PETER PAZMANY CATHOLIC UNIVERSITY Consortium members

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

Compounds with halogen, oxygen and sulfur

(Halogén-, oxigén-, és kéntartalmú vegyületek)

Organic and Biochemistry

(Szerves és Biokémia )

Compiled by dr. Péter Mátyus

with contribution by dr. Gábor Krajsovszky

Formatted by dr. Balázs Balogh

Table of Contents

1. Halogenated hydrocarbons 5 – 34

2. Alcohols and phenols 35 – 48

3. Ethers 49 – 57

4. Hydrocarbons with sulphur 58 – 70

SUBSTITUTED

HYDROCARBONS

SUBSTITUENT: HALOGEN

HALOGENATED HYDROCARBONS

1. Structure:

Substrate Bond

length (Å)

Homolytic

dissociation energy (kcal/mol)

Alkyl-F 1.38 116

Alkyl-Cl 1.77 81

Alkyl-Br 1.91 66

Alkyl-I 2.21 51

1.69 104

60 1.86

CH₂ CH

C

H₂ Cl

Br CH

C H₂

Cl CH

C H₂

p_z p_z p_z

sp² sp²

hlg

-C -C

H₂C CH hlg 4

H₂C CH hlg H₂C CH hlg

2. Physical properties:

a.) good solvents: for lipids with narcotic effects b.) boiling point > hydrocarbons

!

phosgene diethyl carbonate

toxic

detoxification

CHCl

CHCl

O

h C O

Cl

Cl

EtOH C O

H

C

O

H

C

O

Biological properties:

- narcotic effect

- polychlorinated products are toxic

fluothane

F

C CHBrCl

reaction ΔH = -BDE (products) - [ -BDE (reactants)]

Radical reactions Thermochemistry I.

Halogenation of methane

BDE (kcal/mol) F—F → 2 F^• 38

Cl —Cl → 2 Cl^• 58 Br —Br → 2 Br^• 46 I —I → 2 I^• 36 H —F → H^• + F^• 136 H —Cl → H^• + Cl^• 103 H —Br → H^• + Br^• 87 H —I → H^• + I^• 71

H₃C—F + X^• → H₃C^• + HX (1) chain

X—X + ^•CH₃ → X^• + CH₃—X (2) propagation

Preparation of alkyl halides

by radical reaction

Radical reactions Thermochemistry II.

R—H BDE (kcal/mol)

H₃C—H 104

1° C —H 98

2° C —H 94

3° C —H 91

H₃C —F 108

H₃C —Cl 83

Radical reactions Thermochemistry III.

BDE (kcal/mol) 104 58 83

162 186

ΔH_r = - 186 - (-162) = - 24 kcal/mol The first step of chain propagation for halogenation:

bond ΔH_r

H₃C—H -103-(-104) = +1 -87-(-104) = +17 3° C—H -103-(-91) = -12 -87-(-91) = +4

X = Cl X = Br

103

CH

—H + Cl—Cl CH

Cl + HCl

C H X C H X

The first step of chain propagation is endothermic process, but steps (1) and (2) together make the process exothermic.

Bromo radical is more selective radical, than chloro.

Radical reactions Thermochemistry IV.

X X + CH₃ H₃C X + X CH₄ + X CH₃ + HX

(2) (1)

Energy profile of the chain propagation steps of halogenation:

+33 +17 +1

0

-100

I

13

Br -7 Cl

-25

F

-102

F₂ → extremely reactive → explosion I₂ → endothermic → does not react Cl₂ → high reactive → is not selective Br₂ → sluggish → selective (with reactive substrate only)

Radical reactions Thermochemistry V.

CH₃ CH₂ CH₃

Cl₂

Br₂

CH₃ CH₂ CH₂Cl 45 % CH₃ CH₂ CH₃ 55 %

Cl

CH₃ CH₂ CH₂Br < 1%

CH₃ CH CH₃ Br

> 99 %

Summary

Alkylation reactions 1. RX

OEt

OH R—OH

2. RX R—OEt

3. RX SEt

R—SEt 4. RX NH₃

R—NH₂

5.

