Consortium leader 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 ***

2011.11.27.. 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 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

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 2

Aliphatic and aromatic

hydrocarbons

(Alifás és aromás szénhidrogének)

Organic and Biochemistry

(Szerves és Biokémia )

semmelweis-egyetem.hu

Compiled by dr. Péter Mátyus

with contribution by dr. Gábor Krajsovszky

Formatted by dr. Balázs Balogh

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 3

Table of Contents


Organic and Biochemistry: Hydrocarbons

1. Alkanes 6 – 20

2. Alkenes 21 – 42

3. Alkynes 43 – 53

4. Cyclic Compounds 54 – 55

5. Annulanes 56 – 58

6. Aromatic compounds 59 – 75

7. Antiaromatic compounds 76 – 82

8. Reactivity of aromatic compounds 83 – 107

9. Fused polycyclic aromatic hydrocarbons 108 – 116

10. Isolated polycyclic aromatic compounds 117 – 121

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Topics

Hydrocarbons

Alkanes

Alkenes

Alkynes

Aromatic compounds

carboaromatic

heteroaromatic compounds

Substituted hydrocarbons

(discussed according to functional goups)

Chemical structure

Reactivity

(Biological function)



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Hydrocarbons

paraffin hydrocarbons or alkanes or

acyclic saturated hydrocarbons n=1, 2, 3...

olefins and cycloalkanes

n=2, 3, 4... acetylenes, diolefins, cycloalkenes

n=2, 3, 4...

benzene and its homologues

n=6, 7, 8...

CnH2n+2

CnH2n

CnH2n-2

CnH2n-6



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Alkanes (paraffins)

n-alkanes

The stems of the names are of Greek and Latin origin

isoalkanes

(alkyl group) • Isomerism

Homologous series: any two neighboring members of the series

differ by a CH2 group from each other

• chemical properties are rather similar

• physical properties are gradually changing

• Nomenclature

All carbon-carbon bonds are single bonds

many trivial or common names

Ending for all names: -ane



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m.p.

n

even odd

v a n d e r W a a l s forces

( n - a l k a ne ) > ( i s o - a l k a ne ) b.p. b.p.

b.p.

(°C)

0

5 n gas liquid

t r a n s methyl groups

c i s methyl groups

even: carbon atoms pack more closely



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Alkanes

- Oxidation-reduction (in general)

- Some synthetic methods

- Reactivity



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 9

oxidation reduction

e- releasing accepting

O accepting releasing

H releasing accepting

e.g.,

CH4 electron density is shifted towards

the carbon: C is reduced formally

or CH4 could be oxidised (C4- character) (is to be burned).

CCl4 C4+ character, i.e., fully oxidised, CCl4 can not be burned.



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Oxidation and reduction (general remarks)

Oxidation levels of carbon: C

EAC

IPC

reduction oxidation

+ 4

+ 3+ 2+ 1

CC

CC

23

4

- 1- 2- 3- 4

C

CC

CC

2

34

red.

oxid.

fully oxidised

fully reduced



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(formal)

the lowest oxidation level

(R2 = H, alkyl...)



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The most typical oxidating agents: KMnO4; OsO4; CrO3; H2O2; peracids

Reducing agents:

• Catalytic hydrogenation

Ni, Pd, Pt / H2 2 H homolytic

reaction in heterogeneous phase (solid + gas)

alkene/alkyne: easy reduction

benzene: difficult reduction

• Chemical

LiAlH4, NaBH4 H is of nucleophilic character

(ethylene, benzene: do not react)



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Alkanes: syntheses

- Reduction

- Carbon-carbon bond formation



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Synthesis of alkanes:

Fischer-Tropsch synthesis exothermic reaction

Reduction by ‘nascent’

hydrogen

Wurtz reaction

(coupling of alkyl halides)

C C H 2

c a t . C C

H H

C ClNa

2 C C

R X2Zn

2 H2R H

D n C O + ( 2 n + 1 ) H

2 C

n H

2 n + 2 + n H

2 O catalyst

Reduction



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Synthesis of alkanes:

Kishner-Wolff- Huang-Minlon reduction

Clemmensen reduction

C O C H 2

H 2 N N H 2 C N N H 2

- H 2 O

D

base

R B r L i A l H 4

R H + L i B r + A l H 3

R M g X + H 2 O R H + M g ( O H ) X

R L i + H 2 O R H + L i O H

Reduction

C O C - H

H 2

Zn-Hg



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Alkanes: reactions



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Reactions of alkanes

„Parum affinis” = bonds with low polarity, and they are

less polarizable

1. Substitution reactions

halogenation (Cl2 and Br2)

nitration

2. Oxidation

heat of combustion: ~ 157 kcal C H 2 ( )

