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

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) Erich Hückel

Benzene C6H6. 4

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.

Two Lewis structures for the benzene ring. Friedrich Kekule (1865) proposed the tetracovalence of carbon in the structure of benzene (alternating double single bonds) 8

Shorthand notation for benzene rings. 9

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. =>

Substitution Reaction Benzene Benzene reacts mainly by substitution reaction

Some common mono-substituted benzene molecules Toluene, sometimes you see this on marker pens ”contains no toluene” Has the condensed structural formula C6H5CH3 12

Common Names of Benzene Derivatives =>

Disubstituted Benzenes The prefixes ortho-, meta-, and para- are commonly used for the 1,2-, 1,3-, and 1,4- positions, respectively. m nitrotoulene =>

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

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 Phenyl indicates the benzene ring attachment. The benzyl group has an additional carbon. =>

2, 4 dimethyl 3 phenyl pentane phenylcyclopropane Benzyl chloride biphenyl

Common Names for Disubstituted Benzenes =>

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. (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

all ortho, para 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 all ortho, para directing

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 -C=N cyano -N nitro Name of group meta dircting

Heterocyclic Chemistry Cytotoxin- Inhibits DNA-topoisomerase enzymes Happy Tree (China) Heterocyclic Chemistry The largest class of organic compounds. Most drugs contain herocyclic rings

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 Pfizer: Viagra Quinine Erectile dysfunction Treatment of malaria for 400 years (Peru)

Camptothecin Analogues Treating stomach & intestinal ulcers Camptothecin Analogues Pfizer - Irinotecan GSK - Topotecan Ovarian & lung cancer 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 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 Pyridinium ion: pKa = 5.5 Piperidine: pKa = 11.29 diethylamine : pKa = 10.28 1H NMR: d Pyridine is a weak base Pyridine is -electron deficient Electrophilic aromatic substitution is difficult Nucleophilic aromatic substitution is easy

Chemistry of pyridine Electrophilic substitution in pyridine Pyridine is less active, than benzene toward electrophilic agents, because nitrogen is more 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: 37

DMAP (DimethylAminoPyridine) 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 Unreactive, Stable

Nucleophilic aromatic substitution The reaction of pyridines A nucleophile displaces a hydride or halide ion from the aromatic ring

Pyridine as a nucleophile Use Pyridine as a solvent to make esters E.g. Acyl pyridinium ion Reactive intermediate

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

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 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 1H NMR: d

Electrophilic Aromatic Substitution preferred at the 2-position Normal acidic nitration causes polymerization Vilsmeier Reaction Electron-withdrawing group allows substitution at the 3-position

Organic Synthesis with Pyrrole should avoid strong acids i; 1 X SO2Cl2, Et2O ii; 4 X SO2Cl2, Et2O ii

Indole Indole Alkaloids Aromatic due to 10 -electrons Benzene part is non-reactive Electrophilic aromatic substitution occurs at the 3-position Indole Alkaloids Lysergic acid (LSD) Strychnine Mitomycin C

Other Five Membered Heterocycles The least aromatic: The O atom is too electronegative Least reactive More aromatic than Furan Less reactive than pyrrole, but substitution always at 2-position Electrophilic Substitution, not addition Can give addition, as well as substitution products when reacted with E+ Thiophene has similar reactivity to benzene

Electrophilic Aromatic Substitution of Thiophene Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3

Some Reactions of Furan Furan is more reactive than thiophene Addition product Wittig reaction Hydrolysis of acetal Furan is easily cleaved to dicarbonyls

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

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 Diene 4 system dienophile 2 system 4+2 cycloaddition Otto Diels Electron rich Electron poor Kurt Alder Noble Prize in 1950

The configuration of the dienophile is retained Always reacts via the cis-diene Under kinetic control

exo-product forms as the temperature is raised Furan readily undergoes the Diels-Alder reaction with maleic anhydride Thermodynamic exo-product forms as the temperature is raised endo-product More stable due to less steric reasons Aromaticity prevents thiophene from taking part in the Diels-Alder reaction - SO2 This sulfone is not aromatic & very reactive

Five-membered Rings with Two or More Nitrogens pKa = 14.5 (imidazole) pKa = 16.5 (pyrrole) Diazoles Pyrazole Imidazole Imidazole is more basic than pyridine, but more acidic than pyrrole Imidazole + H+ NaOH Imidazole - H+ - H2O Properties: Very stable cation and anion of imidazole is formed

Some Natural Imidazole Compounds Histidine Important ligand to many metalloproteins Is one of the essential amino acids. A relatively small change in cellular pH can result in a change in its charge Body neurotransmitter & local immune response histamine histidine carboxylase Dipeptide in high concentrations in the brain & muscles - Improves social interactions & treatment of autism Carnosine

Tetrazoles are used in drugs as replacements for CO2H Indomethacin Indomethacin Tetrazole derivative Anti-arthritis drug - Non steroidal anti-inflammatory drug – reduces fever, pain, stiffness, delays premature labour & other uses

Bioreductive Anti-Tumour Agents 10 1 Mitomycin C Pyrrolo[1,2-a]benzimidazole (PBI) IC50 ≈ 1.0 µM E. B. Skibo et al., J. Med. Chem., 2002, 45, 1211 K. Fahey, F. Aldabbagh, Tetrahedron Lett., 2008, 49, 5235 More selective to hypoxia Hypersensitive to Fanconi Anemia IC50 ≈ 0.001 µM L. O’Donovan, F. Aldabbagh, Chem. Commun., 2008, 5592. 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

Targeting Hypoxic Cells

Mitomycin C (MMC) SET - activation Two electron activation + 1 e- 10 + 1 e- steps - 1 e- 1 - 1 e- . DNA alkylation CY P450 reductase Two electron activation + 2 e- + 2 H+ DNA alkylation DT-diaphorase S. E. Wolkenberg and D. L. Boger, Chem Rev., 2002, 102, 2477

Measuring the Effect of FANCD2 Expression on Cell Viability ●, ● 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

3. Chemistry of pyrrole, furan, and thiophene 63

Electrophilic substitution in pyrrole, furan and thiophene X = O, NH, or S 64

Examples: 65

Furan is able to act as a diene in the reactions of cycloaddition The Fisher synthesis of indoles 66

Nucleophilic substitution in pyridine 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. 67

Another example: These reactions require very strong nucleophiles and heat, because H- is a very weak leaving group. In ortho- or para-substituted pyridines nucleophilic substitution proceeds much easier. 68

Organic Halogens: 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

Substitution reactions in Table 6:1 have some limitations with respect to the structure of the R group in the alkyl halide 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.

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