· 2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 . 1. Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework

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

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

Consortium leader

PETER PAZMANY CATHOLIC UNIVERSITYConsortium members

SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER

The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund ***

**Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben

***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg.

PETER PAZMANY

CATHOLIC UNIVERSITYSEMMELWEIS

UNIVERSITY

2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 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 Mátyuswith contribution by dr. Gábor Krajsovszky

Formatted by dr. Balázs Balogh


Table of Contentssemmelweis-egyetem.hu

Organic and Biochemistry: Heterocycles

1. Heteroaromatic compounds 4 – 52. Five-membered heterocyclic compounds 6 – 113. Six-membered heteroaromtic compounds 12 – 18


Heteroaromatics



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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


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Heterocyclic compoundsCyclic 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

BNH

B

NHB

borazine


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Saturated heterocycles (‘heterocycloalkanes’)

cyclohexaneX

X = O oxaneS thianeNH piperidine

Y

X

X = Y = NH: piperazine X = O; Y = NH: morpholine

Partially saturated heterocycles (‘heterocycloalkenes’)

cyclohexeneX X = O:

3,4-dihydro-2H-piraneY

X

X = Y = O:2,3-dihydro-1,4-dioxin


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Heteroannulenes(compounds with the greatest possible number ofnon-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]annulenebenzene

XX = N

pyridine

NH

pyrrole


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Annulenes

Unsubstituted monocyclic hydrocarbons with the greatest possible number of noncumulated double bonds. Their general formulaeCnHn (n>6, even number)CnHn+1 (n>6, odd number)

1

2

3

45

67

89

10

[10]annulene

98

7

6

54

3

2

1

1H-[9]annulene

‘[6]annulene’benzene


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* heteroaromatic compounds (heteroarenes)

- follow the 4n+2 Hückel rule

- have many properties comparable to their carboaromatic

analogues


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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 oxaS thiaSe selenaTe telluraN azaP 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).


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Element Valence

Prefix Element Valence

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.


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R ing size C ontain ing n itrogen N ot contain ing n itrogen unsaturated saturated unsaturated saturated

3 (tri) -irine -irid ine -irene -irane 4 (tetra) -ete -etid ine -ete -etane 5 (penta) -ole -olid ine -ole -olane 6 (hexa) -ine -inane -ine -ane 7 (hepta) -ep ine * -epine -epane 8 (octa) -ocine * -ocine -ocane 9 (nona) -onine * -onine -onane 10 (deca) -ecine * -ecine -ecane

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


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- Numbering: O < S < N (oxygen has the lowest possible number)according to the priority order of O > S > N

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

- to be defined: ‘indicated’ H: 1H….

- hydro (dihydro, tetrahydro etc.) - partially saturatedsystems

carbonyl: ‘-one’


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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

34

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)


15


Heteroaromatic compoundsThere are two types:A. having π-electron excess: π-excessive heteroaromatic compoundsB. having π-electron deficiency: π-deficient heteroaromatic compounds

A. Formal derivatization:

average π-electron density ishigher over the carbon atoms than in benzene

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

B. Formal derivatization:

average π-electron density islower over the carbon atoms than in benzene

Y = N, O+, Sb, As



>1 >1

>1 >1

>1

--

>1 >1

>1 >1X

1

1

1

1

1

1

<1

<1

<1

Y

<1

<1

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Physical properties

1. Dipole momentA. 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 NH N

1.68 D 0.71 D 1.57 D 2.20 D


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2. Solubility in water

A. pyrrole > furane > thiophene6 % 3 % 0.1 %

B. pyridine, pyridazine >> pyrimidine, pyrazine

Chemical properties

A. having π-electron excesselectrophilic substitution is easiernucleophilic substitution is more difficult

B. having π-electron deficiencyelectrophilic substitution is more difficultnucleophilic substitution is easier


18


Five-membered heterocyclic compounds




pyrrole furane thiophene

pyrazole imidazole oxazole

thiazole isoxazole isothiazole



NH

NNH

N

S

O S

N

NH

N

O

NO

NS


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 characterTotally 24 systems are possible



