formerly)


or

Friedel-Crafts

reaction

9. Elimination

Similarity to alcohols. NH2/NHR/NR2 bad leaving groups, BUT transformed to cations it turnsinto a good leaving group (see acid catalysed dehydration of alcohols). In case of amines: stable, isolable cations –mostly 4o ammonium compounds

Stabile 3o amine

Specific application: Hofmann's "exhaustive methylation" and Hofmann elimination

Note: The product with lower thermodynamic stability is favoured (less hydrocarbon group attached to the double bond (less highly substituted double bond)). So-called Hofmann product.

This is the opposite orientation than the base-induced 1,2-elimination of alkyl halides - or acid catalysed 1,2-elimination of alcohols (Zaitsev’s rule).


main productHofmann product

The least sterically hindered hydrogen is removed by the base in Hofmann elimination reactions. Methyl groups are deprotonated in preference to methylene groups, and methylene groups are deprotonated in preference to methines.

Preparation of amines

Béchamp-reduction

Nowadays: H2/cat.

Antoine Béchamp

In detail:

World aniline consumption: ~ 4Mt

For 2015: 6.2 Mt

Sodium dithionite

3. Degradation methods

Feature: 1 carbon shorter chain ----- Hofmann rearrangement

Curtius rearrangement - similar to the Hofmann rearrangement, the same isocyanateintermediate

2. Nucleophile substitution

You know: R-Hlg + NH3 gives the mixture of productsGabriel’s synthesis

Good Nu

Preparation of amines 2.

Characterization of other compounds containing a CN single bond. Nitro compounds, nitro bonding system, the

interpretation of electron-withdrawing effect, CH acidity. Preparation of nitro compounds. Preparation of diazonium

salts, aromatic diazonium salts and their reactions and practical significance. Industrial significance of azo

compounds.

Characterization of the most important compounds containing CN = X bond

1. Nitroso- and nitro compounds

Substitutive nomenclature, nitroso / nitro prefix (can

only be specified as a prefix!

Bonding system- nitroso sp2-hybridized nitrogen, non-

bonding electron pair on the hybrid orbitals, unpaired electron in the pz orbital

analogy to the alkenes

- nitro compoundsSimilarity: both N and O sp2 hybridized

Difference: -skeleton built up from hybrid orbitals, a non-bonding electron pair of N exist on pz orbitals three neighbouring and overlapping pz orbitals, four electrons - three-center bond, fully balanced electronic structure

Similarity to the carboxylate, (see later) LCAO-MO: 3 AO → 3 MO

growing number of nodes

Nitro and nitroso compounds 2.Three-center bond consequence: smooth electron distribution both on the oxygen and the nitrogen 4/3 electron Compared to the initial state of N charge deficiency (δ ), O: excess charge (δ ). This is reinforced by the EN difference!

Representation via resonance forms: two equivalent resonance structures!

Two equivalent oxygens !!

Evidence:•planar structure•same NO bond distances (0.122 nm, cf. d (NO) = 0136 nm, d (N, O) = 0115 nm), bonding order between 1 and 2!•O-N-O bond angle, 126o

•large dipole moment (μ = 3.5-4 D)

Consequence:NO2 group is strongly electron-withdrawing (due to -I and empty pz -M effects). Attached to an aromatic ring it is a II. order, deactivating substituent (see Fig. above)Because of the empty pz orbital the neighbouring negative charge is stabilized (mesomeric stabilization)

Physical properties of nitro compounds

High melting and boiling pointCause: zwitterion structure, strong dipole-dipole interactions Poor solubility in water - because of the strong association it does not have any hydration energy gains, remains the original H-bridge and dipole-dipole-stabilized structure

Comp. Mw Bp (oC)

MeNO2 61 101

MeONO 61 -12

Me2CO 58 56

MeCl 49 -24

Chemical properties of nitro compounds

1. Acidity of aliphatic nitro compounds - deprotonation at a-position, CH acidity

LCAO MO: 4 centred, six electrons: delocalized

system

Resonance stabilized anion Actual charge distribution:

Most of the charge on the oxygen: a proof is

the deprotonation

pKa = 7.7 -10 (EtNO2 = 8.5)!!

Consequence: alkali solubility

Application:

Henry reaction

It is generally true: nitro alkanes containing hydrogen in a-position can be easily substituted in a- position (bromination, nitration, etc.).

