PharmD Program Fall 2024 Lecture 8 PDF

PharmD Program Fall 2024 Pharmaceutical Organic Chemistry-I PC 102 Prof. Dr. Ehab Gedawy  Chemistry of Aromatic Compounds Lecture 8 ✓ Reactivity & orientation in electrophilic SE reactions  Reactivity & orientation in electrophilic SE r...

PharmD Program Fall 2024 Pharmaceutical Organic Chemistry-I PC 102 Prof. Dr. Ehab Gedawy  Chemistry of Aromatic Compounds Lecture 8 ✓ Reactivity & orientation in electrophilic SE reactions  Reactivity & orientation in electrophilic SE reactions When substituted benzene undergo SE reactions the already present substituent affect, 1.The rate of SE reactions (Reactivity). If Z donates electrons to benzene ring, If Y withdraws electrons to benzene ring, the ring will be more electron rich & the ring will be poorer in electron & will reacts faster with E+ in SE reactions will reacts faster with E+ in SE reactions.... Y is called Electron withdrawing groups.. Z is called Electron donating groups ▪ (groups with +M effect): ▪ (groups with -M effect): -NH2, -NHR, -NR2, -OH, -OR, -OCOR, -NHCOR -CHO, -COR, -COOH, -COOR, -CONH2, -SO3H, -C≡N, -NO2, ▪ (groups with +I effect): -R, -Ar ▪ (groups with -I effect): -NH3+ ,-CF3, -CCl3, -F, -Cl, -Br, -I 2. Position of the incoming substituent (orientation). A substituent on the ring can also affect the orientation (position in the ring) that the incoming group takes when it replaces a hydrogen atom on the ring Substituents according to their effect on orientation may be either: Ortho–para directors Meta directors Direct the incoming group to a position ortho or para Direct the incoming group to a position meta to itself to itself E+ E+ -NH2, -NHR, -NR2, -OH, -OR, -OCOR, -NHCOR -CHO, -COR, -COOH, -COOR, -CONH2, -R, -Ar -SO3H, -C≡N, -NO2, -F, -Cl, -Br, -I -NH3+ ,-CF3, -CCl3 According to their effect on orientation & reactivity we can classify substituents into: - A- Activating (electron donating) & o-, p- directing groups: Substituents that ↑ Rate of SE reactions & direct the incoming group to o-, p- positions. Powerful activating groups Moderate activating groups Groups with +M effect Groups with +I effect -NH2, -NHR, -NR2, -OH, -OR, -OCOR, alkyl groups (-R), aryl groups (-Ar) -NHCOR Groups that have an unshared electron pair Groups that could stabilize the formed C+ on the atom (oxygen or nitrogen) directly intermediate through inductive effect (+I effect). bonded to the aromatic ring,. examples examples  e.g.1 e.g.2 e.g.3 e.g.4  e.g.5 ❑ Explain why hydroxy group is activating & o- & p- directing groups???? ✓ Hydroxy group has electron-donating effect through mesomeric effect (+M) that increases electron density benzene ring & so activate the ring + Mesomeric (+M) effect Also, (+M) effect stabilize the formed σ-complex intermediate especially that resulted from –o and –p attack. 4 Resonance structures (more delocalization of + ve charge) (especially stable) Explanation: (especially stable) 4 Resonance structures (more delocalization of + ve charge) ❑ Explain why alkyl group in alkylbenzene is activating & o- & p- directing groups???? R group are electron-donating groups & have +I effect, so, they can activate a benzene ring toward electrophilic substitution by stabilizing the formed σ-complex. +I effect of R- ↑ Electron-density +I effect of R- stabilize the Of ring, so activate ring towards formed C+ σ-complex SE reactions G = -OR, -OCOR, -NHCOR , -R, -Ar N.B. in case highly activating groups such as, NH2 , NHR, -NR2, -OH; special condition are needed B- Deactivating (electron-withdrawing) & m- directing groups: ▪ Substituents that ↓ Rate of SE reactions & direct the incoming group to m- positions. Powerful deactivating groups Moderate deactivating groups Groups with -M effect Groups with -I effect -CHO, -COR, -COOH, -COOR, -NH3+ ,-CF3, -CCl3 -CONH2, -SO3H, -C≡N, -NO2 examples examples e.g. 1 e.g. 2 e.g. 3  e.g. 4 Explain why nitro group is deactivating & m- directing groups ???? ✓ Nitro group has electron-withdrawing effect through mesomeric effect (-M effect) & inductive effect (-I effect) that decreases electron density of benzene ring & so deactivate the ring & ↓ rate of SE reactions - Mesomeric (-M) effect of nitro group: ✓ Also, Nitro group destabilize the formed σ-complex intermediate especially those resulted from o- & p- attack. (especially unstable) (especially unstable) Y = -CHO, -COR, -COOH, -COOR, -CONH2, -SO3H, -C≡N, -NO2 , -NH3+ ,-CF3, -CCl3 C- Deactivating & o-, p- directing groups: Substituents that ↓ rate of SE reactions & direct the incoming group to o-, p- positions. -F ; -Cl ; -Br ; -I e.g.1 e.g.2 ❑ Explain why halogen o-, p- directing although they deactivating group ????? Halogens has –I & +M effect but their –I effect ˃˃˃ +M effect. + Mesomeric (+M) effect of chloro- atom:- +M effect of halogens is weaker than OH & NH2 because p orbital of carbon & halogen are of different size carbon has 2p orbital but Cl has 3p orbital ,Br has 4p orbital & I has 5p orbital, so the overlapping between them [2p-3p or 2p-4p or 2p-5p] is less effective than 2p-2p overlap [between C & N or O] X = -F, -Cl, -Br, -I No Reaction ▪ In case compounds with 2 or more rings; one them is activated & other is deactivated ▪ If we use excess from the reactant; reaction will occur in both ring in the activated in o- & p- positions & in the deactivated in m-positio ▪ If we use equimolar concentrations from the reactants (means 1 : 1 mole from benzene & reagent); reaction will occur only in the activated ring in both p- & o- positions Orientation in disubstituted benzenes: 1- The two substituents may direct the entering group into the same position i.e reinforce each other, e.g. nitration of p-nitrotoluene, Example: → 2- Activating groups are usually stronger directors than deactivating groups: Example 1: → Example 2: → 3- When the directing effects of the two substituent groups oppose each other, the more powerful activating group determines the orientation of the incoming group, e.g. bromination of p-toluidine Example: → 4- When the two opposing substituents have approximately equal directing ability, mixture of products are formed. e.g., nitration of o-chlorotoluene gives 4 isomers.  Test your self: Q1) Complete the following equations? 3) 1) 4) 2) 6) 5) 8) 7) 9) 10) Q2) Suppose the steps (equations with all required reagents) for synthesis of the following compounds starting from benzene. Q3) What monobromination product (or products) would you expect to obtain when the following compounds undergo ring bromination with Br2 and FeBr3?