X X

NCH → N


Z = NH pyrazoleO isoxazoleS isothiazole

Z = NH imidazoleO oxazoleS thiazole

Z = NH triazoleO oxadiazoleS thiadiazole

Z = NH tetrazoleO oxatriazoleS thiatriazole

1,2,31,2,41,2,51,3,4

1,2,3,41,2,3,5



NZ

N

NZ

N

Z

N N

NZ




CH2 CH*

COOH

NH2

NNH

CH2 CH2 NH2

NNH

CH2 CH*

COOH

NH2

NH

CH2 CH2 NH2

NH

OH

histidine histamine

trypthophane serotonine




N

S

OCOOH

CH3

CH3

HHNHCR

O

β-lactame thiazolidinepenicyllines

N

O

OCOOH

CH CH2 OH

NH NHO

azetidine 2-azetidineone

clavulanic acid(in: Augmentine)

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Chemical propertiesAromaticity

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’)


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Electrophilic substitutionDirecting: ‘α-effect’

position α is more reactive, than position β

α βIn 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, RSO2

XHE X

HE


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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.

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E

XR

XR E

R is electron releasing (activating) substituent

X

RE

X

R

EX

R

E

XR XR E XR

E

X = O

R is electron withdrawing (deactivating) substituent

X = NR, S


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Reaction types for electrophilicsubstitution

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

OHCHOHCl

ONaCHONaOH

CHCl3

OH

RCNHCl

ZnCl2R

OCO HCl

AlCl3CuCl

CHO


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Reagent

SO2Cl2 0 °C pyrroleCl2 -40 °C furaneMeCONHCl thiophene

pyridine•SO3 furane/pyrroleH2SO4 thiophene

RCOCl/SnCl4 thiophenefurane1-protected pyrrole

Y = Cl

SO3H

R-CO

X X Y


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DeprotonationA.) from the N of pyrrole

Pyrrole is much less basic, than secondary amines are.

N

NNe.g., RMgX, BuLi, NaNH2

-H

NH

NMgX

N N COCH3H

RMgX

H

Ac2O

NH

NCH2

PhCH2BrKOH/DMSO

indole

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B.) Deprotonation of ring carbon atom

There can be a side reaction: ring opening

X

BuLi

X LiX= NR, O, S

XE

E

CH3

COOH

E = CH3 ( CH3I)

CO2


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2. Reaction of protonated cations with nucleophilespyrrole, 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)

NH

Cl

unreactive

O Cl

low reactivity

NH

NO2Br S NO2Br

10 times faster more reactive than the benzene analogue

1000 times faster more reactive thanthe benzene analogue


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X = Br, I

base: NaNH2 / liquid NH3 / N PhCH3

K

Analogous reaction:

‘Halogen dance’

S Xstrong baseSE1 mech.

S

X

BrBr

Br

Br

Br Br

KNHPh


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Diels-Alder reaction

X = N-R(poor yield)

O (easy reaction with high yield)

S (it reacts)

X

R C C R

X

R

R

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Benzo-fused systems

X1

2

34

5

67

(β)

(α)

X = NH indoleO benzo[b]furaneS benzo[b]thiophene

electrophilic substitution: decreased reactivity

Annelation effect:

X = NH β/α >> 1

O β/α < 1

S β/α > 1


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Synthesis of indole:1. Fischer synthesis:

Preparation of tryptamine:

NH

NCCH2-R

R NH

R

RZnCl2

-NH3*

Δ

tryptamine

red.