H3C CH3

HNO3 H3C CH2 NO2 + H3C NO2

2 CnH2n+2 + (3n+1) O2 2nCO2 + (2n+2) H2O

C l C H

4 2

H 3 C C l + H C l C C l 4 D or hn



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Heat of combustion is the enthalpy change for the complet

oxidation of the compound (under standard conditions)



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3. Isomerisation

cf., with data of heat of combustion

H3C CH2 CH2 CH3

AlCl3

HClH3C CH CH3

CH3

20% 80%

+ 6 . 5 O 2

+ 6 . 5 O 2

2 k c a l / m o l

- 6 8 5 . 5 k c a l / m o l - 6 8 7 . 5 k c a l / m o l

4 C O 2 + 5 H 2 O



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Alkanes: as fuels

CH3 C H

CH3

CH3

mágikus savCH3 C

HCH3

CH3

H

CH C CH3

CH3CH3 C CH2

CH3

CH3

CH

CH3

CH3 + H

izooktán



magic acid

isooctane

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Alkenes (olefines)

CnH2n double bond H2C CH CH3

Nomenclature: - the longest carbon chain containing the double bond(s)

- double bond(s)

- branching

Groups: H2C CH ethenyl (vinyl)

H2C CH CH2 2-propenyl (allyl)

H2C C

CH3

1-methyl-ethenyl

alkylidene H3C CH

CH3

CH 2-methyl-propylidene

E, Z isomers

alkenyl



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Relative stability: enthalpy of hydrogenation (kcal/mol)

H3C CH2

C CH2

HC C

H3C

H

CH3

HC C

H3C

H

H

CH3

CH2

H3C CH

2

CH3

- 30.3

1.7

- 28.6

1.0

- 27.6



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1. The disubstituted double bond is more stable, than the

monosubstituted one

2. The trans-isomer is more stable, than the cis

3. The compound having polysubstituted double bond is more stable, than the one

with less substituents reasons:

a) hyperconjugation (σ - π conjugation) is less important

H C C C

b) more sp3 - sp2 bonds are in the more substituted olefin

(delocalisation)

H3C CH3 CH2 CH

H3C

H3C

C

H3C

H3C



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 24

average bond energy

bond energy

C C 82.6 kcal/mol

CC 145.8 kcal/mol

60 kcal/mol ~~bond



C C 1 . 3 3 Å

C C 1 . 5 4 Å

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Temperature (°C) Energy content (kcal/mol)

at room temperature ~ 25

by heating 25 - 50

~ 500 60

π bond: ~ 60 kcal/mol

cis-trans isomerisation usually does not happen,

but ‘push-pull’ or ‘captodative’ ethenes

(activation free enthalpy ≈ 15 kcal/mol)

C C

A E

DB B D

EA

CC

A, B electron-withdrawing, E, D electron-releasing



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 26

atoms marked by red color are in the same plane

cis double bond

a.) planar b.) not planar

C C

C CC

C

H H

H

H

H

H



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 27

Alkenes: Syntheses

Preparation

1. Elimination

X = Cl, Br, NMe3

E2 or E1

E2

E1

( or ) I

CH3COOH

Zn/

HCC

Br

Br

CC

C C

OH

H

H

X

CCbase



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 28

2. Formation of new carbon-carbon double bonds:

Wittig reaction

Ph3P=CHRC O

R1

R2

C CHR

R1

R2

3. Reduction

Syn addition Ni2B

H2

Pd/CaCO3

H2

C CR R

cis

C C

R

H H

R

Lindlar

Li/EtNH2anti addit iontrans olefin



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Alkenes: Reactions

1. Addition reactions (a molecule is added to an another, and

nothing is cleaved)

Electrophilic addition AdE

v = k 2 [ a l k e ne ] [ X 2 ] v = k 2 [ a l k e ne ] [ H X ]

a l k e ne k 2 ( r e l a t i ve )

X 2

H X

Two-steps reactions

Alkene

C

X

CX

X2 C CHX

CC

H

X

CH2 = CH2

CH = CH2

Et

Me2C = CMe2

1

102

106



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 30

Stereochemistry: Anti addition (X = Cl, Br)



C H 3

C H 3

B r 2 + H 3 C

B r

C H 3

B r

B r B r + B r B r B r B r B r B r . . . . . . . . . . . . . . d d d d

B r

B r

C C

B r

B r

C C

B r

B r

C C

d

H H

H 3 C

B r

H

C C

B r B r

C H 3 C H C H 2

d

B r C C

H 3 C

H B r

H

H B r

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Addition reactions of olefins

Addition of hydrogen



CH3

CH3

CH3

H

CH3

HH

2 (cat).

syn addition

CH3

CH3

O

CH3

O

CH3

Met

O-

O-

OsO4 (25 °C) or MnO

4

-

(hydrogen)

syn addition OH

H

OH

H

Met: Os, Mn K salt

H

H

CH3

CH3

Ar

OOH

O OCH3

HCH3

HArCOOH+

syn addition+

1.

