Unit 3: Aromatic and Heterocyclic Chemistry Cytotoxin- Inhibits DNA-topoisomerase enzymes Happy Tree (China)

Unit 3: Aromatic and Heterocyclic Chemistry

Cytotoxin- Inhibits DNA-topoisomerase enzymes

Happy Tree(China)

Aromatic Compounds

• Many aromatic substances have rather simple structures and contain a six-carbon unit (C6H5)

• Arenes = aromatic hydrocarbon• Aromatic: refers to the level of stability for

an arene

• Benzene: is the parent hydrocarbon of the class or aromatic compounds

When Is A Molecule Aromatic?• For a molecule to be aromatic it must:

• Be cyclic• Have a p-orbital on every atom in ring• Be planar• Posses 4n+2 p electrons (n = any integer)

benzene naphthalene

+

cyclopropenyl cation[14]-Annulene

Erich Hückel

4

Benzene C6H6.

Discovery of Benzene

• Isolated in 1825 by Michael Faraday who determined C:H ratio to be 1:1.

• Synthesized in 1834 by Eilhard Mitscherlich who determined molecular formula to be C6H6.

• Other related compounds with low C:H ratios had a pleasant smell, so they were classified as aromatic. =>

Benzene properties

• The carbon to hydrogen ration in benzene suggest a highly unsaturated structure, however it behaves as if it were saturated.

• Does not decolorize bromine solution the way alkenes and alkynes do

• It is not easily oxidized by potassium permanganate

• Does not undergo addition reactions the same as alkenes or alkynes

Benzene

• Benzene is one of the most important commercial organic chemicals with approximately 17 billion pounds produced annually the United States alone.

8

Two Lewis structures for the benzene ring.

• Friedrich Kekule (1865) proposed the tetracovalence of carbon in the structure of benzene (alternating double single bonds)

9

Shorthand notation for benzene rings.

Kekulé Structure

• Proposed in 1866 by Friedrich Kekulé, shortly after multiple bonds were suggested.

• Thus benzene is often written as a circle to remind us of the delocalize nature of the electrons

• Failed to explain existence of only one isomer of 1,2-dichlorobenzene.

CC

CC

C

C

H

H

HH

H

H

Substitution Reaction Benzene

• Benzene reacts mainly by substitution reaction

12

Some common mono-substituted benzene molecules

Toluene, sometimes you see this on marker pens ”contains no toluene”

Has the condensed structural

formula C6H5CH3

Common Names of Benzene Derivatives

OH OCH3NH2CH3

phenol toluene aniline anisole

CH

CH2 C

O

CH3C

O

HC

O

OH

styrene acetophenone benzaldehyde benzoic acid=>

Disubstituted Benzenes

The prefixes ortho-, meta-, and para- arecommonly used for the 1,2-, 1,3-, and 1,4-positions, respectively.

Br

Bro-dibromobenzene or1,2-dibromobenzene

HO

NO2

p-nitrophenol or4-nitrophenol

=>

3 or More Substituents Use the smallest possible numbers, butthe carbon with a functional group is #1.

NO2

NO2

O2N

1,3,5-trinitrobenzene

NO2

NO2

O2N

OH

2,4,6-trinitrophenol

=>

Phenyl and Benzyl

• Aromatic hydrocarbons are classified as arenes.

• The symbol Ar is used for an aryl group ( just as R symbolizes alkyl group)

• Two groups with special names occur frequently in aromatic compounds: phenyl group and benzyl group

Phenyl and Benzyl

Br

phenyl bromide

CH2Br

benzyl bromide

Phenyl indicates the benzene ringattachment. The benzyl group hasan additional carbon.

=>

• 2, 4 dimethyl 3 phenyl pentane phenylcyclopropane

• Benzyl chloride biphenyl

Common Names forDisubstituted Benzenes

CH3

CH3

CH3

CH3H3C

CH3

CO OH

OH

H3Cm-xylene mesitylene o-toluic acid p-cresol

=>

Fused Ring Hydrocarbons

• Naphthalene

• Anthracene

• Phenanthrene=>

Reactivity of Polynuclear Hydrocarbons

As the number of aromatic rings increases, the resonance energy per ring decreases, so larger PAH’s will add Br2.

