rganic Chemistry CM 314 Dr. Laurie S. Starkey, Cal Poly Pomona Alkyl alides: Substitution Reactions - Chapter 6 (Wade) Chapter utline I. Intro to RX (6-1 - 6-7) II. Substitution Reactions A) S N 2 (6-8, 6-9, 6-12) B) S N 1 (6-13, 6-14) C) Leaving Groups, LG (6-11, 11-5) D) Nucleophiles, Nu: (6-10) E) S N 2 vs. S N 1 (6-16) III. Competing Reactions A) Carbocation Rearrangements (6-15) B) Intro to Elimination Reactions (6-17 - 6-21) (Elimination rxns continued in CM 315 & Ch. 7) IV. Solvent Effects (6-10B, 6-13C) 6-1 I. Introduction to Alkyl alides (RX) Types of alides, X = F,, Br, I R X alkyl halide - can be 1, 2, 3, allylic, benzylic - can be prepared by free-radical halogenation (Chapter 4) X vinyl halide (on pi bond) X aryl halide (on benzene ring) Reactivity of Alkyl alides X Nu: base Substitution (CM 314) (replace X with Nu:) (Nu: = nucleophile) Elimination (CM 315) ( - X) (forms an alkene) II. Substitution Reactions Example: Nu: E + product LG Nucleophile (Nu:) - electron-rich (lone pair or pi bond), often has negative charge - seeks electron-deficient species Electrophile (E + ) - electron-poor (δ+ or +) - seeks electron-rich species Leaving Group (LG) - group leaves and takes 2 electrons with it - stable groups (weak bases) make good LG's (e.g., X -, halide) Why are -, Br - and I - good LGs? General Reaction: Nu: R LG Nu LG R 6-2
General Reaction: Nu: R LG Nu LG R What are the possible mechanisms for this substitution reaction? A) simultaneous (concerted) B) stepwise (LG leaves first) 6-2 this is called the S N 2 mechanism (6-8, 6-9, 6-12) this is called the S N 1 mechanism (6-13, 6-14) II. A) S N 2 - Substitution Nucleophilic Bimolecular (Wade 6-8, 6-9, 6-12) Example: C 2 I Mechanism: one step, backside attack S N 2 Kinetics Rate = k [ - ] [ C 2 I] - rate is dependant on both Nu: and E+ - bimolecular reaction - sterics affect the rate of S N 2 R group consider tert-butyl bromide: Kinetics experiment: R Br R Br CN :CN 2 abbrev. carbon type relative rate C 2 C3 C C C C 2 Rate of S N 2 (by type of RX):
S N 2 Energy vs. Progress of Reaction Diagram 6-3 If LG carbon is too sterically hindered (e.g., 3 ), then: E PR S N 2 Transition State Structure I I Transition State (TS) (high energy, partial bonds/charges) What is the hybridization of the carbon in the transition state? sp 4?! Note: the presence of a neighboring (conjugated) p orbital would be good for the S N 2 mechanism because TS would be stabilized (see Wade section 15-10) e.g., allylic LG (next to a pi bond)
Stereochemistry of the S N 2 Mechanism backside attack inversion of stereochemistry 6-4 Nu C 2 typical line drawing point of view: Nu LG is a wedge - like a flipped umbrella - can only be observed at a chiral center - S N 2 usually changes configuration (R to S or S to R), because usually the LG and the Nu: are both #1 priority group S N 2 Summary - one-step mechanism - inversion of stereochemistry Rate (by RX type) methyl > 1 > 2 >> 3 - requires: 1) unhindered LG (on tetrahedral sp 3 carbon) 2) good Nu: (negative charge or N 3 ) Predict the Major Product(s) (S N 2) Include stereochemistry, where appropriate. Write N.R. if no reaction is expected. I Na Br NaCN Na N 3 Br
II. B) Example: S N 1 - Substitution Nucleophilic Unimolecular (Wade 6-13, 6-14) 6-5 C C C C Could this be an S N 2 mechanism? Still a substitution, but a different mechanism (stepwise). S N 1 Mechanism: two key steps (but usually three total steps) Step 1 Loss of the leaving group Step 2 Addition of nucleophile S N 1 Kinetics Rate = k [t-bu] - rate-determining step involves E + only (unimolecular reaction) - rate is independent of [Nu:] - a more stable carbocation will be formed faster Rate of S N 1 (by type of RX): S N 1 Energy vs. Progress of Reaction Diagram Structure of first Transition State, TS-1 E Structure of TS-2? PR
Stereochemistry of the S N 1 Mechanism 6-6 carbocation intermediate racemization S N 1 results in racemization (loss of stereochemistry) due to the achiral carbocation intermediate. (S N 1) NaI (R) acetone (solvent) S N 1 Summary - stepwise mechanism via carbocation Rate (by RX type) benzyl/allyl/3 > 2 >> 1, methyl - more stable carbocation = - racemization occurs - requires: 1) stable carbocation (not 1 or methyl) 2) weak Nu: (usually the solvent, 2 or R, is the nucleophile = "solvolysis") Solvolysis: S N 1 Mechanism is three steps (6-13, 6-14) Example: - Nu: is 2 or R - final deprotonation step required Br Br 6-7