2.

3.

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 32

HX: HCl, HBr (H3O+ + Cl–/Br–

Regiochemistry: Markovnikov's rule ≈ 1870

(H moves to the least, while X to the most substituted carbon.)

Stability of the carbenium ions: 3° > 2° > 1°

P

XHC C

H

R H

H

C C

R

HH

H

H

X

C

R

H

C

H

HH

XC C

R

HH

H

H

Markovnikov’s adduct



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 33

R C H 2 C H 2 X

R C H 2 C H 2

C H C H 2 R +

H X

R C H C H 3

X

R C H C H 3 X

X

z z

E semmelweis-egyetem.hu


2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 34

Markovnikov's rule is valid:

C CR

H

H

H

Anti-Markovnikov orientation:

1. C C HR

H

H

H

OH

H BR'

R'

H2O2

H2O, HOC C

HR H

H

H BR' R'

C CH2

H

R

(where the X in HX is more electropositive, than H)

H XC CH3

X

R

H

I Cl

C CH2I

Cl

R

H

Cl OH

C CH2Cl

OH

R

H

H OH2C CH3

OH

R

HH OSO3H

C CH3

OSO3H

R

H



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 35

Substitution:

Addition vs. substitution

substitution addition regioselective chlorination

in allylic position

RCH2 CH CH2

SeO2

R C CH CH2

O

oxidationR=H

HOOC CH CH2

oxidation (catalytic)

H2C

H2CN

O

O

Br

CCl4

BrCH CH

R

CH2



C H 3 C H C H 2

C l C l

C l 2

2 5 C o C H 3 C H C H

2

C l 2

5 0 0 C o C l C H 2 C H C H 2

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2. Radical reaction AdR

Stability of radicals:

(c.p., with bond dissociation energies, BDE)

HF does not react, since the bond dissociation energy is too high.

HI does not react, since I is not enough reactive.

BrInit.

H Br

CH3 CH CH3

Br

CH3 CH2 CH2Br

Br

HBr

CH3 CH CH2

Br

CH3 CH CH2BrBr

CH3 CH CH2 main product

side product

3o > 2o > 1o



Init.: radical-initiator

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Radical polimerisation

Stabilisation, e.g.,

In CH2 CH2 In CH2 CH2

CH2 CH2

In CH2 CH2 CH2 CH2.............

In (CH2 CH2)nCH2 CH2 H2C (CH2 CH2) CH2 In

n

In (CH2 CH2)n CH2 CH2 CH2 (CH2 CH2) CH2 Inn



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Nucleophilic addition to carbon - carbon multiple bond

Michael addition:

C C EWG

HH

H

HYY CH2 CH2 EWG

base

EWG: CO

H , R

OC

,C

O

OR, NH2

OC C N, NO2 , SOR,

SO2R

,

a.) CH CNH2CNaOEt

EtOHC2H5O CH2 CH2 CN

C COOR1

HC R2NHR2N CH CHCOOR

1b.)



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Physical properties of alkenes

Biological importance:

- fixing conformation

- form homologous series

C n C 5

-

-

liquids

boiling point alkanes

dipole moment of the cis isomer is higher



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H3CS

CH2

CH

NH3COO

H2C

C

NH3

COOH2C

H2C CH2

methionine

enzyme

enzyme



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Diolefins

Cumulated:

Allenes: in two planes perpendicular to each other

Conjugated:

butadiene isoprene

H2C C CH2 H3C C CH

H2C C CH CH2

CH3

H2C CH CH CH2

Br2

1,2 1,4

BrH2C CH CH CH2

Br

BrCH2 CH CH CH2Br

5°C

H2C CH CH CH2



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 42

C CC

B

A

B

A

C C C



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Alkynes



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 44

Acetylenes (Alkynes): Structure

Bond energy is 200 kcal/mol

CnH2n-2

1.2 A°

C CH H

sp sp



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Nomenclature of hydrocarbons

Principal chain: must be chosen according to the following priority:

1. must contain the most unsaturated (double and triple) bonds

2. the carbon chain must be the longest

3. must contain the most double bonds

4. unsaturated bonds must get the lowest locants

5. a double bond must get lower locant, than a triple bond, if there are

alternatives

6. must contain the most substituents, those can be named as prefixes



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 46

C

H3C

CH C

CH3 CH2 CH2

CH2

CH2CH3

1

234

567

2-ethyl 4-methylhepta-1,3-diene

1 2 3 4 5

H2C CH CH2 C CH

pent-1-en-4-yne

123456

H3C CH

CH3

CH2 CH2 C CH

5-methylhex-1-yne



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Groups with one valence (univalent groups)

numbering starts from the carbon with free valence:

