S N 2 Reaction: Effect of Steric Hindrance Color pictures: web.chem.ucla.edu/~harding/sn2sterics.html

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1 2 Reaction: Effect of teric Hindrance Color pictures: web.chem.ucla.edu/~harding/2sterics.html In an 2 reaction, the nucleophile must approach the carbon-leaving group bond from the backside. What is the effect on the 2 reaction rate when the crowding increases at this carbon? Models are useful when considering this idea. The space filling models shown below represent the van der Waals radii of the atoms within the molecules. These models provide a reasonable representation of the true spatial appearance of molecules. The ball and spoke models are also shown to give an alternate view of the same molecule. The molecules are viewed along the C-I bond, with the iodine pointing away. This is the same view as the nucleophile has as it approaches along the backside of the C-I bond. ote that the carbon bearing the iodide becomes less visible as hydrogens are replaced by methyls. Electrophile Ball and tick Model pace Filling Model Methyl iodide CH 3 I methyl Ethyl iodide CH 3 CH 2 I primary (1 o ) 2-Iodopropane (isopropyl iodide) (CH 3 ) 2 CHI secondary (2 o ) 2-iodo-2-methylpropane (tert-butyl iodide) (CH 3 ) 3 CI tertiary (3 o ) 4 Lecture upplement: Ionic ubstitution 2

2 olvents olvent: A substance in which other substances are dissolved. Role of olvent in rganic Reactions Dissolve reactants so they can mingle and achieve transition state orientation Disperse heat Precipitate a product, driving equilibrium to the right ther laboratory considerations Demonstration: Alka-seltzer tablets mix dry H C 2 H + ahc 3 H Citric acid (a solid) H odium bicarbonate (a solid) mix aqueous olvent Effects on 2 Reaction Rate Reaction rate α E a = energy difference between reactants and transition state E a (A) E a (A) Energy solvent A solvent B E a (B) Energy solvent A solvent C E a (C) Reaction coordinate olvent B provides good stabilization of reactants but little for transition state Reaction coordinate olvent C provides little stabilization of reactants but lots for transition state E a (B) E a (A) E a (C) E a (A) rate B rate A rate C rate A Lecture upplement: Ionic ubstitution 2 5

3 How Does olvent tabilize (Interact with) Reactants and Transition tate? oncovalent forces (electrostatic effects) Review Chem 14C tronger interaction (larger charges) = more stabilization Dipole-dipole Ion-dipole Hydrogen bonding Van der Waals (weak; insignificant stabilization; ignored for simplicity) Cl surrounded by CH 3 H: solvent shell provides solvation for Cl. Important olvent Properties Dielectric constant (ε): Ability to insulate unlike charges from each other Higher ε = greater number and magnitude of δ + /δ - on solvent = stronger attraction to solute molecules trength of interactions (stabilization): +/- > δ + /δ - > neutral Greater number and/or magnitude of polar bonds = higher ε Example: CH 3 H (ε = 33) versus CH 3 CH 2 H (ε = 25) ε > 20 = polar solvent; ε < 20 = nonpolar solvent Proticity: Ability to donate hydrogen atom for hydrogen bond Review Chem 14C Protic solvent: can donate hydrogen atom (-H in common solvents) Aprotic solvent: not protic Example: CH 3 H (protic) versus CH 2 Cl 2 (aprotic) 6 Lecture upplement: Ionic ubstitution 2

4 Polar solvents (ε > 20) tructures and Properties of Common rganic olvents ame tructure Proticity Dielectric constant Water Dimethylsulfoxide (DM) H H CH 3 CH 3,-Dimethylformamide (DMF) H (CH 3 ) 2 protic 80 aprotic 49 aprotic 37 Methanol (MeH) CH 3 H protic 33 Ethanol (EtH) CH 3 CH 2 H protic 25 Acetone (2-propanone) onpolar solvents (ε < 20) CH 3 CH 3 aprotic 21 Dichloromethane (methylene chloride) ClCH 2 Cl aprotic 9.1 Tetrahydrofuran (THF) aprotic 7.6 Acetic acid (HAc) CH 3 H protic 6.2 Ethyl ether CH 3 CH 2 CH 2 CH 3 aprotic 4.3 Hexane CH 3 (CH 2 ) 4 CH 3 aprotic 1.9 What Facts Must I Know About olvents? Know structures, but no need to memorize. Know relationship between structure and polarity. Know if a given solvent is protic or aprotic. Learn all this by doing lots of problems, with reference to this table when needed. Lecture upplement: Ionic ubstitution 2 7

5 Which olvent is Best For 2? Most common 2 reaction involves charged ncuelophile, neutral electrophile, transition state with partial charges: R uc + R3C-LG δ- uc LG δ- C R uc CR3 + LG R Fastest 2 (lowest Ea): need solvent that stabilizes transition state (dispersed charges) more than reactants (uc), so nonpolar solvent is best. Problem: uc (usually ionic, such as acl) usually not very soluble in nonpolar solvents (such as hexane). Therefore need polar solvent (such as CH3H or DMF) to dissolve uc. Hydrogen bonding stabilization must be sacrified to achieve transition state (costs energy) so use aprotic solvent. (2 slower, but usually not stopped in polar protic solvent such as CH3H.) = CH3H = F hidden by CH3H = CH3I In order for F and CH3I to reach the 2 transition state, some CH3H molecules (arrows) of the F solvent shell must move out of the way. This desolvation reduces the stability of F, raises Ea and slows the reaction. 8 Lecture upplement: Ionic ubstitution 2

6 Is Hydrogen Bonding Equal for All olvents and ucleophiles? Effect of solvent (DMF versus CH 3 H) on the 2 reaction rate (k) of halide ion nucleophiles: 1 F DMF (aprotic) CH 3 H (protic) Cl 0 Br I -1-2 log k -3 I -4 Br -5-6 Cl -7 F Atomic radius conclusion: Best 2 solvent is... Lecture upplement: Ionic ubstitution 2 9

7 2 Examples Example #1: -Adenosylmethionine (AM): biological methylator H 2 H 2 P P P 2 H 3 CH 3 Adenosyl triphosphate (ATP) H H H H + CH 3 AM Methionine H 3 AM involved in wide range of biological methylations. Example: during the stress response, norepinephrine is converted into epinephrine (adrenaline): This methyl transferred H 2 H 2 CH 3 H 3 H 3 + H H H 2 Amine more nucleophilic than alcohol or phenol + H H H H H H 2 H CH 3 H norepinephrine H epinephrine (adrenaline) 10 Lecture upplement: Ionic ubstitution 2

8 Example #2: ynthesis of zidovudine (AZT), an inhibitor of reverse transcriptase and anti-hiv drug. 3' oxygen must become 3 tereochemistry must be changed But H not a leaving group AZT 5' oxygen must remain Ph 3 C not a leaving group H H Ph 3 C H H 3 CH 3 2 Cl HCl sulfonate = good leaving group Ph 3 C H 3 C H Li 3, DMF 2 reaction Ph 3 C H 3 Lecture upplement: Ionic ubstitution 2 11