Organic and Biochemistry

(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)

Heterocycles: ‘heteroatom is the lord of the rings’

(Heterociklusok: 'heteroatom a gyűrűk ura')

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

(3)

Heteroaromatics

(5)

Heterocyclic compounds

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

- Saturated - Unsaturated Classification:

- number of the ring member atoms - heteroatoms

- number of the heteroatoms - quality of the heteroatoms

(6)

Heterocyclic compounds

Cyclic compounds with at least two different atoms in the ring - inorganic heterocycles: do not contain carbon atom

- organic heterocycles contain at least one carbon atom in the ring

all elements except the alkali metals may serve as ring atoms. All organic heterocycles can be derived from the appropriate carbocyclic compounds by replacement of CH₂ or CH groups by heteroatoms. 4 types of monocycles can be distinguished:

saturated systems, partially unsaturated systems, systems with the greatest possible number of noncumulated double bonds (heteroannulenes), heteroaromatics.

HN B N

H B B NH

borazine

(7)

Saturated heterocycles (‘heterocycloalkanes’)

cyclohexane

X

X = O oxane

S thiane

NH piperidine

Y X

X = Y = NH: piperazine X = O; Y = NH: morpholine Partially saturated heterocycles (‘heterocycloalkenes’)

cyclohexene

X X = O:

3,4-dihydro-2H-pirane

Y X

X = Y = O:

2,3-dihydro-1,4-dioxin Organic and Biochemistry: Heterocycles

(8)

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 Organic and Biochemistry: Heterocycles

(9)

Annulenes

Unsubstituted monocyclic hydrocarbons with the greatest possible number of noncumulated double bonds. Their general formulae

C_nH_n (n>6, even number) C_nH_n+1 (n>6, odd number)

1

2 3 4

6 5 7

8

9 10

[10]annulene

9 8

7 6

5

4 3

2 1

1H-[9]annulene

‘[6]annulene’

benzene

(10)

* heteroaromatic compounds (heteroarenes) - follow the 4n+2 Hückel rule

- have many properties comparable to their carboaromatic analogues

(11)

Nomenclature of heterocyclic compounds

- Hantzsch - Widman’s system: up to ring size of 10 (for larger systems replacement nomenclature is recommended) prefix: indicating the type of heteroatom + suffix indicating the ring size

O oxa

S thia

Se selena

Te tellura

N aza

P phospha

…

B bora

decreasing priority

List prefixes showing heteroatoms, with the appropriate multiplying member, in the given order (numbering of the ring follows this list).

(12)

Element Valen ce

Prefix Element Val ence

Prefix

Oxygen II oxa- Stibium III stiba-*

Sulphur II thia- Bismuth III bisma- Selenium II selena- Silicium IV sila-

Tellure II tellura- Germanium IV germa- Nitrogen III aza- Stannum IV stanna- Phosphorus III phospha-* Plumbum IV plumba-

Arsenium III arsa-* Borone III bora-

Mercury II mercura-

Hantzsch - Widman system (1979)

*with -yne or ene, instead of phospha, arsa, and stiba, phosphor- arsen, and stibium, respectively, must be written.

(13)

R in g size C on tain in g n itrogen N ot con tain in g n itrogen

u n satu rated satu rated u n satu rated satu rated 3 (tri) -irin e -irid in e -iren e -iran e

4 (tetra) -ete -etid in e -ete -etan e 5 (p en ta) -ole -olid in e -ole -olan e

6 (h exa) -in e -in an e -in e -an e 7 (h ep ta) -ep in e ^* -ep in e -ep an e 8 (octa) -ocin e ^* -ocin e -ocan e 9 (n on a) -on in e ^* -on in e -on an e 10 (d eca) -ecin e ^* -ecin e -ecan e

* Expressed by the prefix „perhydro” to the name of the corresponding unsaturated compound.

(14)

- Numbering: O < S < N

(oxygen has the lowest possible number)

according to the priority order of O > S > N

heteroatom gets the lowest possible number substituted N (vs. double bonded N)

- to be defined: ‘indicated’ H: 1H….

