Pharmaceutical Organic Chemistry: Aromatic Compounds PDF

PHARMACEUTICAL ORGANIC CHEMISTRY Aromatic Compounds NESTOR TORZAGLA (Ph.D.)  Definition of Aromatic Compounds  Aromatic compounds are compounds which contain six-membered benzene-like rings with three alternating double bonds. Meaning compounds that contain benzene rings in th...

PHARMACEUTICAL ORGANIC CHEMISTRY Aromatic Compounds NESTOR TORZAGLA (Ph.D.)  Definition of Aromatic Compounds  Aromatic compounds are compounds which contain six-membered benzene-like rings with three alternating double bonds. Meaning compounds that contain benzene rings in their structures are referred to as aromatic compounds. Aromatic compounds can be naturally occurring or synthetic  Naturally occurring aromatic compounds include oestrone (steroid hormone), morphine (analgesic), nucleic acids and some amino acids Definition of Aromatic Compounds  Synthetic aromatic compounds include paracetamol (analgesic) and fluoxetine (antidepressant)  Characteristics of Aromatic Compounds 1. The compound must be Cyclic and planar. 2. The compound must follow Huckel’s Rule (4n + 2) pi Electrons (n = 1,2,3,4,...) 3. Resist addition reaction but prefer substitution reaction. 4. Must have large stabilization (resonance) energy  Nomenclature of Aromatic Compounds There are a large number of non-systematic names; examples of widely used names include benzaldehyde, toluene, phenol, aniline, acetophenone, benzoic acid, ortho-xylene and styrene Nomenclature of aromatic compounds such as derivatives of benzene can be dealt with in four ways:  Monosubstituted benzene  Alkylsubstituted benzene  Disubstituted benzene  Benzene with more than two substituents Naming monosubstituted benzenes follow the same IUPAC manner as other hydrocarbons, with benzene as the parent name.  Nomenclature of aromatic compounds Alkyl substituted benzenes are named according to the size of the alkyl group. For smaller alkyl substituents (six or less number of carbon atoms), the substituted benzene is named as an alkyl substituted benzene. When the alkyl substituent is larger (seven or more carbon atoms), the compound is named as a phenyl substituted alkane. The phenyl substituent may be represented as Ph, or C6H5-  Nomenclature of Aromatic Compounds The following prefixes are used for naming disubstituted benzenes; ortho (o), meta (m) or para (p) Nomenclature of Aromatic Compounds When there are more than two substituents on the benzenes, they are named by choosing a point of attachment as carbon 1 and numbering the substituents on the ring to give lower locants to the substituents. In writing the names, the substituents are presented in alphabetical order. QUESTIONS 1.Identify which compounds are ortho-, meta- and para- disubstituted 2. Draw structures corresponding to the following systematic names: i. p-Bromochlorobenzene ii. p-Nitrotoluene iii.m-Chloroaniline iv.1-Chloro-3,5-dimethylbenzene  Structure and Stability of Benzene  The structure of benzene is described by two theories; the resonance and the molecular orbital theories.  The empirical formula of benzene was long known as C6H6 with no structure assigned.  Kekulé proposed the structure of benzene as six-membered carbon-atom ring with alternating single and double bonds (A).  The molecule oscillates between 2 equivalent structures (A and B) where the single and double bonds continuously interchange positions.   According to the resonance theory, the actual structure of benzene is a hybrid of the two Kekulé structures (A) and (B) which leads to the resonance hybrid (C). Each of structures (A) and (B) is called a canonical form of benzene. Evidence in support of the Kekulé structure of benzene  Monosubstituted benzene always formed only one product (isomer)   Disubstituted benzene formed three products (isomers) Limitations of the Kekulé structure (A and B)  Although unsaturated, the Kekulé structure does not explain why benzene fails to undergo addition reactions typical of alkenes Limitations of the Kekulé Structure  The Kekulé structure does not account for why carbon-carbon bonds of benzene have the same length (139 pm), a value between typical single bond (154 pm) and double bond (134 pm)  The Kekulé structure does not explain why the benzene molecule is unusually stable (150 kJ/mol resonance energy)  NB: The resonance theory explains why the carbon-carbon bond lengths in benzene are equal. The molecular orbital theory explains the other limitations of the Kekulé structure.  Molecular Orbital Theory The carbon atoms of the benzene molecule are sp2-hybridized with each C-atom having an unhybridized p-orbital perpendicular to the plane of the benzene ring Each p-orbital overlaps equally well with both neighbouring p-orbitals As a result, the 6 π electrons of benzene are completely delocalized around the ring, with electron density in all C-C bonds being identical The delocalization of the π system of electrons affords benzene the unusual stability. The benzene molecule is therefore conjugated and planar with the shape of a regular hexagon  Why is benzene not an alkene? Reaction with Br2 Treatment of cyclohexene with Br2 rapidly leads to the addition product 1,2- dibromocohyclxeane. However, benzene reacts only slowly and requires a catalyst to produce the substitution product Bromobenzene  Why is benzene not an alkene? Comparison of heats of hydrogenation of cyclooctatetraene, cyclohexenes and benzene When cis-Cyclooctene is hydrogenated to cyclooctane, 96 kJ mol-1 of energy is released. Cyclooctatetraene produces 410 kJ mol-1 when hydrogenated Hydrogenation of cyclohexene yields 118 kJ mol-1 of energy, while that of cyclohexa-1,3-diene produces 230 kJ mol-1 of energy Heat of hydrogenation for benzene is 206 kJ mol-1, approximately 150 kJ mol-1 less than expected, if benzene were an alkene (356 kJ mol-1) The extra stability of benzene is called aromaticity Why is benzene not an alkene?  REACTIONS OF AROMATIC COMPOUNDS Electrophilic Aromatic substitution  Electrophilic aromatic substitution is the most common reaction of aromatic compounds.  In this reaction, an electrophile (E+) reacts with the aromatic ring by substituting one of the hydrogen atoms.  Several mono-substituted aromatic compounds can be prepared by electrophilic aromatic substitution reactions.  Halogens, alkyl, acyl, nitro, sulfonic acid and hydroxyl groups can be introduced VARIOUS REACTIONS BENZENE CAN UNDERGO General Mechanism for Electrophilic Aromatic Substitution  Compared to alkenes, benzene is very unreactive  Benzene reacts with electrophiles in the presence of Lewis acid catalysts such as AlCl3, FeCl3 and FeBr3 General Mechanism for Electrophilic Aromatic Substitution  The intermediate in electrophilic aromatic substitution is a delocalized cation which is non-aromatic. The cation then loses a proton to restore aromaticity.  Compared with the starting material or the product, the cationic intermediate is unstable.  Formation of the cationic intermediate is therefore the rate determining step of an electrophilic aromatic substitution  The cation is rather stabilized by delocalization NB: The mechanism of aromatic substitution involves two steps, and an intermediate which has been stabilized by resonance  Aromatic Halogenation  Due to the high reactivity of fluorine, direct fluorination of aromatic rings lead to only poor yields of monofluorinated derivatives. Instead, electrophilic fluorinating reagents such as N-fluorobenzenesulfonimide (NFSI) and Selectfluor are used.  Cl2 and Br2 react with benzene in the presence of FeCl3/FeBr3 catalysts to form chloro/bromo benzenes.  Iodine is rather unreactive towards aromatic rings, but in the presence of oxidizing agents such as CuCl2 or H2O2, a reaction takes place leading to the formation of Iodobenzene. Aromatic Halogenation  Aromatic Halogenation NB: Electrophilic aromatic chlorination is one of the steps involved in the synthesis of diazepam (valium). Biosynthesis of several natural products in marine organisms also includes electrophilic aromatic halogenation reactions. The biosynthesis of thyroxine in humans also involves electrophilic aromatic iodination. Aromatic Halogenation  Aromatic Nitration A mixture of conc. HNO3 and H2SO4 produces a nitronium ion (NO2+) which reacts as the electrophile  Aromatic Nitration Aromatic nitration does not occur in nature, however, the nitro group can be reduced to produce corresponding arylamine (ArNH2) such as aniline  Aromatic Sulfonation  The electrophile for sulfonation of benzene can be generated when one molecule of H2SO4 protonates another and loses a molecule of water.  Aromatic sulfonation can also be achieved when the aromatic ring reacts with fuming sulfuric acid (a mixture of H2SO4/SO3)  Aromatic Sulfonation  Aromatic sulfonation does not occur in nature, however, aromatic sulfonation is utilized in the synthesis of dyes and pharmaceuticals such as sulfanilamide  Aromatic Hydroxylation Hydrolysis of benzene diazonium salts to produce phenols. Aromatic hydroxylation is an important reaction in drug metabolism leading to excretion of drug metabolites Aromatic Alkylation Synthesis of aromatic hydrocarbons can be achieved through one of the following named reactions: i. Friedel-Crafts alkylation reaction ii.Clemensen’s reduction iii.Wurtz-Fittig reaction Mechanism of Aromatic Alkylation  Aromatic Alkylation Limitations of Friedel-Crafts alkylation reactions Only alkyl halides can be used for this reaction. Aryl halides and vinylic halides show no visible reaction The reaction is not feasible with aromatic rings already having electron withdrawing substituents or amino groups (-NH2, -NHR, -NR2). The electron withdrawing substituents include –NR3+, -NO2, -CN, -SO3H, -CHO, -COCH3, - CO2H, -CO2CH3 It is difficult to control polyalkylation There can be skeletal rearrangement of the alkyl electrophile into a more stable carbocation either through 1,2-hydride shift or 1,2-alkyl shift Aromatic alkylation reactions occur in a number of biosynthetic pathways such as the synthesis of phylloquinone (Vit. K )  Friedel-Crafts Acylation Reactions An aromatic compound is treated with an alkyl chloride (RCl ) in the presence of AlCl3 catalyst The electrophile is generated by AlCl3 assisted dissociation of an alkyl halide The aromatic ring is acylated with acyl chloride (ROCl) in the presence of AlCl3  Clemmensen’s Reduction Reduction of carbonyl compounds to alkanes using Zn/Hg and HCl  Wurtz-Fittig Reaction The reaction involves aryl halides and alkyl halides in the presence of Na in dry ether to form alkyl substituted benzenes In alkyl benzenes, alkyl substituents react as aliphatic while the phenyl component reacts as an aromatic molecule  Oxidation of Alkyl Benzenes Oxidation of alkyl benzenes with strong oxidizing agents such as acidified KMNO4 produces benzoic acid Effect of Substituents in Electrophilic Aromatic Substitution Reactions Reactivity of the aromatic ring Activating substituents make the aromatic ring more reactive (e.g. – NH2, -OH, -OCH3 etc), while deactivating substituents render the aromatic ring less reactive than benzene (e.g. –CHO, -NO2, -CO2H, -CO2R, -NR3+, etc) Effect of Substituents in Electrophilic Aromatic Substitution Reactions  Substituents influence the orientation of the reaction by being either ortho/para- directors or meta- directors. The hydroxyl (-OH) and amino (-NH2) groups are otho- and para- directors; while substituents such as –CHO and –NO2 are mainly meta- directors.  Generally substituents can be classified into ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators.  Electron donation or electron withdrawal ability of substituents is controlled by the interaction between inductive and resonance effects (mesomeric effects) Electrophilic Substitution on Phenols Benzene reacts with bromine only in the presence of Lewis acid catalysts Phenols react rapidly (3x faster) without a catalyst with bromine to form a product containing three bromine atoms (2,4,6- tribromophenol) at specific positions Nitration of Phenol Nitration of phenol is problematic under normal nitration conditions since concentrated HNO3 oxidizes phenols. Dilute HNO3 is used instead. How to prepare paracetamol from phenol How to prepare salicylic acid and acetylsalicylic acid (aspirin) from phenol