H2C CH vinyl (ethenyl)

HC C CH2 2-propynyl

H2C CH CH2 allyl (2-propenyl)

choosing the principal chain happens according to the usual method

Groups with more, than one valence (polyvalent groups)

-ylidene H3C CH2 CH propylidene

-ylidyne H3C CH2 C H propylidyne



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Alkynes: syntheses

- Elimination reaction

- Carbon-carbon bond formation: alkylation of alkyne

carbon



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Preparation

2. HC C R1. NaNH

2

2. R Br,

,C CR R

1.

KOH,

,R CH2 CX2 R

R C C R,

KOH,

R CH CH R,

X X

R =H,

NaNH2

C CHRif



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Alkynes: Reactions

- Addition

- Substitution

- Oxidation



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Reactions

I. Addition

1. Electrophilic addition: HX → ‘Markovnikov's rule’

HBr HBr

CH3CO

Br

Al2O3

CH2Cl2

H2O

Br2C

R

CH3C CHR C CH2

Br

R

C CH2

Br

R

‘Anti-Markovnikov’: by initiation with peroxides or with light

HBr

H2O2

C CHR RHC CHBr



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X2 (X = Cl, Br)

t r a n s

Addition of an organic acid

Addition of water

H

low temperature

stoichiometric amount of

bromine

vinyl acetate

HC CHCH

3COOH

Zn2

,

CH3

CO

O CH CH2D

Br2C C C CBr

Br



H C C H H 2 C C H O H H 3 C C

O H 2 SO 4

HgSO 4

tautomerisation

H 3 C H 3 C C C H 2

O H

H 3 C C C H

3

O

C C H H 2 SO 4

HgSO 4

tautomerisation

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 53

2. Nucleophilic addition

In the case of olefins, it works only in the presence of a strong

electron withdrawing group in α position (if the olefin is activated).

3. Hydrogenation - Reduction by active catalysts

in the case of a deactivated catalyst: olefin is produced

II. Substitution: - alkylation

III. Oxidative cleavage: - Oxidation

ROHKOHROHC CH C C

H

RO

H

RO CH CH2

vinyl ether

R1

C C RH2

R1

CH2 CH2 R

100 °C

KMnO4C CR1 R

O OpH ~ 7

R1

C C RR

1COOH

R COOH

KMnO4



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Cyclic Compounds - Monocyclic

- Polycyclic

- Isolated cyclic

- Fused polycyclic

- ortho

- ortho and peri

fused

- Bridged cyclic

(contains bridge head atoms)

- Spirocyclic



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 55

isolated ring systems

no common atom in the

rings number of connections

is less by one than the

number

of cycles

ortho-condensed/fused

two common atoms in the

rings

n common edges and

2n common atoms

ortho and peri-fused

n common edges and

less than 2n common

atoms

CH2

CH2

CH2

CH2

CH2

CH CH2

CH CH2

CH2

CH2

H2C

H2C

CH

CH2

CH2

CHCH2

CH2CH2

H2C

H2CC

CH2

4. Spirocyclic

one common atom

Polycyclic compounds:

1. 2.a 2.b

3. Bridged

more than 2 common atoms



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Annulenes

Unsubstituted monocyclic hydrocarbons with the greatest possible number of

noncumulated double bonds. Their general formulae

CnHn (n>6, even number)

CnHn+1 (n>6, odd number)

1

2

3

4

56

7

8

910

[10]annulene

9

8

7

6

5

43

2

1

1H-[9]annulene ‘[6]annulene’

benzene



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Heterocyclic compounds

They contain carbon atom(s) and heteroatom(s) atoms in the ring

- Saturated

- Unsaturated

- Partially saturated

Classification:

- number of the ring member atoms

- heteroatoms

- number of the heteroatoms

- quality of the heteroatoms



11/27/2011. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 58

Heteroannulenes (compounds with the greatest possible number of

non-cumulated double bonds)

These can be derived from annulenes:

- if a CH group is replaced by an X (the same ring size)

- if a HC=CH group is replaced by an X (next lower ring size).

In both cases, the resulting heteroannulene is isoelectronic with the

corresponding annulene.

[6]annulene

benzene

X

X = N

pyridine

NH

pyrrole



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 59

Aromatic compounds: monocyclic, fused and

isolated carboaromatics

- Aromaticity and antiaromaticity

- Aromatic electophilic and nucleophilic substitution



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 60

Benzene

1. hypothetic cyclohexatriene

alternating single and double bonds

2. Resonance structures



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 61

Benzene

1H NMR:

d aromatic H : ~ 7-8 ppm

d olefinic H : ~ 5-6 ppm

Outside magnetic field

induced space

HH



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 62

Bond dissociation energy (BDE)

The energy necessary for the cleavage of a bond resulting in radicals.

