Pharmaceutical Chemistry Lecture 2 PDF

PL1001 Pharmaceutical Chemistry CHEMISTRY OF AROMATIC COMPOUNDS Lecture 2 Dr Alberto Di Salvo Lecture 2 - content Definition of arene etc Mechanism of electrophillic substitution reactions in benzene Friedel-Crafts alkylation Friedel-Crafts acylation Halogenatio...

PL1001 Pharmaceutical Chemistry CHEMISTRY OF AROMATIC COMPOUNDS Lecture 2 Dr Alberto Di Salvo Lecture 2 - content Definition of arene etc Mechanism of electrophillic substitution reactions in benzene Friedel-Crafts alkylation Friedel-Crafts acylation Halogenation of Benzene Nitration of Benzene Definitions Arenes: Aromatic hydrocarbons, as a class of compounds, are called arenes. Phenyl group: The benzene ring with one hydrogen atom removed (C6H5-) is called phenyl group, designated by Ph-. Aryl group: Aromatic hydrocarbons with one hydrogen atom removed are called an aryl group, designated by Ar-. (i.e. substituted benzene ring) Electrophile: Electron-loving or electron-deficient species. Example: +C(CH3)3 (tertiary carbocation) Electrophilic substitution of benzene An elctrophile (E+) reacts with a benzene ring and substitutes (replaces) for one of the hydrogen atoms. H E H H H H E+ (electrophile) H H H H H H The cloud of π electrons exists above and below the plane of the benzene ring. These π electrons are available to be donated to electrophiles. Electrophilic substitution of benzene Benzene’s closed shell MO configuration of six π electrons gives it a special stability. So while benzene is susceptible to electrophilic attack, it undergoes substitution reactions rather than addition reactions. Substitution reactions allow the aromatic sextet of π electrons to be regenerated after attack by the electrophile has occurred. Electrophiles attack the π system of benzene to form a delocalised non-aromatic carbocation (arenium ion or σ-complex). Electrophilic substitution: mechanism Step 1: The electrophile takes two electrons of the six-electron π system to form a σ bond to one of the carbon atoms of the benzene ring. E E E + E H H H E H arenium ion (-complex) Electrophilic substitution: mechanism Step 2: The arenium ion loses a proton from the carbon atom that bears the electrophile. E H E + H+ Examples of electrophilic substitution reactions X X2, FeX3 + HX (X = Cl, Br) Halogenation NO2 HNO3 + H2O H2SO4 Nitration SO3H SO3 H2SO4 + H2O Sulfonation R RCl, AlCl3 + HCl Friedel-Crafts Alkylation COR RCOCl, AlCl3 + HCl Friedel-Crafts Acylation Friedel-Crafts alkylation Developed in 1877 by Charles Friedel & James Crafts The FC alkylation is an electrophilic aromatic substitution reaction where the electrophile is a carbocation, R+. This carbocation is generated by AlCl3 catalysed ionisation of RX. R RX Example of RX = isopropylchloride FC alkylation: mechanism for tertiary alkyl halides Step 1: Formation of carbocation CH3 CH3 AlCl3 H3C Cl H3C + AlCl4- CH3 CH3 Step 2: Formation of arenium ion H3C CH3 CH3 CH3 H CH3 CH3 arenium ion Step 3: Loss of proton from the arenium ion H3C H3C CH3 CH3 + AlCl4- H CH3 CH3 + HCl + AlCl3 FC alkylation: mechanism for primary alkyl halides When the alkyl halide used is primary, step 1 of the mechanism is slightly different. The AlCl3 forms a complex with the alkyl halide and this complex acts as the electrophile. Cl Cl  Cl Cl + Al Cl Al Cl  Cl Cl While this complex is not a simple carbocation, it acts as if it were, and transfers a positive alkyl group to the aromatic ring. Cl Cl  Cl Al Cl Cl Al Cl  H Cl Cl + AlCl3 + HCl Examples of Friedel-Crafts alkylation FC alkylations are not restricted to the use of alkyl halide and AlCl3. Many other pairs of reagents that form carbocations (or carbocation-like species) may be used. These possibilities include using: 1) a mixture of an alkene and a Brønsted acid CH(CH3)2 HF + CH3CH=CH2 Propene Isopropylbenzene 2) a mixture of an alcohol and a Lewis acid OH BF3 + Cyclohexanol Cyclohexylbenzene Limitations to the Friedel-Crafts alkylation reaction Aromatic alkyl halides (aryl halides) or vinyl halides do not react. Reaction does not occur on rings containing strong electron withdrawing substituents (For example: -NO2, -CN, -CHO, -COR etc.) or if the ring bears an -NH2, -NHR, or -NR2 group. Multiple substitutions often take place. Carbocation rearrangements may occur Limitations to the Friedel-Crafts alkylation reaction The primary alkyl halide-AlCl3 complex may undergo a proton shift rearrangement to generate a different (more stable) 2o carbocation. AlCl3 d+ d- + CH3CH2CH2CH2Br CH3CH2CHCH2 BrAlCl3 CH3CH2CHCH3 ( BrAlCl3-) H H+ AlCl3 HBr H CH3 CH2CH3 CH2CH2CH2CH3 Butylbenzene Sec - Butylbenzene Friedel-Crafts acylation Reaction of benzene with an acid chloride to introduce an acyl group (COR) COCH3 AlCl3 + CH3COCl + HCl Excess benzene 80 oC Acetophenone [Acid chlorides can be prepared by treating carboxylic acids with thionyl chloride or phosphorus pentachloride.] Friedel-Crafts acylation: mechanism Step 1: Generation of the acyl cation O O Cl Cl + Al Cl Cl Al Cl R Cl R Cl Cl Step 2: Reaction of benzene with acyl cation Cl O Cl Al Cl O O H Cl R R R + AlCl3 + HCl The electronwithdrawing properties of the acyl group deactivate the substituted benzene ring towards further reaction, therefore poly-acylation is not a problem. Rearrangements of the acylium ion do not occur because such ion is resonance stabilised. Halogenation of benzene In presence of an anhydrous Lewis acid (e.g. FeCl3), benzene reacts readily with either bromine or chlorine to produce the corresponding halobenzene (eg bromobenzene or chlorobenzene). Cl FeCl3 + Cl2 o + HCl 25 C F2 reacts so rapidly with benzene that it requires special conditions and apparatus to carry out the fluorination. I2 is so unreactive that an oxidising agent (e.g. HNO3) has to be used to carry out the iodination. Halogenation of benzene: mechanism Step 1: Formation of the bromo (halo) cation...... + : Br Br :Br + FeBr4-.... : + FeBr3.. Step 2: Electrophilic attack of bromo (halo) cation H H.. +.... + Br: Br: Br:.. etc..... Slow + + Arenium ion Step 3: Proton abstraction and restoration of aromatic ring H Br.... - Br:.. :Br.. FeBr3 + HBr + FeBr3 + Nitration of benzene Benzene reacts slowly with hot HNO3 (conc) to yield nitrobenzene. The reaction can be faster if a mixture of HNO3 (conc) and H2SO4 (conc) is used. NO2 50-55 oC + HNO3 + H2SO4 + H3O+ + HSO4- Note: H2SO4 (conc) increases the rate of the reaction by increasing the concentration of the nitronium ion, NO2+ (electrophile). Nitration of benzene: mechanism Step 1: Generation of the nitrosyl cation (NO2+) HNO3 + 2H2SO4 NO2+ + 2HSO4- + H3O+ Step 2: Attack by nitrosyl cation O H H O N H O NO2 NO2 + H3O+ Worked example Q4. Draw the organic product of the following reaction, and explain the mechanism involved. O O + H3C c + AlCl3 CH3 Cl Q5. Draw the organic product of the following reaction. Cl + Cl2 + FeCl3