Predict the Major Product(s) (S N 2 or S N 1 mechanism? See Wade 6-16) Include stereochemistry, where appropriate. Write N.R. if no reaction is expected. 6-7 K I C Na Br NaI Which would be the faster reaction (A or B)? Explain. (Consider first: S N 2 or S N 1 mechanism?) A B 2 2 Br Br II. C) Leaving Groups (Wade 6-11, 11-5) - weak bases make good leaving groups - more stable = less reactive, weaker base - typical leaving group? halide (X - ) (all have strong conj. acids:, Br, I) Leaving groups F < Br < I Is the Forward or Reverse reaction favored? Best substitution reaction has best LG leaving (gives more stable products so Δ < 0 and ΔG < 0) Na Na
ydroxide, -, is a poor leaving group BUT we can make it better. There are two methods. 1. Add a strong acid (acid protonates the alcohol to make a great LG, 2 ) 6-8 R / Br / I R / RBr / RI 2 mechanism: Na 2. Make a tosylate LG (see Wade 11-5) Ts base S tosyl chloride, Ts Ts tosylate base (- ) Nu: Nu Ts S Nu: S Ts (tosylate LG) why is this more stable than -? Synthesis/"Transform" Problem - Provide the reagents needed to transform the given starting material into the desired product. More than one step may be required. I II. D) Nucleophilicity (Nucleophile strength) (Wade 6-10)
II. D) Nucleophilicity (Nucleophile strength) (Wade 6-10) 1. More electron-rich, better Nu: 6-9 2 2. Periodic Trends: across row: decreasing nucleophilicity N 3 2 down a family: generally increasing nucleophilicity (BUT this trend depends on solvent!) I Good Nucleophiles (Nu:)!!!!!R!! S RS!! CN!N 3!!I!Br!!!! N 3!N 2 R R 3 P!! Weak Nucleophiles (Nu:)!!! 2 R Summary of Substitution Reactions Alkyl Group S N 1 S N 2 3 (tertiary) common rare (N/R) 2 (secondary) sometimes sometimes 1 (primary) rare (N/R) common (methyl) never (N/R) common allyl/benzyl common common (if not 3 )
II. E) S N 2 vs. S N 1 (Wade 6-16) 6-10 S N 2 requires strong Nu: and minimal steric hindrance S N 1 requires a stable carbocation and typically involves a weak Nu: See page 6-7 for examples, and S N 2/S N 1 Predict the Product homework for practice problems. After attempting the homework, let's look more closely at the following problems: C 2 C 2 C 2 C Na III. A) Competing Reactions: Carbocation Rearrangements (Wade 6-15) Ts 2 C C C C 2 C C C C C C 2 Alkyl groups can also shift Et
IV. Solvent Effects (Wade 6-10B, 6-13C) Both S N 1 and S N 2 reactions need PLAR solvents to stabilize charges in the mechanism. 6-11 Protic - has an group - extremely polar - strongly stabilizes charges Aprotic - has no group Solvent Effects on Reaction Rates if you INCREASE solvent polarity, then S N 1 is and S N 2 is e.g. using a protic solvent instead of an aprotic solvent e.g. going from an 80:20, Et: 2 solvent to 50:50 Why is a more polar solvent GD for an S N 1 mechanism? (speeds it up) 2 - carbocation will be better stabilized by more polar solvent - C+ intermediate and transition state are more stable/lower E polar aprotic - E a (lower height of hill), rate of reaction E - S N 1 is FASTER in a more polar solvent PR Why is a more polar solvent BAD for an S N 2 mechanism? (slows it down) Br Br - nucleophile will be better stabilized by more polar solvent - Nu: is more stable, less reactive polar aprotic - E a (increased height of hill), rate of reaction E - S N 2 is SLWER in a more polar solvent PR
CM 314 - We Studied Three Types of Reactions 1. Acid-Base Reaction (proton transfer) (Chapter 1) 6-12 B: A B A: base acid * equilibrium shifts to more stable, weaker acid/base pair 2. Free-Radical alogenation Reaction (Chapter 4) R alkane * for bromination, major product comes from the best (most stable) radical 3. Substitution Reactions (Chapter 6) R LG Br 2 hv R Nu: Nu R LG * S N 2 and S N 1 mechanisms * equilibrium shifts to loss of better (more stable) leaving group, LG Br alkyl halide For each type of reaction, be prepared to: - Predict the major product(s) - Provide detailed reaction mechanisms (curved arrows, etc.) - E vs. PR diagrams, drawing transition states, etc. - Explain stuff (e.g., regiochemistry, stereochemistry, reaction rates, equilibrium direction, etc.) III. B) Competing Reactions: Elimination Rxns (Wade 6-17 - 6-21) (9th Ed. 7-10 - 7-16) E1 Mechanism - Elimination Unimolecular involves carbocation (like S N 1) (or 2 /hv to make R-) These reactions (and all of Chapters 1-6) will be on the cumulative final exam! E2 Mechanism - Elimination Bimolecular one-step mechanism (like S N 2) involving a strong base Na CM 315...competition between all FUR: Substitution (S N 1/S N 2) and Elimination (E1/E2)!