RX R¹R² NH

R N

R¹ R²

RX Ph₃

P [Ph₃P—R]X 6. RX N₃

RN₃ 7. RX CN

RCN (+ R–C=N:)

8. RX

HC

EWG

EWG RC

EWG EWG

9. RX

HN C

O N C

O R

+

N C

OR

10. RX

NO₂

R—NO₂

Further alkylation reactions

1 1 . R - X

1 2 . R - X

1 3 . R - X

1 4 . R - X

H R H

R H l g

R C C R '

R O C O

R ' H l g

C C R '

O C O

R '

Grignard reaction

CH₃I + Mg Et₂O

CH₃ Mg I

O Mg Et

Et

R

X

O Et Et

CO₂ H₂O

R H R COOH

C OH R² R

R¹

C O R¹

R²

Aliphatic nucleophilic substitution

S_N1 and S_N2 alkylation ^{R X + Y R Y + X}

nucleophilic X nucleofugic

S_N1

C Cl

HO slow HO + C + Cl

fast

HO C + C OH + Cl

S

2

inversion

HO +

C Cl



C

HO- Cl-

C HO

intermediate

reaction coordinate E

S_N2

The height of the barriers depends on the substrate considerably!

S_N1





1 

2

1^o 2^o 3^o

CH₃Cl H₃C C

CH₃ CH₃

Cl S_N1

S_N2

CH Cl H

C

H

C

E2 reaction

C C

H

Cl

HO + C C + H₂O + Cl

CH X

C C

H₃C H

H

H H

H base with increased spatial requirements base with decreased

spatial requirements

Reaction:

Mechanism: Step 1.

H ₃ C C C H ₃

B r

C H ₂ C H ₃ E t O H

H ₂ C C C H ₃

C H ₂ C H ₃ + C C H ₃ C

C H ₃ H ₃ C

H

2 5 % 7 5 %

H

C C C H

B r

C H

C H

H

C C C H

C H

C H

+ B r

slow

Step 2.

H₃C CH₂ O H fast

"Hofmann"

H₂C C CH₃

CH₂ CH₃ H₃C CH₂ O H +

H CH₂ C CH₂ H CH₃

CH₃

H₃C CH₂ O H

"Zaitsev"

H₃C C C

CH₃ H₃C

H H₃C CH₂ O H +

H H CH fast

CH₃

C CH₃ CH₃

S

1, S

2, E1, E2 reactions

CH₃X RCH₂X RCHX R

R C X R

R

methyl 1

2

3

bimolecular mechanism (S

2 or E2) S

1/E1 or E2 S

2 mainly S

2, but

strongly hindred B : E2

weak base

(I , Cl , CN ): S

2 strong (RO ):

E2

S

2 ø

solvolysis: S

1/E1 (low T, S

1) strong base (RO ):

E2

Solvent effect

A more polar solvent increases G , if the transition state is less polar, than the starting material.

A more polar solvent decreases G , if the transition state is more polar, than the starting material.





H H H

O H I H

H

H H O

H I H



 H

H H

S_N2 I H₂O

transition state

CH₃ H H N I

Et EtEt

N Et EtEt

C H H

CH₃

 I

N Et

EtEt CH₃ HH

I

transition state S_N2

starting material

starting material

The energy of an alkyl halide is approximately

the same either in polar The transition state is more polar, than the

starting material; a polar solvent can decrease the energy needed for cleavage of the bond by solvation, thus the activation energy is smaller in the case of a polar solvent

activation energy

 

R X

R X

R X

R X

Increasing polarity by ionisation (protic conditions):

S_N1, E1 E2

product distribution:

nucleophilicity/basicity

Aprotic, polar:

S_N2, E2

1° alkyl halogenide

3° alkyl halogenide

2°: according to the nucleophilicity/

/basicity of the reagent

Aromatic halogen compounds

1. S_EAr → substitution of the core

FeCl₃

Cl₂ H Cl

Cl

2. Derivatives halogenated in the side-chain:

R CH₂Cl CH

 h Cl₂ CH₃

OCH₃ ZnCl₂

H O C H OCH₃

Reactivity of halogen compounds toward nucleophiles

group 1.