118 kcal/mol

100 kcal/mol

Bonding energy (BE)

(average bonding energy)

bonding energy for the

O—H bond of water: 118 + 100

2 = 109 kcal/mol

For a molecule having more than two atoms: BDE BE

Determination of BE:

from atomisation heat, that is calculated from combustion heat

H2O H +

H2O H +

HO

O



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 63

Bond energies (25°C)

(average values)

bond kcal/mol kJ/mol

C-H 96-99 400-415

C-C 83-85 345-355

C-Cl 79 330

C-Br 66 275

C-I 52 220

C=C 146-151 610-630

CC 199-200 835



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 64

Resonance energy:

measured energy - resonance structure with the lowest energy

Atomisation heat for benzene : 1323 kcal/mol (measured)

calculated from bonding energies: 1289 kcal/mol (A or B)

A B

Resonance energy: 1289-1323 =

= - 34 kcal/mol

Empirical resonance energy:

3 x (-120) - (-210) = - 150 kJ/mol = - 35.9 kcal/mol

H2

- 120 kJ/mol

H2

- 210 kJ/mol



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 65

H2

2 H2 2 H2

DH = -30.3

kcal/mol

DH = -60.7 kcal/mol

Estimated value from

other unconjugated

dienes or twice the

value for 1-butene

DH = -57.1 kcal/mol

experimental value

About 3.6 kcal/mol

stabilization owing to

conjugation

DH

H 2



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 66



length (Å) energy (kcal/mol)

biligand sp (acetylene) 1.057 120 triligand sp2 (ethene) 1.079 106

quadriligand sp3 (ethane) 1.094 101

120 °

sp2

90 °

180 °

pz

px

sp

109.5 °

sp3

An sp2 orbital has more s character than an sp3 orbital, and bonds

made from sp2-sp2 overlap will be stronger and shorter than those

made from sp3-sp3 overlap.

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 67

H2

2H2

3H2

3H2

Ener

gy

The value for the special stability of benzene as derived from measured and

calculated heats of hydrogenation.

Predicted effect of adding

one more double bond

(–82.2 kcal/mol)

–32.9 kcal/mol delocalization

energy of benzene

ΔH = –82.2 kcal/mol

estimated for hypothetical

1,3,5-cyclohexatriene

Experimental effect of

adding one double bond

(–26.8 kcal/mol)


ΔH = – 28.6 kcal/mol

Energy of

cyclohexane


measured for the real

benzene



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 68

antibonding

orbitals

bonding

orbitals



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 69

The relative energies of the molecular orbitals of benzene derived from a

Frost circle.

Hexagon inscribed inside the Frost circle (relative energies of the molecular

orbitals of planar, cyclic fully conjugated molecules): inscribe the polygon

vertex down, the intersections with the circle will mark the positions of

molecular orbitals

Nonbonding

Three antibonding orbitals

Three bonding orbitals will hold

the six available π electrons

Ener

gy

Radius = 2β 2b

1b 1b



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 70

Benzene

The effort to the lowest energy level forces the structure into the same plane.

Conditions for formation of aromatic systems:

1. There must be a continuously conjugated, cyclic delocalised system

(using pz atomic orbitals).

2. Participation of 4n+2 electrons in the delocalisation (Hückel's rule).

3. The carbon skeleton constructing the cyclic system must be coplanar or

approximately coplanar.



Conditions for formation of antiaromatic systems:

1. There must be a continuously conjugated, cyclic delocalised system

(using pz atomic orbitals).

2. Participation of 4n electrons in the delocalisation.

3. The carbon skeleton constructing the cyclic system must be coplanar or

approximately coplanar.

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 71

cis-1,3-Hexatriene is fully conjugated and can be planar, but the lack of a

ring structure means that overlap between the 2p orbitals on C(1) and C(6) is

essentially zero.

No strong overlap here;

the molecule is not aromatic

cis-1,3, 5-Hexatriene



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 72

Six-membered aromatic rings

Benzene carbon-carbon bond distance: 1.40 Å

c.p., with Csp2-Csp2: 1.48 Å

Csp2=Csp2: 1.32 Å

Pyridine

Pyrilium cation

pyridinium cation

N

H

N

H

N

H

O



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 73

Other aromatic systems containing - sextet

Cyclopentadienide anion

Pyrrol, thiophene, furane

X: NH pyrrol

S thiophene

O furane

H H

pKa = 16

baseH

H

X



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 74

Cyclopentadine is a quite strong acid. The cyclopentadienyl anion is an

aromatic species. For an anion, it is extremely stable.