2. Reduction of nitro group – to aliphatic/aromatic amines (see earlier)

3. Aromatic nitro compounds – difficult SE reaction, a NO2 group is a II. order deactivating substituent

BUT! SN reaction of aryl halides containing nitro groups is easier (see earlier) -

Meisenheimer complex!

Nitro and nitroso compounds 3.

Diazo compounds

Formally alkene derivatives –Substitutive nomenclature ~ diazo prefix

Bonding system: only resonance structures, there is no classical Lewis-Langmuir formula

LCAO-MO description: Three centred bond with four electrons

Its reactions can be derived from its resonance structure

1. Reaction with strongly acidic hydrogen results nitrogen elimination - alkylation / methylation (diazomethane)

Phenols, carboxylic acids: their selective methylation is easy - alcohols do not react

2. In 1,3-dipolar cycloaddition reactions reacts as a dipole (see later)

Preparation of diazo compounds: alkaline cleavage of N-nitroso ureas; in situ generation

Diazonium salts

Formal derivation from diazo compounds – by removal of an electron (also described byresonance structural forms). Preparation (see earlier).

R-NH2 + HONO (diazotization, Griess (1858))

Reactivity derived from resonance structure1. Reactions with nitrogen loss

2. N electrophile

Primarily substitution nomenclature - the main cation name of the hydrocarbon group +diazonium suffix + name of counter ion

Aryl diazonium ions are considerably more stable than their alkyl counterparts.Whereas alkyl diazonium ions decompose under the conditions of their formation, aryldiazonium salts are stable enough to be stored in aqueous solution at 0–5°C for reasonableperiods of time. Loss of nitrogen from an aryl diazonium ion generates an unstable aryl cationand is much slower than loss of nitrogen from an alkyl diazonium ion. Stability is due to:interaction with the aromatic electron system (8-center, 10-electron bonding system and 5resonance structures)

Diazonium salts 2.

1. Reactions involving nitrogen departure (replacement, substitution)

Aryl diazonium ions undergo a variety of reactions that make them versatile intermediatesfor the preparation of a host of ring-substituted aromatic compounds. In these reactionsmolecular nitrogen acts as a leaving group and is replaced by another atom or group. All the reactions are regiospecific; the entering group becomes bonded to precisely the ring position from which nitrogen departs.

1.1. Non-catalyzed reactions

H3PO2: Hypophosphorous acid, phosphinic acid

Diazonium salts 3.

1.2. Copper catalyzed reactions Cu (I) salt: Sandmeyer reaction;

activated copper (powder oralloy): Gatterman reaction

The value of diazonium salts in synthetic organic chemistry rests on two main points. Through the use of diazonium salt chemistry:1. Substituents that are otherwise accessible only with difficulty, such as fluoro, iodo,cyano, and hydroxyl, may be introduced onto a benzene ring.2. Compounds that have substitution patterns not directly available by electrophilicaromatic substitution can be prepared.

Mechanism of Sandmeyer reaction

2. Reactions without nitrogen departure - N-electrophilic attack to a nucleophilePractical significance: azo coupling - SEAr reaction !! (The nitrogens of an aryl diazonium salt

are retained on reaction with e.g. the electron-rich ring of a phenol. Azo coupling occurs.)

BUT! diazonium salt is a weak electrophile → strongly activated aromatic reactant required(R = electron-withdrawing, R1 = electron-donating= OH, NH2)Typically, para substituted product is formed

A further reaction without nitrogen departure- reduction to aryl hydrazine

Azo compounds

Bonding system: Classic + bond sp2 hybridized pillar N atoms ("pyridine-type" nitrogens)

skeleton

Complete analogy to alkenes - diastereomers exist in the

same way

Diazonium salts 4.

Practical significance of azo compounds: conjugated electron system, light absorption in the visible region COLOR!(if exists an appropriate binding these can be used as textile dye!)An important aspect of using different substituents the colour is tuneable.

Mordant red 19

Further options: food colouring

Methyl orange

Further options: Indicators

Aqueous solution

Azo compounds 2.

Sodium 4-[(4-dimethylamino)phenylazo]benzenesulfonate

In a solution becoming less acidic, methyl orange moves from red to orange and finally to yellow with the reverse occurring for a solution increasing in acidity. The entire colour change occurs in acidic conditions.

Azo compounds 3.

Transformation of azo compounds – reduction of N=N double bond

amines grouping and characterization of binding systems

Documents