Alkyl halogenides, benzyl chloride

group 2.

Acid halogenides, e.g.,

group 3.

Phenyl (and aryl) halogenides, e.g., Ph-Cl halogen-ethenes, e.g.,

H₃C C O

Cl H₃C C

O

Cl

H₂C CH Cl H₂C CH Cl

a) _{H2C CH CH2 Cl} ^{- Cl} H₂C CH CH₂

H₂C CH CH₂ H₂C CH CH₂ Z + Z

slow

fast

CH₂ CH₂ CH₂ CH₂

It is analogous stabilization with the allylic cation.

c.p. benzyl radical with allylic radical c.p. benzyl anion with allylic anion

N O

O

Br h

N O

O

+ Br

N O

O

Br N

O

O

H + Br

+ HBr

Aliphatic and aromatic hydroxy compounds:

Alcohols and phenols

Classification:according to the order of the carbon atom bearing the OH group(c.p., with alkyl halogenides)

- Substitutive nomenclature

The principal group is the OH.

As a suffix: -ol

As a prefix : hydroxy

H₃C (CH₂)₃OH n-butanol

primary

H₃C

CH H₃C

OH isopropanol secondary

H₃C C H₃C H₃C

OH tert-butanol tertiary

H₂C CH CH₂ CH₂ OH buta-3-en-1-ol

n-butyl alcohol isopropyl alcohol tert-butyl alcohol 1. Alcohols

(formal)

(R² = H, alkyl...)

2. Phenols

Hydroxyl group(s) is(are) attached to the aromatic ring Nomenclature:

1. Trivial names

OH OH

OH

OH

OH

OH

OH

OH

OH OH phenol pyrocatechol resorcinol hydroquinone pyrogallol

OH

OH HO

OH

CH₃ phloroglucinol cresols (3 isomers)

2. Systematic names

OH

OH

OH

1,2,4-benzenetriol

Chemical properties of alcohols and phenols

1. Acidic strength

mineral acids >carboxylic acids >carbonic acid >phenols >alcohols pKa

H₃C—COOH 4.76

H₂CO₃ 6.3

phenol 9.9

methanol 15.2

- I effect increases acidity (lower pK_a), e.g., halogene substituent - M effect increases acidity, e.g., NO₂ group

Resonance increases acidity, e.g., RCOOH vs. RCH₂OH

Phenol vs. alcohol

Phenolate anion is of greater stability, than alkoxide anion:The negative charge is dispersed

Acidity of phenols is considerably increased due to a -M substituent

O O O O

O O O

O N

H O OH

-H⁺

Alcohols are amphoteric compounds!

Since the pK_a value of an alcohol is about equal to the pK_a value of water, alcoholate can not be prepared in aqueous system.

(pK_a  16, or 15.7)

Alcohols can not be ‘absolutised’ by sodium metal!

oxonium ion conjugated acid

pK_a = 2

R OH + HCl R O H

H

+ Cl

R OH + OH R O + H

O

2. Alkylation Ether formation

Williamson synthesis

Similarly, (CH₃)₂SO₄ could be used for pre-

paration of phenyl methyl ethers.

H₃C CH₂ O Na H₅C₂I

H₃C CH₂ O CH₂ CH₃ diethylether

ONa

C₂H₅I

OC₂H₅

phenetol

phenyl ethyl ether

But: _OH

CH₂N₂ OCH₃

+ N

3. Oxidation

a) Alcohols

oxid.