NH

CH2N(CH3)3

KCN

ICH3I

NH

CH2CNgramine

(CH3)2NH NH

CH2NCH3

CH3NH

NH

CH2CH2NH2

HCHO


37


Six-membered heteroaromtic compounds




Systems with π-electron deficiency1. Pyridine



N

N N

N N N


Derivatization

and so on

pyridazine pyrimidine pyrazine 1,2,31,2,4 triazine1,3,5

1,2,3,5-tetrazine



NN

N

N

N

N

N

NN

N

NN

N

H

N

H

N

- H+


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

O1

5

6H

H3

2

4

O1

5

6

H H

+H-

NO

3

N2

4

O1

5

6H

3

N2

4

O1

5

6

H

H3

N2

4

O1

5

6

H H

+H-

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Nitration / sulfonation

cf. with nitration / sulfonation of nitro-benzeneBut:


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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


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Nucleophilic substitution

N-nucleophile

C-nucleophilealkylation (Ziegler’s alkylation)


Tchitchibabin’s amidation

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Representatives:

1.

NSO2

N

R-COClor

R-SO2-Cl

R

N

O

Cl

R

Cl

a vigorousacylating agent sulfonylating

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


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2. Pharmaceutical industry

Isonicotinic hydrazide (INH)

nicotine

Ca2+antagonist

nicorandil

CONHNH2

N

N CH3

N

NH

ArCOOCH3

CH3H3C

H3COOC

CNH

ONO2

N

O


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N

CH2

H3CO

H3CO

OCH3

OCH3

papaverine

N1

2

8

5 4

36

7

quinoline

N2

1

3

4

8

5

6

7

isoquinoline

N10

9

5 4

8 1

6 3

27

acridine

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cromane

vitamine E

2-phenylcromonetrivial name: flavone

OPh

O

3-phenylcromoneisoflavone

ipriflavone (Osteochin®)

O

Ph

O

O


48


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.




Diazines

1. Synthesis Principle: ‘fragment formation’[4+2] [3+3]E.g.,



NN

N

N

N

Npyridazine pyrimidine pyrazine

NN

N

N

N

N

NN

N

N

N

N

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a) pyridazines [4+2]

*γ-oxo carboxylic acids + N2H4*γ-dioxocompounds + N2H4

O

Ph

Ph

O + N2H4 H2O

Ph

Ph

NN

CH3

OOH

O

+ N2H4 H2O 1. cond.2. oxid.

CH3

NNH

O


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b.) pyrimidines [3+3]

*β-dioxocompounds + urea / amidine

NH2CH=NH

H2NC NH2

O

H3C

CH3

H2CO

O

O

CH3

N

NH

H3C

CH3

N

N

H3C


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c.) pyrazines [4+2]α-dioxocompounds + 1,2-diamines

Chemical properties

pyridine 5.2pyrazine 0.4pyrimidine 1.1pyridazine 2.1

pKa

1. cond.2. oxid.

CH3

CH3

H3C

H3C

N

N

CH3

CH3

O

OH3C

H3C

NH2

NH2

+


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Electrophilic substitution

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

100 % HNO31

2 345

6

H3C

Cl

ClO

NN

NO2

Cl

ClO

NN

H3C

12

3 45

6

HNO3

ΔO

H3CO

N

N

CH3

NO2

O

O

H3CN

N

CH3


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Nucleophilic substitution

a.) Chichibabin reaction

b.) Nucleophilic reactions proceed well with various halogen derivatives

N

X

NH2N

X

X= CH, N

NaNH2

NH3

CH3

N

N NH2

CH3

N

NNH2

decalineΔ


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Reactivity of diazines toward 4-nitrophenoxide

~ ~N

N

ClN

N

Cl

N

N

Cl>

N

N

Cl

>N

N Cl

N

N

Cl

Cl

Cl

H3CON

N

Cl

Cl

NaOCH3room temp.


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Mechanism:enhanced reactivity than in cases of benzene derivatives

1. Addition-elimination (AE)negative charge can appear on the nitrogen → stabilisation

XNuN

NNu

X

N

NN

X Nu

XNuN

N


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Cl

N

NH2

N Npyridyne (aryne)

N

NH2

N NH2

NH2

N

NH2

N

2. Elimination-additionaryne mechanism; ‘cine-substitution’

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


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3. „Abnormal” addition-elimination (AEa)

Condition: good leaving group as N-substituent

(+ 4-isomerof small amount)

KCNCNN

-OCH3HCNN

OCH3

INOCH3


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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* BrH2N

H

Ph

N

N


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5. Vicarious nucleophilic substitution (VNS) of hydrogen

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

H

N

NO2CH2SO2Ph

-HCl

CH-SO2PhNO2

N

baseCl

ClCHSO2Ph CH2SO2PhH

N

NO2NO2

N


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b)

N

NN

ClCH2SO2PhKOH/DMSO H2C

SO2PhN

NN


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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

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2. Carboxylic amide-imidoic acid and similar systems

a.)

b.)