H Br

H BrH Br

Br

H

(mixture of cis and trans isomers) =>

Fused Heterocyclic Compounds

Common in nature, synthesized for drugs.

=>

Physical Properties

• Melting points: More symmetrical than corresponding alkane, pack better into crystals, so higher melting points.

• Boiling points: Dependent on dipole moment, so ortho > meta > para, for disubstituted benzenes.

• Density: More dense than nonaromatics, less dense than water.

• Solubility: Generally insoluble in water. =>

Electrophilic Aromatic substitution

• The most common reaction of aromatic compounds involves substitution of other atoms or groups for a ring hydrogen

• Chlorination

• C6H6 + Cl2 ----- C6H5Cl + HCl FeCl3 is catalyst

Electrophilic Aromatic substitution

•

• bromination

• nitration

• sulfonation

Friedel-Crafts reaction

• Refers to Alkylation of aromatics

• The Friedel-Craft alkylation reaction has some limitations…it cannot be applied to an aromatic ring that already has one it a nitro or sulfonic acid group

Ortho, Para-directing and Meta-directing groups

• Substituents already present on an aromatic ring determine the position taken by a new substituent.

• Certain groups are ortho, para directing, and others are meta directing

Directing and activation effects of common functional groups (groups are

listed in decreasing order of activation)

• Substituent group• -NH2, -NHR, -NR2

• -OH, -OHCH3, -OOR

• O• -NHC—R

• -CH3, -CH2,CH3, -R

• ________________________• -F, -Cl, -Br, -I• ________________________

• Name of group • Amino• Hydroxyl, alkoxy

• acylamino• Alkyl• ________________________• Halo

• ________________________

Directing and activation effects of common functional groups (groups are

listed in decreasing order of activation)Substituent group O O-C-R, -C-OH acyl, carboxy O O-C-NH2, -C-OR carboxamindo, carboalkoxy O-S-OH sulfonic acid O-C=N cyano O-N nitro O

• Name of group

Heterocyclic Chemistry

The largest class of organic compounds.

Most drugs contain herocyclic rings

Cytotoxin- Inhibits DNA-topoisomerase enzymes

Happy Tree(China)

Definition: Heterocyclic compounds are organic compounds that contain a ring structure containing atoms in addition to carbon, such as sulfur, oxygen or nitrogen, as the heteroatom. The ring may be aromatic or non-aromatic

Significance – Two thirds of all organic compounds are aromatic

heterocycles. Most pharmaceuticals are heterocycles.

Examples

Quinine

Pfizer: Viagra

Treatment of malaria for 400 years (Peru)Erectile dysfunction

N

N

Me

N NHMe

NNC

H

H

Ovarian & lung cancer

GSK - TopotecanPfizer - Irinotecan

Camptothecin Analogues

Treating stomach & intestinal ulcers

More soluble & less side-effects

Heteroatoms

• Are atoms other than carbon or hydrogen that may be present in an organic compound.

• The most common heteroatoms are oxygen, nitrogen and sulfur

Six Membered Heterocycles: Pyridine

N N

Hpyridine piperidine

Pyridine replaces the CH of benzene by a N atom (and a pair of electrons)

Hybridization = sp2 with similar resonance stabilization energy

Lone pair of electrons not involved in aromaticity

N

H

HH

H H

pyridine

8.5

7.1

7.5

1H NMR: Pyridinium ion: pKa = 5.5

Piperidine: pKa = 11.29

diethylamine : pKa = 10.28

Pyridine is a weak basePyridine is -electron deficientElectrophilic aromatic substitution is difficultNucleophilic aromatic substitution is easy

Chemistry of pyridine

Electrophilic substitution in pyridine

N CH3H3C

H N O 3

H 2 S O 4 N CH3H3C

NO2

81%

Pyridine is less active, than benzene toward electrophilic agents, because nitrogen ismore electronegative, than carbon and acts like an electron withdrawing substituent,including the meta-directing effect.