- hydro (dihydro, tetrahydro etc.) - partially saturated systems

carbonyl: ‘-one’

(15)

Indicated/added hydrogen

a) indicated hydrogen: marking position of the ‘extra’ hydrogen atom which can occur at different positions; it is in front of the name, and it must be assigned the lowest possible locant.

N¹

2

4 3

5 3H-pyrrole

b) added hydrogen: it must be used because of the presence of a structural change in the ring described either by suffix or by prefix: it is in brackets, after the number describing the position of the suffix or prefix, and it is of lower priority than the heteroatoms

N HN

O

3(2H)-pyridazinone

(not 6(1H)-pyridazinone) Organic and Biochemistry: Heterocycles

(16)

Heteroaromatic compounds

There are two types:

A. having π-electron excess: π-excessive heteroaromatic compounds B. having π-electron deficiency: π-deficient heteroaromatic compounds A. Formal derivatization:

average π-electron density is higherover the carbon atoms than in benzene

X = O, S, NR, PR, Se, Te

B. Formal derivatization:

average π-electron density is lowerover the carbon atoms than in benzene

Y = N, O⁺, Sb, As

>1 >1

>1

--

>1 >1

X

1

1 1

1

<1

Y

<1

(17)

Physical properties

1. Dipole moment

A. π -excessive heteroaromatic compounds

dipole moment of this type of heteroaromatic compounds is smaller, than that of the perhydro derivative (with the exception of pyrrole!)

B. π -deficient heteroaromatic compounds

dipole moment of this type of heteroaromatic compounds is greater, than that of the perhydro derivative.

Examples:

O O N

H N

1.68 D 0.71 D 1.57 D 2.20 D

(18)

2. Solubility in water

A. pyrrole > furane > thiophene 6 % 3 % 0.1 % B. pyridine, pyridazine >> pyrimidine, pyrazine Chemical properties

A. having π-electron excess

electrophilic substitution is easier

nucleophilic substitution is more difficult B. having π-electron deficiency

electrophilic substitution is more difficult nucleophilic substitution is easier

(19)

Five-membered heterocyclic compounds

(20)

pyrrole furane thiophene

pyrazole imidazole oxazole

thiazole isoxazole isothiazole

N H

N N H

N S

O S

N N H

N O

N S

(21)

Azoles and other five membered rings

These can be derived from heteroaromatic compounds with at least one heteroatom through replacement of a CH by a N. Azoles are 5-membered heterocyclic compounds containing at least one nitrogen and the greatest possible number of noncumulated double bonds in the ring

N is of basic character Totally 24 systems are possible

X X

N

CH → N

(22)

Z = NH

pyrazole

O

isoxazole

S

isothiazole

Z = NH

imidazole

O

oxazole

S

thiazole

Z = NH

triazole

O

oxadiazole

S

thiadiazole

Z = NH

tetrazole

O

oxatriazole

S

thiatriazole 1,2,3

1,2,4 1,2,5 1,3,4

1,2,3,4 1,2,3,5

semmelweis-egyetem.hu

N Z

N N Z

N Z

N N N Z

(23)

CH₂ CH^* COOH NH₂

N N

H

CH₂ CH₂ NH₂

N N

H

CH₂ CH^* COOH NH₂

N H

CH₂ CH₂ NH₂

N H O

H

histidine histamine

trypthophane serotonine

(24)

N S

O

COOH CH₃ CH₃ H

H NH C

R O

β-lactame thiazolidine penicyllines

N O

O

COOH

CH CH₂ OH

NH NH

azetidine 2-azetidineoneO

clavulanic acid (in: Augmentine)

(25)

Chemical properties

Aromaticity

Scales of many types Generally

benzene > thiophene > pyrrole > furane Reactivity

- electrophilic attack on one of the carbons of the ring

→ substitution

- electrophilic attack on the heteroatom: seldom happens, except for the pyrrole anion

- nucleophilic attack only by cations - Diels-Alder (‘measure of aromaticity’)

(26)

Electrophilic substitution

Directing: ‘α-effect’

position α is more reactive, than position β

α β

In solution:

furane > thiophene > pyrrole Reason: complex formation happens with furane

However: more β-substitution takes place in the case of thermodynamic control (high temperature, acid catalysis)

-there is a tendency for migration!

