Chapter 08 Nucleophilic Substitution Part 02

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1 hapter 08 Nucleophilic Substitution Part 02 EM 341: Spring 2012 Prof. Greg ook 2012 Gregory R ook

2 Solvent Effects in Nucleophilic Substitution R X Y R Y X SLVENT Polar reactions - we need polar solvents non-polar solvents alkanes l 4 polar protic solvents polar aprotic solvents 3 N acetonitrile 3 S 3 DMS - dimethylsulfoxide ( 3 ) 2 N P N( 3 ) 2 N( 3 ) 2 MPA - hexamethylphosphortriamide N 3 3 DMF - dimethylformamide Gregory R ook

3 Solvent Dielectric onstant Gregory R ook

4 Solvents in the SN2 Mechanism transition state SLVENT RELATVE RATE FR S N DMS DMF 3 N MPA , Gregory R ook

5 Polar Aprotic best for SN2 δ- 3 S 3 δ transition state Polar aprotic solvents can separate and stabilize ionic reagents. 3 3 δ 3 S S 3 δ δ- δ- 3 S 3 3 δ- δ- Na S 3 δ δ δ- 3 S δ 3 δ- S 3 δ δ δ- S 3 3 S δ- δ Gregory R ook

6 Polar Aprotic best for SN2 δ- 3 S 3 δ transition state Polar protic solvents like water will surround a nucleophile with -Bonds making it less reactive. Thus, protic solvents retard the rate of S N 2 reactions Gregory R ook

7 Solvents in the SN1 Mechanism R R R RDS R RR carbocation intermediate R R 2 (- ) R R R R SLVENT RELATVE RATE FR S N , , Gregory R ook

8 Polar Protic best for SN1 Mechanism R R R R R R RDS 2 R R RR R R carbocation intermediate (- ) δ- δ Polar solvents stabilize the carbocation by surrounding it with the negatively charged oxygens δ δ δ R δ δ δ Protic solvents stabilize the leaving group by surrounding it with acidic protons Br Gregory R ook

9 omparison of SN1 and SN2 S N 1 S N 2 SUBSTRATE 3 >> 2 > 1 1 > 2 >> 3 NULEPLE Weak K Strong LEAVNG GRUP Stable Anions Stable Anions SLVENT Polar Protic Polar Aprotic STEREEM Racemic 100% inversion Gregory R ook

10 Elimination vs Substitution E1 Elimination X RDS Rate = k [R-X] X E2 Elimination X RDS Rate = k [R-X] [base - ] X Gregory R ook

11 Elimination vs Substitution Basicity of the anion and Structure of the alkyl halide and/or base most important Br Na % 87% Na 2 3 Br % 9% Gregory R ook

12 Elimination vs Substitution - substrate Gregory R ook

13 Elimination vs Substitution Bulky bases favor E2 over SN2 3 Na 3 R Br R R 13% 87% Gregory R ook

14 Elimination vs Substitution Base strength vs nucleophilicity l NaN N DMS Gregory R ook

15 Elimination vs Substitution Tertiary substrates will undergoe elimination under even mild basic conditions. Under neutral conditions, SN1 substitution will take place. Br major minor 3 2 Na 2 3 minor major Gregory R ook

16 Sulfonates as Leaving Groups R S S S l a sulfonic acid p-toluenesulfonic acid p-toluenesulfonyl chloride (Tos-l) R S l pyridine R S Gregory R ook

17 Leaving Group Abilities Gregory R ook

18 Stereochemistry of Tosylation-Substitution Tos-l Tos NaN N pyridine DMF inversion PBr 3 inversion Br NaN DMF inversion N Gregory R ook

19 Summary of Elimination vs Subsitution R-X S N 1 E1 S N 2 E2 1 X X favored favored with strong base 2 3 ok favored in protic solvents no base ok can compete witn S N 1 favored with strong nucleophile X favored with strong base favored with strong or weak base Gregory R ook

20 Som examples Br A: NaN, MPA B: K( 3 ) 3, ( 3 ) 3 Br Br A: 3 2 Na B: 3 2 Na A: Na 2 3 B: 3 2, heat Gregory R ook