It undergoes this reaction only under drastic conditions, ex nitration or bromination and requires high temperatures and strong acid catalyst

Example:

DMAP (DimethylAminoPyridine)

N

NCH3CH3

NN

H

N

NO2

+

ii

i, HNO3, H2SO4

Whereas acylations “catalyzed” by pyridine are normally carried out in pyridine as the reaction solvent. Only small amounts of DMAP are required to do acylations

Attempted Electrophilic Aromatic Substitution

NN

AlCl3

N

R

O

+

iiii

ii, AlCl3, RCOCl_

Unreactive, Stable

Nucleophilic aromatic substitution

• The reaction of pyridines

• A nucleophile displaces a hydride or halide ion from the aromatic ring

N

Me I

N

Me+ I

_

O

O

O OH O

O

O

R X

O

R OR

+ Pyr

+Pyr

R1-OH 1

X = OAc, Cl, Br

Pyridine as a nucleophile

Use Pyridine as a solvent to make esters

N

O R

+

Acyl pyridinium ionReactive intermediate

E.g.

Nucleophilic Substitution at 2- and 4-positions of pyridine is most favoured

N Cl N Cl

Nu

N Nu_

_Nu

N Cl N SPh

PhSH, NEt3

93%

E.g.

N

Br

Br

N

NH2

BrNH3 (aq)

65%

Heterocycles

• The pyridine ring can be fused with benze rings t produce polycyclic aromatic heterocycles.

• Examples of 6-membered heterocycles include quinoline and isoquinoline

Five Membered Heterocycles: Pyrrole

N

H

H

H

H

H

Pyrrole

6.5

6.2

1H NMR: Aromatic: Thus, 6 electrons

Sp2 hybridised and planar

Lone pair tied up in aromatic ring

Pyrrole is -electron excessive

Thus, Electrophilic Aromatic Substitution is Easy

Nucleophilic Substitution is Difficult

N

HN

H O

H

O

H NMe2

N

SO2Ph

N

SO2Ph

Me

O

N

H

Me

O

N

H

N

H

NO2N

H

NO2

+

1. POCl32. Na2CO3, H2O

59%

Ac2O, AlCl3

rt

NaOH (aq)

82%

AcONO2, AcOH/ -10 C+

51% 13%

Electrophilic Aromatic Substitution preferred at the 2-position

Normal acidic nitration causes polymerization

Vilsmeier Reaction

Electron-withdrawing group allows substitution at the 3-position

N

H

N

H

H

H N

H

N

H

H

H N

H

H++

+

reaction continues to give polymer

Organic Synthesis with Pyrrole should avoid strong acids

N

H

N

H

Cl

N

H

N

H

ClCl

ClCl

80%

80%

i; 1 X SO2Cl2, Et2O

ii; 4 X SO2Cl2, Et2O

i

ii

Indole

Lysergic acid (LSD) Strychnine

Indole Alkaloids

N

H

Indole

N

HN

H

CHOVilsmeier

55%

Aromatic due to 10 -electrons

Benzene part is non-reactive

Electrophilic aromatic substitution

occurs at the 3-position

OCONH2

N

OMe

NH

NH2

Me

O

O

Mitomycin C

Other Five Membered Heterocycles

N

HS O

Pyrrole

Thiophene Furan

The least aromatic:The O atom is too electronegative

Can give addition, as well as substitution products when reacted with E+

Less reactive than pyrrole, but substitution always at 2-position

More aromatic than Furan

Electrophilic Substitution, not addition

Least reactive

Thiophene has similar reactivity to benzene

Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3

Electrophilic Aromatic Substitution of Thiophene

SS

O

H

O

H NMe2

S S NO2

S S ClS Cl

Cl

+

1. POCl32. Na2CO3, H2O

68%

HNO3, AcOH, Ac2O / -10 C

85%

43%

SO2Cl2, heat

10%

S SO

O

O

O

O OO

O

O

O

+ZnCl2, 100 C

+ZnCl2, 0 C

83%

95%

Some Reactions of Furan

OO

Br

Br

Br

Br O

OMeMeO

H H

CHOOHC

OPh3P

OHC

CHO

CHOOHC

Br2, CCl4 Br2, MeOH

H+, H2O

+_

not a clean reaction

Furan is more reactive than thiophene

Addition product

Hydrolysis of acetal

Wittig reaction

Furan is easily cleaved to dicarbonyls

Furan is a source of 1,4-dicarbonyls in Organic Synthesis

O

OMeMeO

H H

O OH H

O

R H

O RH

O RHR H

O O RR

OR R O OR R

cis-butenediol(too unstable to isolate)