CH2 CH + B HBbase,

The cyclopentadienide

anion is easily formed

A pentagon inscribed in a circle (vertex down)

Antibonding

molecular

orbitals

Nonbonding

Bonding

molecular

orbitals

pKa = 15 E

ner

gy



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 75

cycloheptatrienylium cation

(tropylium cation)

aromatic

OH

-OH

6

7

6

5 4

3

21

H



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 76

Antiaromatic compounds

4 electrons

generally: 4n electron

Much less stable, than the appropriate

non-aromatic compound!

Antiaromaticity: the electron circuit is destabilizing the system.

Paramagnetic circuit: the outer hydrogen atoms have lower chemical

shifts, than of the appropriate non-aromatic system.



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 77

The relative energies of the molecular orbitals of cyclobutadiene derived from a

Frost circle.

Ener

gy

Nonbonding

molecular

orbital Nonbonding molecular

orbital

Bonding molecular orbital

Antibonding molecular orbitals

Delocalized cyclobutadiene

A square inscribed in a

circle (vertex down)



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 78

The electronic occupancy of the four molecular orbitals for square

cyclobutadiene.

Ener

gy

Nonbonding

molecular orbital

Nonbonding molecular

orbital

Bonding molecular orbital

Antibonding molecular orbital



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 79

not biradical (since it is square-

shaped); antiaromatic

antiaromatic

H H

HH

H I

H

Ag

H

HH

HH

HI

HH

H

Ag



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 80

H

cyclooctatetraene

Homoaromatic compound (ions):

presence of one or more sp3 carbon in the conjugated cycle

H1

H7

Hb Ha23

67

H H

H

H

HH

H

H

1

2

8

Na10

aromatic

d Hb = - 0.3 ppm

Ha = 5.1

H2-H

6 = 8.5

ppm

ppm

d

d



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 81

Ener

gy

The molecular orbitals of planar cyclooctatetraene.

Two electrons must occupy nonbonding orbitals.

Nonbonding

molecular

orbital

Nonbonding molecular

orbital

Bonding

molecular

orbitals

Antibonding

molecular

orbitals

Delocalized cyclooctatetraene

An octagon inscribed

in a circle (vertex down)



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 82



A O

E

cyclooctatetraene

8 electrons

planar

benzene

6 electrons cyclobutadiene

4 electrons

antibonding

non-bonding

bonding

1.33 A o

1.46 A o

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 83

Reactivity:

substitution (electrophilic or nucleophilic depending on the

substrate)

addition: very difficult, under harsh conditions



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 84

Aromatic electrophilic substitution (SEAr)



X

X = mostly H

slow Y

X

Y

X

Y

X

Y

X

Y

Y fast

- X

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 85

cyclohexadienyl cation

(resonance stabilized)

Y

H



W = Wheland intermediate arenium ion: s complex

W

X = H

E

z

Y

H Y

Y H

Y H d +

d +

d + d +

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 86

Why substitution (not addition)?

A B

Resonance energy: 1323-1289 =34 kcal/mol

Csp2-H Br2 subst(C-Br): exotherm -11 kcal/mol

C=C Br2 addition (C(Br)-C(Br)): exotherm -27 kcal/mol

cyklohexene: addition, not substitution! (both thermodynamic and kinetic control!)

BUT! benzene: if addition, aromaticity would be lost!



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 87

1. Nitration NO2N

O

O

Nitrating agents:

a) Nitrating acid: for benzene, or for compounds

with lower reactivity

b) HNO3, for more active compounds (amines, phenols)

c) NaNO2 + F3C-COOH

d) Nitronium salts: +NO2BF4–

H2SO4 + HNO3 H2NO3 + HSO4

H2NO3 + H2SO4 H3O + NO2+ HSO4



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 88

2. Halogenation

Cl2 or Br2 Br

Br2

FeBr3

FeBr3 [FeBr4]Br2 Br

Iodination: I2 is not reactive in itself

I2 + SbCl5

I2 + AgNO3

ICl

Reactivity of halogenation agents:

Cl2 > BrCl > Br2 > ICl > I2



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 89

3. Sulfonation SO3H

H2SO4

Reagents: conc. H2SO4, SO3, oleum

4. Friedel-Crafts reaction

a) Alkylation R

RClAlCl3

Alkylating agents: R-X (alkyl halogenide)

olefins

alcohols

catalyst: Lewis acid

(CH3)3C Cl FeCl3 (CH3)3C FeCl4

R-X: R-F > R-Cl > R-Br > R-I



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 90

b) Acylation

Mechanism of it:

+ R C

O

Cl

C

O

R+ HCl

H3C C

O

Cl+ AlCl 3 H3C C

O

Cl

AlCl 3

H3C C O AlCl 4

H3C C O AlCl 4



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 91

Direction rules in SEAr reactions

Other substitutions reactions of monosubstituted benzene derivatives:

1.

