"SN2 Reaction Effect of Steric Hindrance"
SN2 Reaction: Effect of Steric Hindrance Color pictures: web.chem.ucla.edu/~harding/SN2sterics.html In an SN2 reaction, the nucleophile must approach the carbon-leaving group bond from the backside. What is the effect on the SN2 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. Note that the carbon bearing the iodide becomes less visible as hydrogens are replaced by methyls. Electrophile Ball and Stick Model Space Filling Model Methyl iodide CH3I methyl Ethyl iodide CH3CH2I primary (1o) 2-Iodopropane (isopropyl iodide) (CH3)2CHI secondary (2o) 2-iodo-2-methylpropane (tert-butyl iodide) (CH3)3CI tertiary (3o) 4 Lecture Supplement: Ionic Substitution – SN2 Solvents Solvent: A substance in which other substances are dissolved. Role of Solvent in Organic Reactions • Dissolve reactants so they can mingle and achieve transition state orientation • Disperse heat • Precipitate a product, driving equilibrium to the right • Other laboratory considerations Demonstration: Alka-seltzer tablets mix dry O HO CO2H O + NaHCO3 HO OH Citric acid Sodium bicarbonate (a solid) (a solid) mix aqueous Solvent Effects on SN2 Reaction Rate Reaction rate α Ea = energy difference between reactants and transition state Ea (A) Ea (A) Ea (B) Ea (C) solvent A solvent A solvent C Energy Energy solvent B Reaction coordinate Reaction coordinate Solvent B provides good stabilization of Solvent C provides little stabilization of reactants but little for transition state reactants but lots for transition state Ea (B) Ea (A) Ea (C) Ea (A) rate B rate A rate C rate A Lecture Supplement: Ionic Substitution – SN2 5 How Does Solvent Stabilize (Interact with) Reactants and Transition State? → Noncovalent forces (electrostatic effects) Review Chem 14C → Stronger interaction (larger charges) = more stabilization • Dipole-dipole • Ion-dipole • Hydrogen bonding • Van der Waals (weak; insignificant stabilization; ignored for simplicity) Cl surrounded by CH3OH: solvent shell provides solvation for Cl . Important Solvent 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 • Strength of interactions (stabilization): +/- > δ+/δ- > neutral • Greater number and/or magnitude of polar bonds = higher ε Example: CH3OH (ε = 33) versus CH3CH2OH (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 (O-H in common solvents) • Aprotic solvent: not protic • Example: CH3OH (protic) versus CH2Cl2 (aprotic) 6 Lecture Supplement: Ionic Substitution – SN2 Structures and Properties of Common Organic Solvents Polar solvents (ε > 20) Name Structure Proticity Dielectric constant Water O protic 80 H H O Dimethylsulfoxide aprotic 49 (DMSO) S CH3 CH3 O N,N-Dimethylformamide aprotic 37 (DMF) H N(CH3)2 Methanol (MeOH) CH3 OH protic 33 Ethanol (EtOH) CH3CH2 OH protic 25 O Acetone (2-propanone) aprotic 21 CH3 CH3 Nonpolar solvents (ε < 20) Dichloromethane ClCH2Cl aprotic 9.1 (methylene chloride) Tetrahydrofuran (THF) aprotic 7.6 O O Acetic acid (HOAc) protic 6.2 CH3 OH Ethyl ether CH3CH2OCH2CH3 aprotic 4.3 Hexane CH3(CH2)4CH3 aprotic 1.9 What Facts Must I Know About Solvents? • 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 Supplement: Ionic Substitution – SN2 7 Which Solvent is Best For SN2? Most common SN2 reaction involves charged ncuelophile, neutral electrophile, transition state with partial charges: R Nuc + R3C-LG δ- Nuc C LG δ- Nuc CR3 + LG R R Fastest SN2 (lowest Ea): need solvent that stabilizes transition state (dispersed charges) more than reactants (Nuc), so nonpolar solvent is best. Problem: Nuc (usually ionic, such as NaCl) usually not very soluble in nonpolar solvents (such as hexane). Therefore need polar solvent (such as CH3OH or DMF) to dissolve Nuc. Hydrogen bonding stabilization must be sacrified to achieve transition state (costs energy) so use aprotic solvent. (SN2 slower, but usually not stopped in polar protic solvent such as CH3OH.) = CH3OH = F hidden by CH3OH = CH3I In order for F and CH3I to reach the SN2 transition state, some CH3OH 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 Supplement: Ionic Substitution – SN2 Is Hydrogen Bonding Equal for All Solvents and Nucleophiles? Effect of solvent (DMF versus CH3OH) on the SN2 reaction rate (k) of halide ion nucleophiles: DMF (aprotic) CH3OH (protic) 1 F Cl 0 Br I -1 -2 I log k -3 -4 Br -5 Cl -6 -7 F Atomic radius conclusion: Best SN2 solvent is.... Lecture Supplement: Ionic Substitution – SN2 9 SN2 Examples Example #1: S-Adenosylmethionine (SAM): biological methylator NH2 NH2 N N N O CH3 N O O O N S N O P O P O P O N O N O O O O O SN 2 NH3 Adenosyl triphosphate (ATP) OH OH HO OH + SAM O CH3 S Methionine O NH3 • SAM involved in wide range of biological methylations. • Example: during the stress response, norepinephrine is converted into epinephrine (adrenaline): This methyl transferred NH2 NH2 N N N O N O CH3 S S N N N N O O O O NH3 NH3 HO OH HO OH SN2 + + OH Amine more nucleophilic than alcohol or phenol OH H HO NH2 HO N CH3 norepinephrine epinephrine HO HO (adrenaline) 10 Lecture Supplement: Ionic Substitution – SN2 Example #2: Synthesis of zidovudine (AZT), an inhibitor of reverse transcriptase and anti-HIV drug. 3' oxygen must become N3 Stereochemistry must be changed But HO not a leaving group O AZT O 5' oxygen must remain Ph3CO not a leaving group NH NH Ph3CO HO OH N O N O O O N3 CH3SO2Cl HCl O O sulfonate = good leaving group O NH NH H3C LiN3, DMF S O Ph3CO SN2 reaction Ph3CO N O N O O O O N3 Lecture Supplement: Ionic Substitution – SN2 11