H+, H2O

acetal acetal

+1

1 11 - H2O

acetalaldehyde + 2 x alcohol

H+, H2O

acid-catalysed

Diels–Alder reaction

• is an organic chemical reaction (specifically, a cycloaddition) between a conjugated diene( chemical with 2 double bonds) and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system

The Diels-Alder Reaction

Otto Diels

Kurt Alder

Noble Prize in 1950

O

O

O

O

O

O

+100 C

benzene

100%Diene

4 systemdienophile2 system 4+2 cycloaddition

Electron rich

Electron poor

O

H

O

H+

30 C

100%

H

H

O

O

OMe

OMe

H

H

CO2Me

CO2Me

H

H

O

OMe

O

MeO

H

H

CO2Me

CO2Me

+

+

The configuration of the dienophile is retained

Always reacts via the cis-diene

O

O

O

O

O

O

H

H

HH

OO

O

+25 C

100%

endo product(100%)

Under kinetic control

OO

O

O

Thermodynamicexo-product forms as the

temperature is raised

endo-product

Furan readily undergoes the Diels-Alder reaction with maleic anhydride

More stable due to less steric reasons

Aromaticity prevents thiophene from taking part in the Diels-Alder reaction

S

O

OX

S OO

X

X

+- SO2

This sulfone is not aromatic & very reactive

Five-membered Rings with Two or More Nitrogens

Diazoles

N

N

H

NN

H

ImidazolePyrazole

Imidazole is more basic than pyridine, but more acidic than pyrrole

N

N

H

H

N

NH

H

N

N

N

N

+

_

_

Imidazole + H+

Imidazole - H+NaOH

Properties: Very stable cation and anion of imidazole is formed

pKa = 14.5

(imidazole)

pKa = 16.5

(pyrrole)

- H2O

Histidine

Is one of the essential amino acids.A relatively small change in cellular pH can result in a change in its charge

Some Natural Imidazole Compounds

Important ligand to many metalloproteins

histidine carboxylase

histamine

Carnosine

Dipeptide in high concentrations in the brain & muscles- Improves social interactions & treatment of autism

Body neurotransmitter & local immune response

N

O

OMe

O

Cl

H

N

OMe

O

Cl

NN

NNH

Indomethacin

Tetrazole derivative

Tetrazoles are used in drugs as replacements for CO2H

Anti-arthritis drug- Non steroidal anti-inflammatory drug – reduces fever, pain, stiffness, delays premature labour & other uses

Indomethacin

Bioreductive Anti-Tumour AgentsOCONH2

N

OMe

NH

NH2

Me

O

O

N

N

O

OR

O

O

N

Me

N

N

O

O

N

N N Tr

O

O

( )n

IC50 ≈ 1.0 µM

IC50 ≈ 0.001 µM

Mitomycin C

E. B. Skibo et al., J. Med. Chem., 2002, 45, 1211

K. Fahey, F. Aldabbagh, Tetrahedron Lett., 2008, 49, 5235

Pyrrolo[1,2-a]benzimidazole (PBI)

M. Lynch, S. Hehir, M. P. Carty, F. Aldabbagh, Chem. Eur. J. 2007, 13, 3218

S. Hehir, L. O’Donovan, M. P. Carty, F. Aldabbagh, Tetrahedron 2008, 64, 4196

1

10

L. O’Donovan, F. Aldabbagh, Chem. Commun., 2008, 5592.

Hypersensitive to Fanconi AnemiaMore selective to hypoxia

Targeting Hypoxic Cells

Mitomycin C (MMC)

SET - activation

O

O

N

NH2

Me

OCONH2

OMe

NH

O

O

N

NH2

Me

OCONH2

NH

OMe

O

O

N

NH2

MeNH2

DNA

O

O

N

NH2

Me

OCONH2

OMe

NH N

NH2

Me

OCONH2

OMe

OH

OH

NH N

NH2

Me

OH

OH NH2

DNA+ 2 e-

+ 2 H+

CY P450 reductase

Two electron activation

DT-diaphorase

.