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Tautomerisation - heterocycles

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


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γ-pyrone it is closer to this!(aromatic resonance

structure)

4-hydroxy-pyrilium cation


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polar medium gas phase


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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-pyridine2-X-pyrimidine / 4-X-pyrimidine2-X-pyrazine3-X-pyridazine4-X-pyridazine2-X-imidazole

- in vapour phase: hydroxy/thiol form is the dominant one

2. X = NH2 amino form is the dominant one


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Halogenated pyridines

a.)

b.)

2- or 4-amino


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2. Ring-chain

OH

CO

H

c.p., with carbohydrates

cyclohemiacetal

5

4

32

1

O O

H

H

H

S

H3C

O

OH

(CH2)nN

N

N

C O

H

(CH2)nS

H3C

O

NNH

N


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3. Substituent tautomerisation

4. Valence isomerisation valence tautomerisation

N OC

O

CH3N OC

O CH3

NN

N N N N

NN

N NN

N


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Dimroth’s rearrangement

N

N

CH3

NH2

HON

N

CH3

NH2HO

NNH

OHCH3

N

N

NH CH3

INH2

N HClS

NH CH2CH3

NS

NH

CH2CH3 HCl

XYX

Y


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Benzo fused diazines/azines

NN

NN

N

Ncinnoline phthalazine quinazoline

N

N

NN

quinoline quinoxaline isoquinoline


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Reactivity1. Electrophilic substitution: on the benzene ring

N

N

N

43%

47%

N

80%

10%

NN

33%

28%


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2. Nucleophilic substitution

halogenated derivatives of the heterocyclic ring

Azino-diazine: it is a triazanaphthalene derivative

e.g., N N

N

Cl

NN

POCl3

NHNH2

NN

N2H4 . H2ONHN

O


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Diazino-diazines: these are tetrazanaphthalene derivatives

The most importantrepresentative:

pteridine

N

N

N

N1

2

34 5

6

78

X= OH, R=H folic acidX= NH2, R=CH3 methotrexate

N

N

N

N

X

H2N

CH2 NR

COOHCON-CH(CH2)2COOH

H


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folic acid

tetrahydrofolic acid folinic acid

uracil thyminesynthesis of purine

methothrexate

NH

N CH2-NH-H H

NH

N CH2-N-

HC

O


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Benzo-fused pteridine: riboflavineVitamin B2

H3C

H3CO

NH

NN

N

CH2O

HOCH

HOCH

HOCH

CH2OH


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Nucleophilic substitution of halogens

1.

2.3.

Purine

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

some importantderivatives:

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

Cl

Cl

Cl

N

N N

NH

1

2

34

56

78

9

N

N

N

N

HN

N

N

NH

9


81


uric acidxanthine

R1 = R2 = CH3, R3 = H theophyllineR1 = R3 = CH3, R2 = H theobromineR1 = R2 = R3 = CH3 caffeine



NH

NH NH

N

O

O NH

NH NH

NH

O

O

O

N

N N

N

O

O

R2

R1

R3

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

Three-membered heterocyclic compounds

ethylene sulfide

thiacyclopropane

Hantzsch-Widmann name

Radicofunctional name

Replacement name

ethylene oxide

oxacyclopropane

ethylene imine

azacyclopropane

1

23

1

23

1

23

H

O

O

NH

O

oxaziridine

NH

N

dioxirane diaziridine

1

23

1

23

1

2

3

structuralisomers

H2C N N

diazomethane

oxirene thiirene 1H-azirine 2H-azirine

1

23

1

23

O S N

H

N

H

2-azirine 1-azirine

N

N

H

1

23

3H-diazirine

HO S

thiirane

N

oxirane aziridine

Nomenclature


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halohydrin

R CH CH2R CO3H

O

R

oxirane derivatives

R CH CH2

OH

Cl

Cl2 / H2O

KOH

+HCl

R:

Cl

m-chloroperbenzoic acidperbenzoic 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 closureWith contribution of atoms from olefin [2] and peracid [1]


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Only singlet carbene (not triplet)is suitable.