K₂Cr₂O₇/H₂SO₄/water/15-20^oC J o n e s r . :

C o l l i n s r . :

Swern oxid.: (CH₃)₂SO₄ / oxalyl chloride aldehyde carboxylic acid

ketone

mixture of carboxylic acids (chain cleavage)

mixture of carboxylic acids

ox R CHO ox R COOH R CH2OH

R

CH R

OH oxid. R C R

O

oxid.

R C R

OH R

dipyridine - CrO₃/CH₂Cl₂/20^oC could be

oxidized

R

CH R

OH

p-benzoquinone

oxidizing agents: e.g., K₂CrO₇ / H₂SO₄ Ag₂O

OH

OH

oxid.

O

O

b) Phenols

- tertiary alcohols: narcotics

CH₃CH₂OH euphoria intoxication (3 g/l)

CH₃CH₂OH alcohol

dehydrogenase

H C

O

CH₃ ^aldehyde

dehydrogenase

Disulfiram

C O CH₃

OH

Acetyl

Coenzyme A

e.g., HC C C OH CH₃

CH₂CH₃

CH OH

CH₂N

CH₃ CH₃ R

;

OCH₂ R

CH OH

CH₂N H CH₃

-Adrenoceptor agonists -Adrenoceptor agonists

Absolutisation of ethanol

1. 96% → by azeotropic distillation 2. Removal of traces of water:

• It can not be made by sodium metal! Na + H₂O → NaOH since it is dissolved!

• Mg or CaH₂

Mg + 2 H₂O → Mg(OH)₂ + H₂ CaH₂ + 2 H₂O → Ca(OH)₂ + 2 H₂

these hydroxides are not dissolved in alcohol

diprivane iv. anesthetic agent

Cl Cl

Cl OH

TCP antiseptic agent

HC CH

OH CH₃ CH₃ H₃C

H₃C

HO HO

CH OH

CH₂NHR

R = CH₃ adrenaline

H noradrenaline

HO HO

CH₂ CH₂NH₂ dopamine

ETHERS

Two hydrocarbon groups with one free valence are connected by an oxygen atom.

R O R,

derivatives of water/alcohols/phenols

1. a. R = R’ simple ethers v.

b. R  R’ mixed ethers 2. a. Aliphatic or

b. Cyclic

Nomenclature

1. Radicofunctional nomenclature

2. Substitutive nomenclature

CH₂CH₂OH O

CH₃

2-methoxyethan-1-ol 3. Cyclic ethers

H₃C CH CH CH₂OH

O a)

epoxide 2,3-epoxibutan-1-ol

b) for larger rings: name the heterocycle

• only as prefixes, then the name for the RO- group is:

alkoxy, aryloxy

H₃C CH₂ O CH₃ ethyl methyl ether

H₃C

dimethyl ether O CH₃

• Trivial names

anisole guaiacol verathrol

OCH ₃ OCH ₃

OH

OCH ₃

OCH ₃

Ethers, as protected derivatives of alcohols:

1. Trityl ethers (prepared from 1^o alcohols only)

2. Tert-butyl ethers

Ph₃C Cl + R CH₂ OH pyridine - HCl

R CH₂ O CPh₃

H₂ / Pd or H

H₂C C

CH₃ CH₃

+

R OH Ph OH

or

H₂SO₄ R O Ph O

or

C(CH₃)₃ C(CH₃)₃

HI

Physical properties of ethers:

- Boiling point alkanes ~ ethers < Alcohols Reason:

There are H-bridges in alcohols.

- Conformation: similar to that of alkanes

O

The bond angle of oxygen is very close to of the CH₂.

- Dipole moments: ethers > alkanes (the C-O bond is polar)

R O H

R O H

R O H

Chemical properties of ethers

Ethers are stable in diluted acid, except for the epoxides or vinyl ethers.