2. The reaction rate can be lower or higher than of benzene

deactivating, or activating substituent

3. Formation of the product is usually kinetically controlled.

4. Product ratio might depend on the irreversibility of the reaction.

Y Y

W

Y

W

Y

W1,2 (ortho) 1,3 (meta)

1,4 (para)



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 92

Relative rates of nitration of some arenes

C 6 H 5 X Relative rate

X = OH 1000

X = CH 3 25

X = H 1

X = I 0.2

X = Cl 0.03

X = NO 2 6x10 -8

X = N + (CH 3 ) 3 1x10

-8



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 93

Orientation preferences and reaction conditions for the

nitration of some benzene derivates



Substrate C 6 H 5 X Product composition Reaction conditions

ortho meta para X = NO 2 7 88 1 HNO 3 /H 2 SO 4 /100

o C

X = CH 3 62 5 33 HNO 3 /H 2 SO 4 /25 o C

X = OCH 3 71 1 28 HNO 3 /Ac 2 O/10 o C

X = OH 55 1 45 HNO 3 /H 2 O/20 o C

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 94

Reaction profile

Hammond principle:

The transition state is similar to the intermediate, thus if some-thing is

stabilizing the intermediate, it is stabilizing the transi-tion state, too.

On the other side, if something is destabilizing the intermediate, it is

destabilizing the transition state.

EE

zz



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 95

Possible disubstituted intermediates

ortho

meta

para

Y

H

W

Y

H

W

Y

H

W



Y

H W

Y

H W

Y

H W

Y

H

W

Y

H

W

Y

H

W

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 96

The ring has charge, resulting in:

a) stabilization, if Y is a substituent with electron releasing effect (+I); its

effect is the most marked where it is attached to the carbon with charge

directly ortho and para direction (but it is stabilizing everywhere)

destabilization, if Y is a substituent with electron withdrawing effect

(-I); its effect is the most marked for the ortho and para isomer: general

deactivating and meta direction

Y

H W

Y

H W

Y

H W



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 97

b) Resonance interaction (Y has a lone electron pair)

additional resonance structures could be drawn:

ortho meta para

there is no further

resonance structure

Stability of the ortho and para intermediate is even bigger, since

- number of resonance structures is higher, and

- charge is dispersed in even larger space.

Y

H

W.....

Y

H W

.....



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 98

Three classes of substituents

1. OӨ, NR2, NHR, NH2, OH, OR, NHCOR, OCOR, SR, F, Cl, Br, I

(lone pair of electrons)

Their resonance (mesomeric) effect is +; ortho- and para- directing

groups.

The result is the combination of the inductive and mesomeric effects.

a) OӨ (there is no -I effect), NR2, NHR, NH2, OH: strongly

activating, ortho- and para-directing groups.

b) OR, NHCOR, OCOR, SR weak activating, ortho- and para-

directing groups.

c) F ~ benzene, ortho- and para-directing groups.

d) Cl, Br, I: deactivating, ortho- and para-directing groups.



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 99

2. R3N, NO2, CF3, CN, SO3H, CHO, COR, COOH, COOR, CONH2,

CCl3, (H3N)

(There is no lone electron pair at the atom connected to the ring):

Their -I effects are remarkably strong.

Deactivating and m-directing groups.

3. Alkyl (R)-, aryl group (Ar)

R: +I effect and hyperconjugation

activating, o- and p-directing group

Ar: -I effect and strong/weak +M(-M) effect

activating, o- and p-directing group



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 100

Groups with +M or -M electronic effect

+M effect -M effect

O

S

NR2

NHR

NH2

NHCOR

OR

OH

OCOR

SR

SH

Br

I

Cl

F

R

Ar

NO2

CN

COOH

COOR

CONH2

CONHR

CONR2

CHO

COR

SO2R

SO2OR

NO

Ar



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 101

NO2

H

, NO2

Eact Eact

CH3NO2

H

Eact

CH3

NO2

H Eact

CH3

NO2H

CH3

, NO2

CH3

, NO2

CH3

, NO2



a.) Eact (benzene) b.) Eact (ortho) c.) Eact (meta) d.) Eact (para)

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 102

NO2

H

CF3NO2

H

CF3

NO2

H

CF3

NO2H

, NO2 , NO2

CF3

, NO2

CF3

, NO2

CF3



a.) Eact (benzene) b.) Eact (ortho) c.) Eact (meta) d.) Eact (para)

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 103

Aromatic nucleophilic substitution reactions

SNAr mechanism

a) Cl

NO2

+ OC2H5

slow

NO O

OC2H5Cl

OC2H5Cl

NO2

OC2H5Cl

NO2

OC2H5Cl

NO2

fastreaction

NO2

OC2H5

- Cl



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 104

The SNAr goes through an intermediate!

