+ + CH 11: Substitution and Elimination Substitution reactions

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1 C 11: Substitution and Elimination Substitution reactions Things to sort out: Nucleophile Electrophile -- > substrate Leaving Group S N 2 S N 1 E 1 E 2 Analysis Scheme Kinetics Reaction profile Substrates and steric concerns Strength of nucleophile Leaving Group Ability Solvent Effects Stereochemistry S N 2 Nucleophilic Substitution involving two molecules in RDS. Kinetics The classic one step reaction! + + LG Nu: 3 C LG Nu C 3 Rate = k [R-LG] [Nu: - ] bimolecular mechanism requires collisions between two molecules. Transition state Orbital view, in which Nu = LG. 1

2 Generalized Reaction Profile, in which Nu =/= LG Note the reversibility and the positions of the reactants and products. Substrates and Sterics R group Rxn rate C 3 1 C 3 C x 10 2 C 3 C 2 C x 10 2 (C 3 ) 2 C 8.3 x 10 4 (C 3 ) 3 CC x 10 7 (C 3 ) 3 C 0 Substrates and hybridization Draw the transition state of the reaction of Nu: -- with Vinyl bromide. Strength of the Nucleophile A nucleophile is like a base. The strength of a base is determined from the pka of the conjugate acid. If A is a strong acid, A is a weak base. What is the pka range? If A is a weak acid, A is a stronger base. What is the pka range? What is the difference between a base and a nucleophile? ow would you classify S - vs O - in terms of basicity? In terms of nucleophilicity? 2

3 Relative Nucleophilic Strength Species Name Relative nucleophilicity NΞC cyanide 126,000 S thiolate 126,000 I Iodide 80,000 O hydroxide 16,000 Br Bromide 10,000 N 3 Azide 8,000 N 3 Ammonia 8,000 NO 2 Nitrite 5,000 Cl chloride 1,000 C 3 CO 2 acetate 630 F fluoride 80 C 3 O methanol 1 2 O Water 1 Trends in Nuclephilicity ot nucleophiles Reasonable nucleophiles Not-so-good nucleophiles Good nucleophiles have high or low negative charge. Good nucleophiles are large and polarizable or small and compact. Which direction in a row increases nucleophilicity? In a column? ow do nucleophiles differ from bases? Effect of Leaving Group Poor bases are better LG; good bases are poor LG. Good LGs are stabilized as anions. Good LGs are CBs of of strong acids. Poor LGs are less stable anions. Poor LGs are CBs of weak acids. 3

4 Classic Issue in organic chemistry: Alcohols are stable because O - is a poor LG Alternative strategy is to associate O with an atom that makes a stronger bond than the C-O bond. The O-S bond stabilizes the negative charge on O. ighly oxidized SO 4 2- called sulfate, organo version R-SO 3 - called sulfonate, the most popular one is called tosylate. Solvent Effects Polar solvents are necessary to separate ions and stabilize the rather polar transition state. ow is the polarity of solvents measured? NaO is not soluble in hexane. NaO is soluble in water. ow about acetone? Alcohol? 4

5 owever, protic solvents inhibit small compact nucleophiles (especially F - and O). Protic solvents essentially are - bonding solvents. Polar Aprotic Solvents Resonance Structures O O O - O - 3 C C 3 acetone O DMF N C 3 C 3 C 3 C 3 ( 3 C) 2 N N S C 3 DMSO O P MPA N(C 3 ) 2 N(C 3 ) 2 C + 3 C C 3 acetone O - DMF N + C 3 C 3 S + 3 C C 3 DMSO ( 3 C) 2 N 3 C C + N - O - P + MPA N(C 3 ) 2 N(C 3 ) 2 Acetonitrile Acetonitrile Polar Protic Solvents 2 O C 3 O C 3 C 2 O C 3 N 2 5

6 Common Solvents for Organic Reactions Name Structure bp, o C dipole moment dielectric constant water -O methanol C 3 -O ethanol C 3 C 2 -O propanol C 3 C 2 C 2 -O butanol C 3 C 2 C 2 C 2 -O formic acid acetic acid formamide acetone tetrahydrofuran (TF) methyl ethyl ketone ethyl acetate acetonitrile N,N-dimethylformamide (DMF) diemthyl sulfoxide (DMSO) hexane C 3 (C 2 ) 4 C benzene diethyl ether C 3 C 2 OC 2 C methylene chloride C 2 Cl carbon tetrachloride CCl

7 Stereochemistry S N 2 reactions proceed with inversion of stereochemistry. I Br NaI acetone I Br (R) Does R always go with S? O Cl 3 C I NaO 2 O (S) O Cl C 3 S N 1 Nucleophilic Substitution with one molecule in RDS -- unimolecular S N 2 cannot always take place if the factors above prevent it. When substitution occurs anyway, the mechanism must be different. I Mechanism Rate = k [(C 3 ) 3 Br] only the concentration of the 3 0 alkyl halide 7

8 Reaction as such as it is. Reaction is usually solvolysis. The reaction rate is proportional to the stability of the cation Rate is proportional to Stability of C+ R 3 C+ ~ benzylc 2 + > R 2 C+ ~ allylc+ > 2 RC+ >> 3 C+ Role of Nucleophile 8

9 Leaving Group Ability Would S N 1 favor good or poor LG? Role of Solvent: Solvent stabilizes the heterolytic cleavage formation of cation and anion. What does this mean to S N 2 reactions? Stereochemistry leads to racemization Examples -- Solvolysis What is the role of the solvent? Why is there a slight ee in this reaction? 9

10 There is no clear distinction between the two mechanisms, but there are trends. Classify these reactions as S N 1 or S N 2 C 2 C 2 3 C C2 + CN Br C 3 alcohol (fast) C 2 C 2 + Br - 3 C C2 CN C 3 alcohol R + CN Br (slower) S C 3 alcohol 3 C C C 2 Br + CN No reaction (slower) C 3 3 C alcohol 3 C C 3 C Br C + 3 S S C + Br - 3 C C R 2 (fast) S C 2 C 3 3 C alcohol 3 C C 3 C Br C + 3 S S C + Br - 3 C C R 2 (slower) S C 2 C 3 3 C C 2 C 2 2 O 3 C C 2 C 2 C 2 C 2 C 3 3 C C Br 3 C C O O C C 3 3 C C S acetonitrile C C S R 2 C 2 C3 10 CN Br

11 Predict products and mechanisms from these substitution reactions: Answers at Elimination Elimination is the formation of an alkene by removing -LG from a molecule. Is the nucleophile a base (-seeker) or a C-seeker 11

12 E 1 Mechanism S N 1 vs E 1 Zaitseff s Rule and Regiochemstry There must always be a Beta- available for elimination to occur. 12

13 Mechanism of E 1 elimination E 2 Bimolecular elimination always needs strong base Rate = k [R-LG] [base] E 2 vs S N 2 Base vs Nucleophile 13

14 E 2 vs S N 2 Substrate too hindered E 2 vs S N 2 --Beta- available and sterics sufficient Mechanism of E 2 process 14

15 E 2 occurs with anti-periplanar relationship between LG and Beta- This can lead to stereoselectivity. Explain the product ratios. Why do you get both cis and trans alkenes? For Summary of S N 1, S N 2, E 1 and E 2 go to this link There is also a table on p