Br, Cl, acyl, RSO, RSO

X

H

E X

H E

(27)

Electrophilic substitution

Relative reaction rates

Ac₂O/SnCl₄ acetylation (25°C)

1 11.9

COCl₂/DMF formylation (30°C)

1 107.0 thiophene

furane Substituent effect

Similar to the situation with benzene, e.g., NO₂, COOEt are deactivating substituents, while CH₃ is activating.

[b] condensed benzene ring is deactivating, with directing into position β.

(28)

E R X

R X E

R is electron releasing (activating) substituent

X

R E

X R X E

R E

R X R X E

R X

E

X = O R is electron withdrawing (deactivating) substituent

X = NR, S

(29)

Reaction types for electrophilic substitution

Acid sensitivity (thiophene is the least sensitive)

halogenation, sulfonation, Friedel-Crafts, formylation Reimer-Tiemann

Houben-Hoesch Gattermann

R

X

R

X E

E

R is electron withdrawing (deactivating) substituent

OH CHO ONa HCl

NaOH CHO CHCl₃

OH

RCN HCl

ZnCl

₂

R

O CO HCl

AlCl

₃

CuCl

CHO

(30)

Reagent

SO₂Cl₂ 0 °C pyrrole

Cl₂ -40 °C furane

MeCONHCl thiophene

pyridine•SO₃ furane/pyrrole

H₂SO₄ thiophene

RCOCl/SnCl₄ thiophene

furane

1-protected pyrrole Y = Cl

SO₃H

R-CO

X X Y

(31)

Deprotonation

A.) from the N of pyrrole

Pyrrole is much less basic, than secondary amines are.

N N N

e.g., RMgX, BuLi, NaNH₂ -H

NH

NM gX

N N COCH₃

H

RMgX

H Ac₂O

NH N

CH₂ PhCH₂Br

KOH/DMSO indole

(32)

B.) Deprotonation of ring carbon atom

There can be a side reaction: ring opening X

BuLi

X Li X= NR, O, S

X E

E CH₃ COOH E= CH₃( CH₃I)

CO₂

(33)

2. Reaction of protonated cations with nucleophiles pyrrole, furane, thiophene form polymers in mineral acids and/or ring opening may occur 3. Reaction of halo derivatives with nucleophiles

(e.g., with CH₃O^-, in the presence of piperidine)

N H

Cl

unreactive

O Cl low reactivity

NH

NO₂

Br Br S NO₂

10 times faster more reactive than the benzene analogue

1000 times faster more reactive than the benzene analogue

(34)

X = Br, I

base: NaNH₂ / liquid NH₃/ N Ph CH₃ K

Analogous reaction:

‘Halogen dance’

S X

strong base S

_E

1 mech.

S

X

Br Br

Br

Br Br

KNHPh

(35)

Diels-Alder reaction

X = N-R(poor yield)

O (easy reaction with high yield)

S (it reacts)

X

R C C R

X

R

(36)

Benzo-fused systems

X 1

2 3 4

5 6

7 (β) (α)

X = NH indole

O benzo[b]furane S benzo[b]thiophene

electrophilic substitution: decreased reactivity Annelation effect:

X = NH β/α >> 1

O β/α < 1

S β/α > 1

(37)

Synthesis of indole:

1. Fischer synthesis:

Preparation of tryptamine:

NH N C

CH₂-R

R N

H R R ZnCl₂

-NH₃

* Δ

tryptamine

red.

NH

CH₂N(CH₃)₃

KCN CH₃I I

NH

CH₂CN gramine

(CH₃)₂NH N H

CH₂N

CH₃ CH₃ NH

NH

CH₂CH₂NH₂ HCHO

(38)

Six-membered heteroaromtic compounds

(39)

Systems with π-electron deficiency

1. Pyridine

N

N N

N N N

(40)

Derivatization

and so on

pyridazine pyrimidine pyrazine 1,2,3

1,2,4 triazine 1,3,5

1,2,3,5- tetrazine

N N

N

N N N

N N N N

H

N H

N - H⁺

(41)

Oxygen analogues: there are many!