+ 1 e-

- 1 e-

- 1 e-

1

10

DNA alkylation

S. E. Wolkenberg and D. L. Boger, Chem Rev., 2002, 102, 2477

steps

DNA alkylation

Measuring the Effect of FANCD2 Expression on Cell Viability

N NH

OMe

OCONH2O

O

NH2

Me

N

N

OMe

OMe

N Tr

●, ● PD20i cells (lack FANCD2)▲, ▲ PD20:RV (express FANCD2)

K. Fahey, L O’Donovan, M. Carr, M. P. Carty, F. Aldabbagh, Eur. J. Med Chem. 2010, 45, 1873-1879

0

20

40

60

80

100

0 2 4 6 8 10

Concentration (x 10-3µ M)

Ce

ll V

iab

ility

%

N

H

N-

RMgBr

pKa = 23

Pyrrole is a stronger acid, than secondary amines, due to the aromatic stabilization of the conjugate base

N

H

pKa = 44

3. Chemistry of pyrrole, furan, and thiophene

>

= 1.7 D

All three heterocycles have an atom with at least one lone electron pair, involved to the aromatic conjugation. It is evidenced both by physical and chemical properties.

N

H

O S

O O

pyrrole furan thiophene

>

Reactivity in electrophilic substitution:

= 0.7 D

b.p. = 31.4 oC b.p. = 67 oC

>

X

X E

H

X E

H

X E

H

X

HH

X

H

H

preferred substitution1

2

3

E+

E+

+

++

++

Electrophilic substitution in pyrrole, furan and thiophene

X = O, NH, or S

N

H

N

H

NO2 N

H

NO2

+50%

15%

O O

O

50%

S S NO2 S

NO2

+

70% 5%

a c e t ic a n h yd r id e ,B F 3 ,

C H 3 C O O H

2 0 oC

a c e t ic a n h yd r id e

H N O 3 , 2 0 oC

a c e t ic a n h yd r id e

H N O 3 , 2 0 oC

Examples:

O

+O OO

O

O

O

O

HH90%

Furan is able to act as a diene in the reactions of cycloaddition

The Fisher synthesis of indoles

N

HIndoleNH NH2

+ CH3

O

N

H 2-Phenylindole

P o lyp h o sp h o r ic a c id+ NH3

Nucleophilic substitution in pyridine

N NNH270%

+ +H2 NaOH 1 . N a N H 2 , h e a t

2 . H 2 O

NH2-

N-

NH2 H

CH-

NNH2 HN

CH-

HNH2

The most contributing structure

NNH

H

+ H-

NNH-

OH2

The presence of nitrogen enables pyridine to react with nucleophilic agents, like an electron withdrawing substituents enables benzene to participate in such reactions,including the ortho-directing effect.

These reactions require very strong nucleophiles and heat, because H- is a very weakleaving group. In ortho- or para-substituted pyridines nucleophilic substitution proceeds much easier.

Another example:

N N

50%

P h L i

h e a t+ LiH

N Cl N OCH395%

N a O C H 3

C H 3 O H+ NaCl

Have practical uses for example: solvents, insecticides, herbicides, fire

retardants, cleaning fluids, refrigerants, polymers ex teflon

Aryl Halides Ar-X

Organic compounds with a halogen atom attached to an aromatic carbon are very different from those compounds where the halogen is attached to an aliphatic compound(alkanes, alkenes, alkynes).

While the aliphatic compounds readily undergo nucleophilic substitution and elimination reactions, the aromatic compounds resist nucleophilic substitution, only reacting under severe conditions or when strongly electron withdrawing groups are present ortho/para to the halogen.

Nucleophilic substition

• Nucleophile: electron rich reactants sharing electrons with electrophiles ex SN1 and SN2 and nuclephilic acyl substitution rxn

• Electrophile: electron poor reactant . They seek electrons and form bonds with nucleophiles.

• Nucleophilic substitution reaction: a reaction in which a nucleophile displaces a leaving group from a substrate.