E

z

Meisenheimer complex

Reactivity for the halogens: F>Cl~Br>I

An example: Cl

NO2

NO2

+ (CH3)2NH

N(CH3)2

NO2

NO2



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 105

b)

An example: the Balz-Schiemann reaction

NN

+ N2

slow fast

Y

Y

NN

+ N2

fastFNH2

1. NaNO2 / HCl

2. NaBF4

BF4

+BF3



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 106

Electrophilic , or nucleophilic reagent

proton, or halogenide as leaving group



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 107

SE2Ar

SN2Ar

Wheland intermediate

Meisenheimer intermediate

Cl

NO2

+ NO2

Cl

NO2

O2N H

Cl

NO2

NO2

+ BH

Cl

NO2

+ OH

Cl OH

NO2

OH

NO2

+ Cl



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 108

Fused polycyclic aromatic hydrocarbons



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 109

Fused polycyclic aromatic hydrocarbons

Resonance structures are not equivalent ones.

Naphthalene

1

2

3

45

6

7

8

C1-C2 = 1.36 Å

C2-C3 = 1.42 Å Resonance energy: 61 kcal/mol



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 110

Anthracene 1

2

3

45

6

7

8

9

10

Br2

BrH

H BrResonance energy: 84 kcal/mol

Phenanthrene

1

2

3

4

5

6

7

8

9

10

Resonance energy: 92 kcal/mol



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 111

H H H

indene

pKa ~ 20

indenide anion

10 electrons

H H H

fluorene

pKa ~ 23fluorenide anion

14 electrons

base

base



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 112

Naphtalene Anthracene Phenantrene

Chrysene Pyrene

Tetracene Coronene



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 113

Fused polycyclic hydrocarbons

45

1

2

36

7

8

SEAr

1. The first substituent goes into position 1.

2. Where does the second substituent go?

- if the first substituent is at position 1 and activating

it goes into position 4.

- if the first substituent is at position 2 and activating

it goes into position 1.

3. If the second substituent is deactivating (or halogen atom)

it goes into position 5 or 8 at the other ring



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 114

80oC

H2SO4

140oC

H2SO4

140oC

H2SO4

SO3HH

SO3H1

2

3

45

6

7

8

1-naftalinszulfonsav 2-naftalinszulfonsav

Kinetic vs. thermodynamic control



1-naphtaline sulphonic acid 2-naphtaline sulphonic acid

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 115

Addition reactions Hydrogenation

Birch reduction

Na/NH3

C2H5OH

H2/NiHH

HH

tetraline1,4-dihydro-naphthalene

Pt, high pressure

H

Hcis decaline

H

H

trans decaline



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 116

Fluorene

CHCH2

9

8

7

6 5 4 3

2

1

D

KOH

K

O

CH3COOH

Na2Cr2O7

fluorenone



14 π electrons

aromatic

pKa = 23

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 117

Isolated polycyclic aromatic compounds



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 118

Isolated polycyclic aromatic compounds

1. Biphenyl derivatives

45o 135o 225o 315o

A

B

A

B

Atropisomerism:

e.g., A = COOH; B = NO2

2. Di- and triphenylmethane

Compound Conjugate base pKa

benzene 43

toluene 41

diphenylmethane 34 CH

CH2



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 119

R S

HOOC

Br

COOH

Br6 '

2 '

6

2

COOH

Br

HOOC

Br

tükörsík

C

Br

COOHBr

1

2

3 4

HOO c2COOH

Br

BrHOOC

c2

1

2

34

Axial chirality - atropisomerism



mirror

2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 120

Compound Conjugate base pKa

triphenylmethane C

31

Ph3CH NaNH2 Ph3C Na

sodium triphenyl

methanide

Ph3CCl Ph3C Cl

trityl cation

trityl chloride

Ph3CCl R CH2OH Ph3C O CH2R alkyl trityl ether

H2/Pd

or H

R CH2 OH

R C H O H

R '

R C

R ' O H

R " there is no reaction



2011.11.27.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 121

2

aril-halogenid

Hlg

R

2 Cu/D

CuHlgR R

2 Cu/DHSO4

R

N N

2

arildiazónium-

hidrogénszulfát

N2 + Cu HSO4

3 C6H6 + CHCl3AlCl3

3 HCl(C6H5)3CH C6H5CHCl2 + C6H6

AlCl3

2 HCl

Biphenyl and triphenylmethane



arylhalogenide aryldiasonium-

hidrogensulphate

Documents

Consortium leader 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 ***