1,2-oxazinium (aromatic)

2H-1,2- oxazine

6H-1,2- oxazine

4H-1,2- oxazine pyrilium

(aromatic)

2H-pyrane 4H-pyrane

H

O

3

2 4

O

1 5

6 H

H

3

2 4

O1 5

6

H H +H^-

N O

3

N

2 4

O

1 5

6 H

3

N2 4

O

1 5

6

H H

3

N2 4

O1 5

6

H H +H^-

(42)

Nitration / sulfonation

cf. with nitration / sulfonation of

nitro-benzene But:

(43)

Nitration

a.) It takes place through the conjugate acid, it is very difficult (~ 300°C) might be facilitated by electron releasing groups

b.) Nitration takes place without protonation of the ring nitrogen, if the starting material is a very weak base; it is not so difficult

(44)

Nucleophilic substitution N-nucleophile

C-nucleophile

alkylation (Ziegler’s alkylation)

Tchitchibabin’s amidation

(45)

Representatives:

1. N SO ₂ N

R-COCl R-SO or ₂ -Cl

R

N

O Cl

R

Cl a vigorous

acylating agent sulfonylating agent

it is even better to use 4-(dimethyl-amino)-pyridine

(46)

2. Pharmaceutical industry

Isonicotinic hydrazide (INH)

nicotine

Ca

²⁺

antagonist

nicorandil CONHNH

₂

N

N CH

₃

N

N H Ar

COOCH

₃

CH

₃

H

₃

C H

₃

COOC

C NH ONO

₂

N

O

(47)

N

C H₂ H₃CO

H₃CO

OCH₃

papaverine

N1 2 8

5 4

3 6

7

quinoline

N²

1

3 4

8 5 6

7

isoquinoline

N

10 9

5 4

8 1

6 3

2 7

acridine

(48)

cromane

vitamine E

2-phenylcromone trivial name: flavone

O

Ph O

3-phenylcromone isoflavone

ipriflavone (Osteochin

^®

)

O

Ph O

O

(49)

Aromaticity

Aromaticity is decreased by ring oxygens, by increasing number of heteroatoms, by benzo-annelation, and/or by presence of a carbonyl group, in these cases there is increased tendency for addition reactions.

(50)

Diazines

1. Synthesis Principle: ‘fragment formation’

[4+2] [3+3]

E.g.,

N N

N

pyridazine pyrimidine pyrazine

N N

N N N

N N

N N N

(51)

a) pyridazines [4+2]

*γ-oxo carboxylic acids + N₂H₄

*γ-dioxocompounds + N₂H₄

O Ph Ph

O + N₂H₄ H₂O

Ph Ph

N N CH₃

O OH O

+ N₂H₄ H₂O 1. cond.

2. oxid.

CH₃ N NH O

(52)

b.) pyrimidines [3+3]

*β-dioxocompounds + urea / amidine

NH

₂

CH=NH H

₂

NC NH

₂

O

H

₃

C

CH

₃

H

₂

C

O O

O CH

₃

N

NH H

₃

C

CH

₃

N N H C

(53)

c.) pyrazines [4+2]

α-dioxocompounds + 1,2-diamines

Chemical properties

pyridine 5.2

pyrazine 0.4

pyrimidine 1.1 pyridazine 2.1 pK_a

1. cond.

2. oxid.

CH₃ CH₃ H₃C

H₃C

N N CH₃

CH₃ O

H₃C O H₃C

NH₂

+

(54)

Electrophilic substitution

pyridazine / pyrimidine:

activating group(s) and/or vigorous conditions are needed!

100 % HNO₃

1

2 3

4 5 6

H₃C

Cl Cl O

N N

NO₂ Cl Cl O

N N H₃C

2 1

3 4

5 6

HNO₃ O Δ

H₃C O N

N CH

NO₂ O

O H₃C

N N CH₃

(55)

Nucleophilic substitution a.)

Chichibabin reaction

b.)