Cleavage of ethers:

R O R'

HI R

R' O H Nu R OH

R' Nu + OR

AlCl₃ OH

+ RCl H₂C CH₂

O

+ H₂O H

CH₂ CH₂

HO OH

+ H₂O H

H₂C CH OR H₃C C

O H

+ ROH

More important ethers: are used as solvents

OR CH₂ CH₂

HO

Ethylene glycol monoalkyl ether

OR CH₂

CH₂ RO

„monoglyme”

CH₂ OR CH₂

CH₂ O CH₂

RO

„diglyme”

O

Crown ethers

18-Crown-6 12-Crown-4 15-Crown-5

„Host-guest”

Additional types:

cryptand cryptate (containing N) podand open-chained bi- or polycycles,

but bending toward each other lariate crown ether + side chain

Na O O O

O O Li

O O

O O

K O

O

O O O

O

Compounds containing C-S bonds Thiols (thioalcohols and thiophenols) Thioethers or sulfides

- disulfides - sulfoxides - sulfones

- sulfonic acids Nomenclature

CH₃SH

HSCH₂CH₂OH PhSH RS^– CH₃SCH₃

methanethiol

2-mercaptoethanol 2-sulfanylethanol

thiophenol benzenethiol

thiolate (c.p., with alcoholate)

dimethyl sulfide (c.p., with ethers)

As a prefix: alkylthio-, arylthio- (c.p., with alkoxy-, aryloxy-);

alkylsulfanyl-, arylsulfanyl is prefered

CH CH H C S CH H C S CH

O

H₃C SO₃H

H₃C SO₂Cl

methanesulfonic acid

methanesulfonic acid chloride (mesyl chloride)

SO₃H

benzenesulfonic acid SO₃H

H₃C

4-toluenesulfonic acid SO₂Cl

H₃C

4-toluenesulfonic acid chloride (tosyl chloride)

1. Acidity

H₂S HS 7.0 H₂O HO 15.7 RSH RS 10-11 ROH RO 16-17 ArSH ArS 6-8 ArOH ArO 8-11

pK_a

Thiols are poorly soluble in water (there are no H bridges).

2. Solubility

R S R'

O

R S R' O

R S R' O

O

2 R S R'

O

O

R S OH O

O

2 R S OH

O

O

Reactions

R SH R S

O

O

OH [O]

thiol sulfonic acid

SH CH₂

C H₃

2 H₃C ^CH2 ^S S CH₂ CH₃

ethanethiol diethylsulfide

HOOC CH CH₂ SH HOOC CH CH₂ S S CH₂ CH COOH [O]

2

[O]

[H]

More important representatives H₃C S CH₃

O

„DMSO” dimethyl sulfoxide

it is an excellent aprotic solvent (for S_N2 reactions) But: it is a teratogenic compound

mesylate

tosylate Excellent leaving groups in nucleophilic substitution reactions:

tosyloxy, mesyloxy H₃C SO₂ OR + Nu H₃C SO₃ + RNu

H₃C SO₂Cl ROH

base H₃C SO₂ OR

base

H₃C SO₂Cl ROH H₃C SO₂ OR

-Naphthol -Naphthoic acid

H₂SO₄ NaOH

SO₃Na

methionine

cysteine amino acids cystine

saccharin (+)-biotin (Vitamine H)

(Z)-ajoene

NH N

H

S

O

OH

H H

H

S O

C S

H₂ CH₂

S

CH CH₂ C

H₃ CH₂ CH₃

NH S

O

O O

NHOS ₃Na

NaCN

NaOH

CN

160 °C OH 95 % H₂SO₄

SO₃Na 80 °C

100 % H₂SO₄

H SO₃H

NaOH ^COOH

Z 1. NaHSO₃

2. NH₃

NH₂

Sulfonamides

- biosynthesis of folic acid is blocked by them in bacteria

NH₂

COOH

NH₂

SO₂NH₂

NH₂

SO₂NH

N N

OCH₃

Quinoseptyl

X ClSO₃H

X SO₂Cl ArNH₂