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Unformatted text preview: Chapter 6: Nucleophilic Substitution of Haloalkanes
Guanine base of DNA Leaving group Nucleophile Nucleus Toxic The C-X Bond is Polarized
+ - Electrophilic CH3 Cl Electronegativity (4.0) (3.2) (3.0) (2.7) Trends are a function of dipoledipole and London forces Nucleophilic Substitution: General
Color scheme: Nu, E, L, and curved arrows: e-Flow - + Nu
Nucleophile (Nu) C X Nu C + X - Electrophile (E) Leaving group (L) Remember: Acid-base reactions B + H A B H +A B = Nu when H is attacked, we call it base B.
When C (or other nuclei) attacked, we call it nucleophile Nu. - conjugate acid base Note: no (simple) H calculations possible on ionic reactions; bond strengths refer to homolytic, not heterolytic, dissociation. Note: Tertiary halides are notably absent from this list. Mechanism
In general: how do we study it ?
1. Kinetics 2. Stereochemistry 3. Modify substituents: look for electronic and steric effects 4. Isotope effects: Usually H/D DH C--H < C--D 5. Modify reagents/subtrates: Nu, E, L, solvent Kinetics
For HO + CH3 Cl CH3OH + Cl Rate = k [CH3Cl][ OH] 2nd order Points to bimolecular mechanism (TS) Hence name: SN2 bimolecular, nucleophilic substitution Transition State
CH3Cl + -OH
_ ? What is TS structure? We can look at stereochemistry. CH3OH + Cl- Two extreme approaches of Nu : C X Front Back Frontside attack: Retention of configuration. Backside attack: Inversion of configuration. Which one is it?
Test: Use chiral X
enantiomerically pure C * Frontside Displacement Frontside Backside Displacement Backside H H3C CH3CH2 C S Br + I - H I R C CH3 CH2CH3 + Br Result: Inversion (no S -product) Chemical Consequences of Inversion
1. Retention: By double inversion - H H H + I +H S C C C Br SH - I R R - I R - Br CH3 CH3 CH3 2. Inversion does not necessarily mean: R S
CH3CH2O - CH3Sb + C H H3C c S a Br b S CH3CH2O C a SCH3
H c CH3 + X- - 3. Diastereoisomerization Br H S
H3C H S -CN
- Br- H CN S
H3C H R Cis R S Br I - Br- R R I Trans CH3 CH3 Leaving Group Ability "L"
(kinetic parameter) Nu + C L B + H A What makes a good L- (A-) ? Remember from the discussion on acidity: 1. Ability to accommodate e-pair (charge) : e-Negativity + resonance 2. Size of the orbital describing the e-pair. 3. Indirectly: Bond strength C--L (H--A) - - F < Cl < Br < I Halides as L
Increasing, going down periodic table (PT). Same trend as HX: Why? Because: HF HCl HBr HI pKa 3.2 -2.2 -4.7 -5.2 DH 135 103 87 71 Goes down in PT And: Orbital size increases from 2p to 3p to 4p... As noted earlier: This trend is opposite that expected on the basis of electronegativity (goes down in PT). Along a row of PT: L increases to the right
(same trend as acidity) R L or H A:
Electronegativity wins ! CH3< NH2< OH< F : pKa 50 DH 105 35 107 15.7 3.2 decreases, but 119 135 increases And: Size of orbital decreases.
In practice: only F- is a reasonable leaving group in this row. Hydroxide can be, in special cases. Generally: L increases to the right and down PT. But, superimposed on these trends: Resonance. For example, for same leaving atom, e.g., RO : O O CH3O < CH3CO < CH3S O
(of acid) 15.5 4.7 -1.2 O Neutral L are good: relatively nonbasic
1. Protonated alcohols: L = H2O + R OH + H +H R O H Nu- R Nu + H2O Use ROH plus HBr, or HI, or H2SO4 + R N N + Nu 2. Diazonium ions: L = N2 , a superleaving group R Nu + N N For practical purposes: Here is where L- ability ends (going down PT) Nucleophilicity "Nu"
(kinetic parameter) Affected by charge, basicity, solvent, polarizability, sterics. 1. Charge (for same atom): HO > H2O ; H2N > H3N ; SO4 > ROSO3 The more charged, the more nucleophilic
2- 2. Basicity: Decreases to the right in PT, so does Nu: H3N > H2O ; H2N > HO ; HO > F
Comparison of neutral and charged Nu: (See pKa table) - - H2N > HO > H3N > F > H2O As expected: Trend opposite L ability - - - Down the PT: Murky! Basicity goes down, hence Nu should too (opposite L). But not true: Nu increases! The reason: Solvent effects and polarizability (deformability of orbital of
Nu ) have a strong influence.
+ + For charged Nu- :
- + Protic solvents have acidic H ; e.g., RO H or R Nu - H OR hydrogen bonds: N H. -using They surround charged Nu , Protic Solvents: Fluoride is a Worse
Nucleophile Than Iodide
+ + Hydrogen bonds + + Solvent shell increases "size" of Nu - , hence Nu increases going down PT. For uncharged Nu , same trend, but now due to polarizability H2O < H2S < H2Se (CH3)3N < (CH3)3P Polarizability operates also for charged Nu, which already benefit from lesser solvation: especially fast. Increasing Polarizability Improves Nucleophilicity More polarizable Less polarizable The Story Changes In Polar Aprotic Solvents, Which dissolve salts do not form H bonds enable formation of "naked" anions
cause huge rate increases with all Nu follow trends in basicity SolventMeOH SolventDMF Review: Range of Nucleophilicities
Depends on: charge basicity polarizability H-bonding Summary Trends in the Periodic Table
e-Negativity > DH and orbital size L
or NuProtic solvent, polarizability e-Negativity < DH and orbital size "Naked" anions, aprotic solvents Steric Effects
Sterics for L: Larger = better Sterics for Nu: Larger = worse, e.g., CH3O > (CH3)3CO
- Sterics around E are the most significant. Sterics around electrophilic R Br + I :
CH3 145 CH3CH2 1 C L R I + Br- relative rates
(CH3)2CH 0.078 (CH3)3C 0 Alpha versus beta branching: : Mechanism changes CH3CH2 CH3CH2CH2 (CH3)2CHCH2 (CH3)3CCH2 1 0.8 0.03 slow! 10-5 DireStr Walba ...
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