Nucleophilic reactions proceed well with various halogen derivatives

N X

NH₂ N

X

X= CH, N NaNH₂

NH₃

CH₃ N

N NH₂

CH₃ N NH₂ N

decaline Δ

(56)

Reactivity of diazines toward 4-nitrophenoxide

~ ~

N N N Cl

N

Cl N

N Cl

N

>

N

Cl N

>

N Cl

N N Cl

Cl

H₃CO N N Cl

Cl NaOCH₃

room temp.

(57)

Mechanism:

enhanced reactivity than in cases of benzene derivatives 1. Addition-elimination (AE)

negative charge can appear on the nitrogen → stabilisation

X N Nu

N

Nu X N

N N

X Nu

X N Nu

N

(58)

Cl N

NH₂

N N

pyridyne (aryne)

N

NH₂

N NH₂ NH₂

N

NH₂ N

2. Elimination-addition

aryne mechanism; ‘cine-substitution’

Conditions: - the leaving group must be in non-activated position - the entering nucleophile should be a strong base

(59)

3. „Abnormal” addition-elimination (AE

_a

)

Condition: good leaving group as N-substituent

(+ 4-isomer

of small amount)

KCN

CN N

-OCH

₃

H

N CN OCH

₃

N I

OCH

₃

(60)

4. ANRORC

Addition Nucleophilic Ring Opening Ring Closure

Mechanism:

Br N

N Ph

*

KNH₂

NH₂ Ph

N N

*

(83% ANRORC)*

*

NH₂ Ph

N N Br

* NH*

Ph N

NH₂

* Br H₂N

H

Ph N

N

(61)

5. Vicarious nucleophilic substitution (VNS) of hydrogen

Conditions: electrophilic aromatic system, and stable carbanion containing the leaving group.

H N

NO₂

CH₂SO₂Ph

-HCl

CH-SO₂Ph NO₂

N base

Cl ClCHSO₂Ph

CH₂SO₂Ph H

N

NO₂ NO₂

N

(62)

b)

N N N

ClCH

₂

SO

₂

Ph

KOH/DMSO H

₂

C

SO

₂

Ph N N N

(63)

Tautomerism

it is a special type of isomerism

* spontaneous reversible isomerisation tautomerisation

* in a broader scope: any type of reversible isomerism belongs to here

Varieties: 1. Oxo-enol

(64)

(65)

2. Carboxylic amide-imidoic acid and similar systems a.)

b.)

(66)

Tautomerisation - heterocycles

1. Prototropic X = O, S, (NH) it depends on the solvent!

(67)

(68)

γ-pyrone it is closer to this!

(aromatic resonance structure)

4-hydroxy-

pyrilium cation

(69)

polar medium gas phase

(70)

Summary:

1. X = O, S are similar to each other - in polar medium (oxo-, or thioxo form is the dominant one, except for 3-X-pyridine)

50%

2-X-pyridine / 4-X-pyridine

2-X-pyrimidine / 4-X-pyrimidine 2-X-pyrazine

3-X-pyridazine 4-X-pyridazine 2-X-imidazole

- in vapour phase: hydroxy/thiol form is the dominant one 2. X = NH₂ amino form is the dominant one

(71)

Halogenated pyridines a.)

b.)

2- or 4-amino

(72)

2. Ring-chain

OH

C O H

c.p., with carbohydrates cyclohemiacetal

5 4

3 2

1

O O

H H

H S H₃C

O

OH (CH₂)_n N N

N C O

H (CH₂)_n S

H₃C O

N NH N

(73)

3. Substituent tautomerisation

4. Valence isomerisation valence tautomerisation

N O C O

CH

₃

N O

O C CH

₃

N N

N N N N

N N

(74)

Dimroth’s rearrangement

N N CH₃

NH₂

HO

N N CH₃

NH₂ HO

N H N

OH CH₃

N N

NH CH₃

I NH₂

N HCl S

NH CH₂CH₃

SN NH

CH₂CH₃ HCl

X Y

Y X

(75)

Benzo fused diazines/azines

N N

N

cinnoline phthalazine quinazoline

N

N N

quinoline quinoxaline isoquinoline

(76)

Reactivity

1. Electrophilic substitution: on the benzene ring

N N N

43%

47%

N

80%

10%

N N

33%

28%

(77)