Aziridines are carcinogen compounds.C N

benzonitrile2H-azirine derivative

carbene

N1

2

3

CH2N2

CH2

e.g.,

halohydrin

R CH CH2

OH

Cl

R CH CH2

Br

Br

NH3

R CH CH2

SH

Br

halothiol

H2S

S

R

thiirane derivative

+HBr

HBrKOH

R CH CH2

Cl

NH2haloamine

SOCl2R CH CH2

OH

NH2aminoalcohol

+HClKOH

H

HCl

aziridine derivative

N

R


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C C

O

HH

(CH2)7COOHCH3(CH2)7

C C

O

H(CH2)7COOH

HCH3(CH2)7

C CH H

CH3(CH2)7 (CH2)7COOH

oleic acid

CH3COOH

O

20°C, 3 hone-stepsyn-addition

C C

O

HCH3(CH2)7

(CH2)7COOHH

C C

O

H(CH2)7COOH

CH3(CH2)7H

C CCH3(CH2)7 H

H (CH2)7COOH

elaidinic acid

CH3COOH

O

20°C, 3 hone-stepsyn-addition

enantiomers

enantiomers

1:1

1:1

stereospecific

Epoxidation with peracid without catalyst


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Asymmetric oxidation of alkenesSharpless epoxidation

+

+

COOEt

EtOOC OH

HHO

H

COOEt

EtOOC H

HOH

HO

diethyl tartrate enantiomers

allyl alcoholderivative

H

CH2OH

H

OO

OO

H

CH2OHH

O

OO

H

CH2OHH O

Ti[OCH(CH3)2]4

(CH3)3C O OHCH2Cl2

Ti[OCH(CH3)2]4

(CH3)3C O OHCH2Cl2

stereospecific diastereo(enantio-)selectiveKnowles, Noyori, Sharpless 2001 Nobel-prize, Chemistry, chiral catalysis


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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 δNH3

δ

KOH

SOCl2

CH2 CH2

Cl NH2 KOH

aziridine

NH

HN

CH2CH2OH

CH2CH2OH

O

diethanolamine

N CH2CH2OH

CH2CH2OH

CH2CH2OH

triethanolamine


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CH CH2

OHY

R

O

R

HO

R

H

O

R

H

O

R

H

Y

Nu

HR CH

O

CH2

Nu

R CH

OH

CH2

Nu

Ring opening – it may occur with acid or with baseDifferent regiochemistry: with acid: SN1-like mechanism (alkyl cation of higher order is more stable)with base: SN2 mechanism (for sterical reasons, the nucleophile attacks the carbon of lower order)


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ROCH2 CH2

OH ORLiAlH4

CH2 CH3

OH

O

CH2 CH2

OH

OHRMgBr

CH2 CH2

O R

MgBr

CH2 CH2

OH R

HO

NH4Cl


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1 2

12

NHR1

R2

HCl

O S

thiirane

SCN

O

HO CH2CH2 SH2-sulfanylethanol

RO CH2CH2 SH2-alkoxyethanethiol

Cl CH2CH2 SH2-chloroethanethiol

NR1

R2CH2CH2 SH

2-dialkylaminoethanethiol

/ ROH

/ H2O H2S

RO

HO


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Acetylcholine: neurotransmitter of parasympatic nervous system(it can be found in the parasympatic part of the vegetative nervous system and in the central nervous system)

Some important derivatives:

O

+ N

CH3

CH3

CH3

HCl acetylcholine chloridecholine chloride

HOCH2CH2N(CH3)3

Cl

COCH2CH2N(CH3)3

O

H3C

Cl

(CH3CO)2O


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Ar R name

NH

CH

CH3

CH3

CH

CH3

CH3

pindolol

Visken

propranolol

Inderal

prototypes:

RNH2

Ar O CH2 CH CH2

OH ClO

CH2OAr

O

CH2 Cl

steric reason

Ar OH competing reaction

epichlorohydrin

Ar OH +HCl

HO

RNH2

Ar O CH2 CH CH2

OH NHR

β-adrenoceptor blocker

a) pathway(main pathway)a) pathway

b) pathway

b) pathway


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Four-membered heterocyclic compounds

oxetane thietane azetidinetrimethylene oxide trimethylene sulfide trimethylene imine

oxacyclobutane thiacyclobutane azacyclobutane

oxet(ene) thiet(ene) azet

SO1 2

34

N1 2

34

1-azetine 2-azetine

N1 2

34

HN1 2

34

1,2-dihydro-1,2-diazet

HN NH1 2

34

1,2-dithiet

S S1 2

34

HNSO1 2

34

Nomenclature


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ClOCCH3

O

HOO Cl

ClClHS

SH2S

AlCl3

KOH

HCl

BrBr

NTs

HN

H3C SO2NH2

Ts NH2 LiAlH4

ether

Preparation Intramolecular ring closure


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RMgXR CH2CH2CH2OH

OBr CH2CH2CH2 Br

HBr

LiAlH4CH3CH2CH2OH

RNHCH2CH2CH2OHRNH2

Chemical properties


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αβ

NH2

OEtO

OHHO O

αβ

NHO

αβ

1

23

SO

PhPhPh

H3C

OO

αβ

EtOH

ethercyclic amide(antibiotics)

β-propiolactampropano-3-lactam

propano-3-thiolactone

Nu H Nu HYO

NuOHY

YHONu

O

C

CPh Ph

S

CH3C Ph

[2+2]

cycloaddition

H2O

cyclic thioester

β-propiothiolactone

propano-3-lactone

cyclic ester

β-propiolactone


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Some important derivativesβ-Lactam antibiotics· Penicillins· CephalosporinsAntibiotics: natural compounds produced either by microorganisms (e.g., fungi), or by a higher organism against oth-er microorganisms (e.g., bacteria) to block the life and reproduction of the bacteria. Antibiotics are efficient in low concentration.b-lactame ring of penicillins is sensitive to acids, bases, or penicillinase enzyme. Nowadays penicillins with broad therapeutic range also exist (see microbiology).Cephalosporins (1948) makes the other main group of the b-lactame antibiotics. These are resistent to penicillinase enzyme. The bacterium produces penicillinase/cephalosporinase enzyme in order to be resistent against the given penicillin/cephalosporin derivative. Thus, newer and newer penicillin/cephalosporin derivatives must be synthesized. Their total synthesis is possible, but it would be too expensive, thus new derivatives are produced by semisynthetic methods. The fermentation processes are combined by chemical methods (beginning of biotechnology).Clavulanic acid: inhibitor of the β-lactamase with low antibiotic effect. Clavulanic acid is produced by Streptomyces clavurigeus (the same fungus also produces penicillin as well as cephamycin).Augmentin® contains amoxycillin and potassium clavulanate.


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β -Lactam antibiotics

azetidin + thiazolidine azetidin + [1,3]thiazidine

Basic skeletons

N

S

O

1

2

3

45

67

8

1

penamlactam

Penicillium notatum

cephamlactam

Cefalosporium acremonium

1

N

S

O

CH3

CH3

O

HHH2N

OH

2

34

56

7N

S

OO

O OHO

CH3

HHH2N1

2

345

67

8

N

S

O

2

34

56

7

penicillins "-cillin" cephalosporins "cef(a)-"

cephalexin

S

O

N HH

7

cephalotin

NO

O

N H

CH3

6

H

oxacillin

7-aminocephalosporinic acid7-ACS

6-aminopenicillinic acid6-APS

penicillinase enzymecleaves

cephalosporinase enzymecleaves

H HNC

O

CH2

6

benzylpenicillinG-penicillin

CH33

HNC

O

CH

NH2

7

H

O

O

CH33


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NHO

β -Lactam skeleton

N

S

O

HRNHCH3

CH3

COOHPenicillins

N

O

OOH

COOHClavulanic acid

N

Y

Z

COOH

XRNH

O

Cephalosporins (X=H, Y=S)