Nucleophilic substition

• OH + CH3CH2—Br H2O CH2CH3—OH + Br

• Hydroxide ion is the nucleophile• It reacts with the substrate ethyl bromide• It displaces bromide ion which is the leaving

group

Examples of Nucleophilic

• The most common nucleophiles are :

• Oxygen

• Nitrogen

• Sulfur

• Halogens

• carbon nucleopiles

Reactions of common nucleotides

with alkyl halides

In aryl halides, the carbon to which the halogen is attached is sp2 hybrizided. The bond is stronger and shorter than the carbon-halogen bond in aliphatic compounds where the carbon is sp3 hybridized. Hence it is more difficult to break this bond and aryl halides resist the typical nucleophilic substitution reactions of alkyl halides.

The same is true of vinyl halides where the carbon is also sp2 hybridized and not prone to nucleophilic substitution.

Substitution reactions in Table 6:1 have some limitations with respect to the

structure of the R group in the alkyl halide

• Another limitation that often occurs is when the nucleophile is either an anion or a base or both

Nucleophilic substitution mechanisms

• There are two main nucleophilic substitution mechanisms:

• SN1

• SN2

• The SN part of each symbol stands for substitution nucleophilic

• The numbers will be explained later

SN2 mechanism

• Is a one-step process in which the bond to the leaving group begins t break as the bond to the nucleophile begins to form.

• The nucleophile attacks from the back side of the C—L bond.

• At some stage the nucleophile and the leaving group are both partly bonded to the carbon at which the substitution occurs.

• As the leaving group departs with its electron pair, the nucleophile supplies another electron pair to the carbon atom.

SN2 mechanism

• The number 2 to show that two molecules – the nucleophile and the substrate are involved

SN2 mechanism

• SN2 mechanism is a one-step process favored for methyl and primary halides.

• It occurs more slowly with secondary halides and usually not at all with tertiary halides.

• It occurs with inversion of configuration and its rate depends on the concentration of both the nucleophile and the substrate

SN1 mechanism

• A two step process where the bond between the carbon and the leaving group breaks first and then the resulting carbocation combines with the nucleophile

• The number 1 designates the mechanism because the slow or rate determing step involves only one of the two reactants

SN1 mechanism

• SN1 mechanism is a two step process and is favored when the alkyl halide is tertiary. The SN1 process occurs with racemization and its rate is independent of the nucleophile’s concentration.

• Racemization: a 50:50 mixture of enantiomers

Enantiomers

• A pair of molecules that are nonsuperimposable mirror images of one another

Comparison of Sn2 and Sn1 substitutions

Dehydrohalogenation, an elimination reaction: the E2 and E1 mechanisms

When an alky halide with a hydrogen attached to the carbon adjacent to the halogen-bearing carbon reacts with a nucleophile, 2 competing reaction paths are possible: substitution or elimination

. Substitution

elimination

elimination reactions of alkyl halides

• In an elimination ( dehydrohalogenation) reactions of alkyl halides, a hydrogen atom and a halogen atom from adjacent carbons are eliminated and a carbon-carbon double bond is formed.

Elimination reactions

• E2 mechanism: reactions of alkyl halides : a one step process in which HX is eliminated and a C=C bond is formed .

• B is the nucleophile, acting as a base, removes the proton (hydrogen on a carbon adjacent to the one that bears the leaving group designated X

• At the same time the leaving group departs a double bond forms

Elimination reactions

• E1 mechanism: is a two step process with the same first step as an SN1 reaction (slow and rate-determining ionization of the substrate to give a carbocation)

Polyhalogenated aliphatic compounds

•Polyhalogenated compounds are industrially created compounds substituted with multiple halogens.

• Many of them are very toxic and bioaccumulate in humans, and have a very wide application range.

•They include the much maligned PCBs, PBDEs, and PFCs as well as numerous other compounds.

PCB and PBDE

• Polychlorinated biphenyl: (PCB) is any of the 209 configurations of organochlorides with 1 to 10 chlorine atoms attached to biphenyl, which is a molecule composed of two benzene rings and is used as dielectric and coolant fluids, for example in transformers, capacitors, and electric motors

• Polybrominated diphenyl ethers or PBDEs, are organobromine compounds that are used as flame retardant

PFC and CFC

• perfluorinated compound (PFC) 1s an organofluorine compound with all hydrogens replaced by fluorine on a carbon chain

• used to make fluoropolymers such as Teflon, among other applications

• Chlorofluorocarbons (CFC) also known as freon are polyhalogenated compounds containing chlorine and fluorine