2. Nucleophilic substitution

halogenated derivatives of the heterocyclic ring

Azino-diazine: it is a triazanaphthalene derivative

e.g., N N

N

Cl N N POCl₃

NHNH₂ N N N₂H₄ ^.H₂O

NH N O

(78)

Diazino-diazines: these are tetrazanaphthalene derivatives

The most important representative:

pteridine

N N

N

1

N

2

3 4 5

6 7 8

X= OH, R=H folic acid

X= NH₂, R=CH₃ methotrexate N

N

N N X

H₂N

CH₂ N R

COOH

CON-CH(CH₂)₂COOH H

(79)

folic acid

tetrahydrofolic acid folinic acid uracil thymine

synthesis of purine methothrexate

N H

N CH

₂

-NH-

H H

N H

N CH

₂

-N- H O C

(80)

Benzo-fused pteridine: riboflavine Vitamin B

₂

H₃C H₃C

O

NH N

N N CH₂

O HOCH

HOCH HOCH

CH₂OH

(81)

Nucleophilic substitution of halogens

1.

2. 3.

Purine

(7H)-9H-imidazo[4,5-d]pyrimidine (unique numbering)

some important derivatives:

- guanine - adenine - xanthine - theophylline - theobromine - caffeine

Cl Cl

Cl N

N N

NH

1 2

3 4 6 5

7 8 9

N N

N N H

N N

N NH⁹

(82)

uric acid xanthine

R¹ = R² = CH₃, R³ = H theophylline

R¹ = R³ = CH₃, R² = H theobromine

R¹ = R² = R³ = CH₃ caffeine

N H N

H N

H

N O

O N

H N

H

N H O

O

N

N N

N O

O R²

R¹

R³

(83)

Three-membered heterocyclic compounds

ethylene sulfide thiacyclopropane Hantzsch-Widmann name

Radicofunctional name Replacement name

ethylene oxide oxacyclopropane

ethylene imine azacyclopropane

1

2 3

1

2 3

1

2 3

H

O O

NH O

oxaziridine

NH N

dioxirane diaziridine

1

3 2

1

2 3

1 2 3

structural isomers H2C N N

diazomethane

oxirene thiirene 1H-azirine 2H-azirine

1

2 3

1

3 2

O S N

H N

H

2-azirine 1-azirine

N N

H

1

2 3

3H-diazirine

O S H

thiirane

N

oxirane aziridine

Nomenclature

(84)

halohydrin

R CH CH₂ R CO₃H O

R

oxirane derivatives

R CH CH₂ OH

Cl Cl₂ / H₂O

KOH

+HCl R:

Cl

m-chloroperbenzoic acid

perbenzoic acid

HCl

R CH CH₂ Br

Br

Br₂ / CCl₄

Preparation

Ethylene oxide is used for gas sterilisation. It must be diluted with carbon dioxide, otherwise explosive mixture would be formed with air. Peracids are explosive, toxic compounds!

[2+1] intermolecular ring closure

With contribution of atoms from olefin [2] and peracid [1]

(85)

Only singlet carbene (not triplet) is suitable.

Aziridines are carcinogen compounds.

C N

benzonitrile

2H-azirine derivative carbene

N¹

2

3

CH2N2 CH2

e.g.,

halohydrin R CH CH2

OH

Cl R CH CH2

Br

NH3

R CH CH2

SH

Br halothiol H2S

S

R

thiirane derivative +HBr

HBr KOH

R CH CH2

Cl

NH2

haloamine SOCl2

R CH CH2

OH

NH2

aminoalcohol

KOH +HCl

H HCl

aziridine derivative N

R

(86)

C C O

H H

(CH₂)₇COOH CH₃(CH₂)₇

C C

O

H

(CH₂)₇COOH CH₃(CHH₂)₇

C C

H H

CH₃(CH₂)₇ (CH₂)₇COOH oleic acid

CH₃COOH O

20^°C, 3 h one-step syn-addition

C C

O

H CH₃(CH₂)₇

(CH₂)₇COOH H

C C

O

H

(CH₂)₇COOH CH₃(CH₂)₇

H

C C

CH₃(CH₂)₇ H

H (CH₂)₇COOH elaidinic acid

CH₃COOH O

20^°C, 3 h one-step syn-addition

enantiomers

enantiomers 1:1

1:1

stereospecific

Epoxidation with peracid without catalyst

(87)