N

Y

O

OH

H3CZ

COOH

Penems (Y=S)

Carbapenems (Y=CH2) N

Y

O

OH

H3C

COOH

SNHR

Tienamycin (R=H)

2-Azetidinon-1-phosphonate

Cephamycins (X=OCH3, Y=S)

NO

RNH

P

O

O

OCH3

K

Monobactams

NO

RNHX

SO2O K


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Seven-membered heterocyclic compounds

SS

1,2-dithiepane

OO

1,2-dioxepane

11

2 2

12

3

1

2

3

12

3

YNH

1,2-oxazepane

1,2-thiazepane

Y=O

Y=S

NH

azepane

S

thiepane

1

2O

oxepane

12

3

N

H4H-azepine

4 45

1

2O

oxepine

1

2S

thiepine

12N

H

1H-azepine

N H

2H-azepine

1

2

3

N

H

3H-azepine

1

2

3

Nomenclature, some important derivatives


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1,2-oxazepine

1,2-thiazepine

Y=O

Y=S1H-1,4-diazepine1H-1,2-diazepine

1

1H-1,3-diazepine

12

3

N

N

H1

2

3

YN

2

3

N

N

H1

45

2

3

NN

H

N

R

1

2

34

56

7

8

910 11

dibenzoazepine derivatives

R Name

(CH2)3NCH3

CH3

imipraminantidepressant

CO NH2

10,11

carbamazepine

antiepileptics


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Benzodiazepine derivatives

N

NNO2

OH1

4

7

nitrazepamEunochtin

N

N

CH3 O

OCl

1

5

7

clobazamFrisium

N

N

CH3O

CH3O

CH3

OCH3

OCH3

CH2CH3

12

3

4567

89

tofisopamGrandaxin

N

N

CH3 O

Cl

1

4

7

diazepam

SeduxenValium

N

NO

NHCH3

Cl

1

2

3

4567

8

9

chlorodiazepoxideEleniumLibrium

Grandaxin: anxiolitics free from sedative side-effects (eg. It can be administered before driving)(Kőrösi Jenő GYKI, EGYT, 1966. Hungarian patent)


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CH3O

CH3OO

CH3

CH2CH3

O

H3COOCH3

CrO3

CH3COOH / H2O

CH2CH3

CH3

OCH3

OCH3

CH3O

CH3O

diisohomogenol

Grandaxintofisopam

N

N

CH2CH3

CH3CH3O

CH3O

H3CO

OCH3

1/ H2N NH2 . HX

2/ HO

Preparation


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Cl

NH

CH3

+NH

Cl

N

CH3

H2N

O

Cl

Cl

N

CH3

NOH H

POCl3P2O5

Cl N

N

CH3

medazepamRudotel


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Cl

NO2

NH

+C

O

CH2C

O

EtO

HO Cl

NO2

N C

O

CH2

COEtO

Zn/HCl

N

NO

O

H

NaOCH3CH3Br

N

NO

O

CH3

clobazamFrisium

PCl5

C

O

CH2C

O

EtO

HO

PCl5 C

O

CH2C

O

EtO

Cl


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Heterocyclic Compounds with Practical Application


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N

N

CH3

CH3

Cl

Clomipramine

N

O

Cl

N

NH Amoxapine

Tricyclic Antidepressants

All current antidepressant rely upon the principle of enchancingmonoamine neurotransmission interferring with presynaptic transporterthat reimports the neurotransmitter from the synaptic cleft once releasedfrom presynaptic nerve terminals.

dibenzo-azepine ring dibenzo-oxazepin ring


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N

S

CH3

NH3C CH3

Promethazine

All the ‘classical’ tricyclic antidepressant have a basic three-ring pharmacophore. The therapeuthic and commercial success of N-aminoalkylphenothiazines such as (for instance) promethazine and chlorpormazine initiated an enormous effort in the molecular modification.

