Pharmaceutical Chemistry Lecture 3 PDF

PL1001 Pharmaceutical Chemistry CHEMISTRY OF AROMATIC COMPOUNDS Lecture 3 Dr Alberto Di Salvo Lecture 3 - content Substituent effects Activating groups Inductive and Resonance effects Preparation of Toluene Reactions of Toluene Substituent effects: Activating/...

PL1001 Pharmaceutical Chemistry CHEMISTRY OF AROMATIC COMPOUNDS Lecture 3 Dr Alberto Di Salvo Lecture 3 - content Substituent effects Activating groups Inductive and Resonance effects Preparation of Toluene Reactions of Toluene Substituent effects: Activating/Deactivating effect When a substituted benzene undergoes electrophilic attack, groups already on the ring affect the reactivity of the benzene ring toward further substitution. They can either: activate the ring (activating groups), making it more reactive than benzene, i.e. -OH substituent makes the ring 1000 times more reactive than benzene or, deactivate the ring (deactivating groups), making it less reactive than benzene, i.e. -NO2 substituent makes the ring more than 10 million times less reactive. Substituent effects: Activating/Deactivating effect INDUCTIVE EFFECT: An inductive effect is the withdrawal or donation of electrons through a sigma bond due to electronegativity and the polarity of bonds in functional groups (electrostatic interaction). - EWG EDG + Electron Withdrawing Group Electron Donating Group (i.e. -F, -Cl, -Br etc) (i.e. -CH3 etc) -I +I Substituent effects: Activating/Deactivating effect Relative rate of reaction depends on whether the substituent group (-S) withdraws or releases (donates) electrons (relative to hydrogen) S = electron releasing (donating) group (EDG): faster reaction + + S S S + E+ + + S releases elctron + E H Transition state E H Arenium ion is stabilized is stabilized Reaction is faster S = electron withdrawing group (EWG): slower reaction + + S S S + E+ + + S withdraws elctron + E H Transition state E H Arenium ion is destabilized is destabilized Reaction is slower Substituent effects: Activating/Deactivating effect RESONANCE EFFECT (or mesomeric effect): A resonance effect is the withdrawal (i.e. by -CO, -CN, -NO2) or donation (i.e. by -X, -OH, -OR) of electrons through a π bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring or donation of a lone pair of electrons... - :O :-.... - :O : : O: :O : C C C + C H H H H -M + + Electron withdrawing effect.. + + _ +.. O.. O.. O.. O H H H.. H _.. _.. +M Electron donating effect Substitution effects: Orientation Effect The orientation of the reaction is also affected by the group already present on the benzene ring. The positions on the benzene ring can be classified as follows: Subst o o Subs = Subsitutent already present on ring o = ortho position m = meta position m m p = para position p i.e. nitration of chlorobenzene yields ortho-nitrochlorobenzene (30%) and para-nitrochlorobenzene (70%). Cl Cl Cl NO2 HNO3 H2SO4 + (30%) (70%) NO2 Substitution effects: Orientation Effect Substituent groups are classified as either ortho-/para- directors or meta- directors. All activating groups are ortho-/para-directing. All deactivating groups other than the halogens are meta-directing. The halogens are unique in being deactivating but ortho- and para-directing. Substitution effects: Orientation Effect Substitution effects: Orientation Effect – Meta- Directors + + CF3 +  CF3 + E+ + + CF3 CF3 CF3 CF3 E E E E+ + Highly Ortho attack H H H unstable contributor + + CF3 CF3 CF3 CF3 + + Meta attack E+ H H H + E E E CF3 CF3 CF3 CF3 + Para attack + + E+ E E H E H Highly unstable contributor Substitution effects: Orientation Effect – Ortho-/Para- Directors : NH2 + : NH2 : NH2 : NH2 NH2 E E + E E+ E Ortho H H H H attack + + : NH2 : NH2 : NH2 Relatively stable : NH2 contributor + + Meta attack E E E+ E H H + H : NH2 + : NH2 : NH2 NH2 : NH2 + Para attack + E+ E H E H E H E H Relatively stable contributor Substitution effects: Orientation Effect – Ortho-/Para- Directing Halogens........ + : Cl: : Cl: : Cl: : Cl: : Cl: E E + E E+ E Ortho H H H H attack + +........ : Cl: : Cl: : Cl: Relatively stable : Cl: contributor + + Meta attack E E E+ E H H + H...... : Cl: +.... : Cl: : Cl: Cl: : Cl: + Para attack + E+ E H E H E H E H Relatively stable contributor * Electron withdrawing inductive effect influences reactivity ** Electron donating resonance effect governs orientation Substitution effects: summary _________________________________________________________________________________ Substituent Reactivity Orientation Inductive Resonance effect effect effect __________________________________________________________________________________ - CH3 Activating Ortho, para Weak; A None - OH, - NH2 Activating Ortho, para Weak; B Strong; A - F, - Cl, - Br, - I Deactivating Ortho, para Strong; B Weak; A - N +(CH3)3 Deactivating Meta Strong; B None - NO2, - CN, Deactivating Meta Strong; B Strong; B - CHO, - COOCH3, - COCH3, - COOH __________________________________________________________________________________ » A = electron-donating; B = electron-withdrawing Toluene (methyl-benzene): preparation Toluene can be prepared by the Friedel-Crafts alkylation of benzene. CH3 AlCl3 + CH3Cl + HCl Toluene: reactions Oxidation: Toluene can be oxidized to its corresponding carboxylic acid CH3 COOH KMnO 4 H O 2 Note: Reaction occurs with 1o and 2o, but not 3o alkyl side chains. Bromination: yields the benzylic bromide O CH3 CH2Br * N-Bromosuccinimide (NBS) N Br O CCl4 Worked example Q6. Draw the organic product from the following reaction. Cl + Cl2 + FeCl3 Q7. When a nitrobenzene (shown below) undergoes further electrophillic substitution reactions, they occur primarily at which position(s)? NO2 Answer: meta position. NO2 is electron withdrawing and leads to relatively unstable resonance contributors after attack at the ortho and para positions. No unstable contributor can be drawn after attack at the meta position