Asymmetric oxidation of alkenes Sharpless epoxidation

+

COOEt

EtOOC OH

HOH

H

COOEt

EtOOC H

H

OH HO

diethyl tartrate enantiomers

allyl alcohol derivative

H

CH₂OH H

O O

O

O H

CH₂OH H

O

O H

CH₂OH

H O

Ti[OCH(CH₃)₂]₄ (CH₃)₃C O OH

CH₂Cl₂

Ti[OCH(CH₃)₂]₄ (CH₃)₃C O OH

CH₂Cl₂

stereospecific diastereo(enantio-)selective

Knowles, Noyori, Sharpless 2001 Nobel-prize, Chemistry, chiral catalysis Organic and Biochemistry: Heterocycles

(88)

Chemical properties

Baeyer strain is greater for 3-membered rings than for 4-membered ones. As a consequence of this ring opening, reactions are easier for the former ones.

In ointment, lacquer CH₂ CH₂

OH NH₂ O

O δ

NH₃

δ

KOH SOCl₂

CH₂ CH₂

Cl NH₂ KOH

aziridine NH HN

CH₂CH₂OH

O

diethanolamine

N CH₂CH₂OH CH₂CH₂OH

CH₂CH₂OH triethanolamine

(89)

CH CH₂ OH Y

R O

R

H O

R

H

O

R

H

O

R

H

Y

Nu

R CH H O

CH₂ Nu

R CH OH

CH₂ Nu

Ring opening – it may occur with acid or with base Different regiochemistry:

with acid: S_N1-like mechanism (alkyl cation of higher order is more stable) with base: S_N2 mechanism (for sterical reasons, the nucleophile attacks the carbon of lower order)

(90)

RO CH₂ CH₂ OH OR LiAlH₄

CH₂ CH₃ OH

O

CH₂ CH₂ OH

RMgBr OH

CH₂ CH₂

O R

MgBr

CH₂ CH₂ OH R HO

NH₄Cl

Organic and Biochemistry

Heterocycles: ‘heteroatom is the lord of the rings’

Organic and Biochemistry

Compiled by dr. Péter Mátyus

with contribution by dr. Gábor Krajsovszky

Formatted by dr. Balázs Balogh

Table of Contents

Heteroaromatics

Heterocyclic compounds

Heterocyclic compounds

Annulenes

* heteroaromatic compounds (heteroarenes) - follow the 4n+2 Hückel rule

- have many properties comparable to their carboaromatic analogues

Nomenclature of heterocyclic compounds

Hantzsch - Widman system (1979)

* Expressed by the prefix „perhydro” to the name of the corresponding unsaturated compound.

- Numbering: O < S < N

according to the priority order of O > S > N

heteroatom gets the lowest possible number substituted N (vs. double bonded N)

- to be defined: ‘indicated’ H: 1H….

- hydro (dihydro, tetrahydro etc.) - partially saturated systems

carbonyl: ‘-one’

Indicated/added hydrogen

Heteroaromatic compounds

Physical properties

O O N

H N

Five-membered heterocyclic compounds

Azoles and other five membered rings

X X

N

pyrazole

isoxazole

isothiazole

imidazole

oxazole

thiazole

triazole

oxadiazole

thiadiazole

tetrazole

oxatriazole

thiatriazole 1,2,3

1,2,4 1,2,5 1,3,4

1,2,3,4 1,2,3,5

Chemical properties

Electrophilic substitution

α β

X

H

E X

H E

Electrophilic substitution

RCN HCl

ZnCl

R

O CO HCl

AlCl

CuCl

CHO

X X Y

Deprotonation

N H

Cl

S X

strong base S

1 mech.

S

X

Br Br

Br

Br

Br Br

KNHPh

Diels-Alder reaction

X

R C C R

X

R

R

N SO ₂ N

R-COCl R-SO or ₂ -Cl