N

S

Cl

N

CH3

CH3

Chlorpromazine


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N

N

NNH3C

Cl

Cl

Triazolam

N

N

F

Cl

O

N

CH3 CH3

Flurazepam

Benzodiazepine analogs have also been prepared where the lactam carbonylhas been incorporated into a 1,2,4-triazolyl heterocycle as seen in triazolam.

Electron withdrawing groups on the aryl group are generally observedbut polar substituents attached to the lactam amide group, illustrated influrazepam.

Benzodiazepine Tranquilizers


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N

NCl

O

OH

CH3

Temazepam

N

N

Cl

Cl

O

OH

Lorazepam

H

Polar hydroxy group at the 3-position present in temazepam and lorazepam,hints at a significant flexibility in those regions.


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N

NHCH3Desipramine

O

N

CH3

CH3

Doxepin

Desipramine and doxepin interact with a variety of biological targets like muscarinic receptors.

Their side effects may be orthostasis (hypotensio posturalis), dry mouth and constipatio.

Tricyclic Monoamine Transport Inhibitors


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Clothiapine

S

NC

O

+

S

NH

CO N

NCH3

POCl3

N

N

CH3

H

S

NH2

Cl C Cl

O

S

NN

NCH3

Synthesis of clothiapine, which is an atypical antipsychotic drug of thedibenzothiazepine chemical class.

Antipsychotic and Antihypertensive Drugs


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NHCl CH2 CN

NCH2 CN

LiAlH4

NCH2 CH2 NH2

H3C S CNH2

NH2

S-methylthyuroniumhydrogensulphate

- CH3SH

NCH2 CH2 NH C

NH

NH2

Guanetidine

azocane

- HCl

HSO4

Guanethidine is an antihypertensive drug that reduces the release of catecholamines, such as noradrenaline. It is transported across thesympathetic nerve membrane by the same mechanism that transports norepinephrine itself, and uptake is essential for the drug's action.Guanethidine is used to treat hypertension.


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H2N

O

O N

OH H

CH3

CH3

Atenolol

O N

OH H

CH3

CH3

OH3C

Metoprolol

Antiarrhythmic Drugs

Atenolol and metoprolol are β-adrenoceptors blockers. They have someselectivity for the β1-adrenoceptor. Some β1-adrenoceptor blockers arealso partial agonists.


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NHCH3SO2

ON

CH3

NH SO3CH3

Dofetilide

Sotalol and dofetilide are potassium channel blockers. The prototypical drug is D-solatolol. It prolongs ventricular cardiac action potentials. Further methanesulfonanilide derivatives is dofetilide. Methanesulfonanilide derivatives block the open channel configuration. They appear to bond within the transmembrane pore at a fairly well-definied site.

N

OH H

CH3

CH3

NHCH3SO2Sotalol


116

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O

HOOC

NH2

NH

N

O

OH

NO

OH

HOOCNocardicin AN

SO2OH

OCH3

NH

ONHO

HOOCNH2

Sulfazecin

β-Lactam Antibiotics

Structures of some natural β-lactam antibioticswith different core structures

β-Lactam antibiotics inhibit of the synthesis of bacterial peptidoglycan cell wall. Many enzymes are involved in the overall biosynthesis of the cell wall, but is isthe final cross-linking reaction which is inhibited by penicillin and its derivatives. This leads to a cell wall framework that is no longer interlinked.


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N

SNH

OHO

O

OCH3

OCH3

O

Methicillin

N

SNH

OHO

OO

COOH

S

TicarcillinDevelopment of synthetic penicillins afforded new gruops of these antibiotics.


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N

HOH

OCOOH

S

NH2

Epithienamycin

Clavulanic acid (see above) and epithienamycin are the representativesof β-lactamase enzym inhibitors.

β-Lactamase Inhibitors


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Documents

· 2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 . 1. Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework