Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy INTRODUCTION What is a REACTION MECHANISM? It provides insight into electron movement and bonding that takes place during a chemical transformation. It provides a useful means of predicting the product(s) of chemical reactions. It provides unequivocal proof of the given pathway (in terms of electron movement and binding) that a reaction follows. Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) ADDITION SUBSTITUTION ELIMINATION Electrophilic Nucleophilic Electrophilic Nucleophilic EW C C R R R R C O R 1 R 2 C C R R R X H R Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) ELECTROPHILES electron-poor species those that possess:
greatly reduced electron density, e.g., BF 3 , AlCl- 3
Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) NUCLEOPHILES electron-rich species which may have:
excess negative charges; fractional negative charges; or lone pairs of electrons that can readily be used for formation of bonding molecular orbitals e.g., carbanions, hydroxides, alkoxides, sulfides, halides, cyanides, carboxylates, phenoxides and azides Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) ADDITION ELECTROPHILIC REACTIONS Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) ADDITION NUCLEOPHILIC REACTIONS Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) ADDITION NUCLEOPHILIC REACTIONS (continued) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) SUBSTITUTION ELECTROPHILIC REACTIONS Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) SUBSTITUTION ELECTROPHILIC REACTIONS (continued) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) SUBSTITUTION NUCLEOPHILIC REACTIONS C X + - + Nu - C Nu + X -
OH SH NH 2 CN OR SR NHR CCR Nu - = NR 2
X = Cl Br I A substitution reaction in which a nucleophile (Nu - ) replaces a leaving group (L) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) SUBSTITUTION NUCLEOPHILIC REACTIONS Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) SUBSTITUTION NUCLEOPHILIC REACTIONS (continued) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Nu - C X C X Nu - X - C Nu -
Nu -
X -
C Nu -
C X + C Nu C Nu S N 2 S N 1 Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Rate = k [RX][Nu - ] Substitution Nucleophilic Bimolecular (S N 2) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) C C 6 H 13
CH 3
Br H C C 6 H 13
CH 3
H HO NaOH S N 2 ()-2-Bromooctane [] = 39.6 0 100% OP (+)-2-Octanol [] = +10.3 0 100% OP Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) k 1
k 2 k 2
Rate = k 1 [RX] Substitution Nucleophilic Unimolecular (S N 1) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) S N 2 S N 1 Second-order kinetics First-order kinetics Rate = k [RX][Nu - ] Rate = k 1 [RX] Complete stereochemical inversion Racemization (and inversion) Absence of rearrangement Rearrangement CH 3 W > 1 0 > 2 0 > 3 0 3 0 > 2 0 > 1 0 > CH 3 W Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Factors Affecting Mechanism 1. Nature of leaving group 2. Nature of alkyl group of the substrate 3. Nature of nucleophile 4. Concentration of nucleophile 5. Nature of solvent Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Reactivity of Leaving Group Rate of Both S N 2 and S N 1 1. Nature of leaving group Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) 2. Nature of alkyl group of the substrate SN1 Reactivity Increases SN2 Reactivity Increases Steric Hindrance Carbocation Stability Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) S t r e n g t h
o f
N u c l e o p h i l e
Charge Electronegativity Delocalization Strong nucleophile favors S N 2. Weak nucleophile favors S N 1. 3. Nature of nucleophile Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) An increase in [Nu - ] speeds up the second-order reaction but has no effect on the first-order reaction. 4. Concentration of the nucleophile A decrease in [Nu - ] slows down the second-order reaction but has no effect on the first-order reaction. [Nu - ] S N 2 S N 2 [Nu - ] indirectly favors the S N 1
favors the S N 2
Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) 5. Nature of solvent Polar Aprotic Solvent S N 2 Polarity Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Polar protic Solvent S N 1 Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) C H C + C R C + C H C C + C H C R C C C R + + + Rearrangement (1,2-Shift) - takes place to yield a more stable carbocation Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Rearrangement (1,2-Shift) C H 3 CH 2 CH 2 + C H 3 CH + CH 3 C H 3 C CH 2 + CH 3 H C H 3 C + CH 3 CH 3 C H 3 C CH 2 + CH 3 CH 3 C H 3 C + CH 2 CH 3 CH 3 Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Rearrangement (1,2-Shift) C H 3 C CH 2 CH 3 CH 3 Br C 2 H 5 O - ? C H 3 C CH 2 CH 3 CH 3 Br C 2 H 5 OH ? Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) ADDITION-SUBSTITUTION REACTIONS - involving the carbonyl center Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) AROMATIC NUCLEOPHILIC SUBSTITUTION Cl N + N + O - O O - O + Nu - Nu N + N + O - O O - O + Cl - Cl + Nu - Nu + Cl - H + , H 2 O
Department of Pharmaceutical Chemistry
University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) ELIMINATION REACTIONS Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Rate = k 1 [RX] Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Rate = k [RX][B - ] Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Factors Affecting Mechanism (S N vs E) 1. Stability of alkene product 2. Nature of nucleophile Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) Elimination Increases Substitution Increases C H 2 CH 2 C CH 2 R H C CH 2 R R C C H R R H C C R R R H C C R R R R 1. Stability of alkene Department of Pharmaceutical Chemistry University of the Philippines ManilaCollege of Pharmacy ORGANIC REACTIONS (Review) 2. Nature of Nucleophile weakly basic nucleophile substitution (I - , Br - , RS - , N 3 - , RCOO - )
strongly basic nucleophile and highly branched elimination /sbmSS2011-2012