Chap. 8 Substitution Reactions Y + R X R' Y + X Nucleophilic not necessarily the same as R Electrophilic S N 1 slow (C 3 ) 3 CCl (C + Cl - 3 ) 3 C + (C 3 ) 3 C + OC 2 C 3 C 3 C 2 O C 3 C 2 O d[( C ) 3CCl] rate = 3 = k[( C3) CCl 3 ] dt (C 3 ) 3 C OC 2 C 3 S N 2 C 3 O - C + 3 O C 3 Br 3 C O C 3 + Br - nucleophile nucleofuge d[ C Br] rate = = k[ C3Br][ C3O dt 3 The rxn mechanism encompasses a wide spectrum two-dimensional rxn coordinate diagram for S N 2 ] L loose transition state T tight transition state P product-like TS (late) R reactant-like TS (early) extreme of loose TS extreme of tight TS an energy minimum S N 1 carbocation interm. carbanion interm S N Ar an energy minimum
Three dimensional rxn coordinate with E as third axis Effect of moving down (stabilizing) the energy of a corner (species) move the TS away from the corner along the rxn coordinate Effect of moving down (stabilizing) the energy of a corner (species) perpendicular to the rxn coordinate, shift the TS toward the corner. a better leaving group E The effect of nucleophile, substrate, leaving group, solvent on the geometry and energy of TS can be analyzed based on these principles with better leaving group, the TS shift toward the left.
S N 1 Reaction k 1 R X R + + X - k -1 R + + Y - k 2 R Y d[ R Y ] rate = = k dt s. s. a [ R ][ Y d[ R+ ] = 0 = k1[ R X ] k dt k1[ R X ] [ R+ ] = k [ X ] + k [ Y ] 1 1 k1k2[ R X ][ Y Rate = k [ X ] + k [ Y 2 ] ] 2 2 + 1 ] [ R + ][ X ] k if [X - ] very small (early stage) k -1 [X - ] << k 2 [Y - ] Rate = k 1 [R X] if [X - ] increases, rate decreases (common ion effect) Effect of Structure on S N 1 reaction rate of solvolysis 3 > 2 > 1 > methyl parallel the stability of carbocation size of R 1, R 2, R 3 in R 1, R 2, R 3 C-X rate of solvolysis for R(C 3 ) 2 CCl, rel.rate 1 for Me rate of bridgehead system 1.67 Et 1.58 Pr rel reactivity 2 [ R + ][ Y ] Effect of Solvent Grunwald-Winstein eq log(k/k 0 ) = my where Y = log(k t-bucl, solvent, k t-bucl, methanol ) m sensitivity of the substrate to solvent ionizing power Y ionizing power
Schleyer s eq rate in a given solvent log(k/k 0 ) = l N OTs + my OTs rate in reference solvent, 80% ethanol N OTs solvent nucleophilicity l sensitivity to solvent nucleophilicity Y OTs ionizing power m sensitivity to ionizing power Y OTs = log (k/k 0 ) for 2-Adamantyl tosylate OTs N OTs = log (k/k 0 ) 0.3Y OTs S N 1 rxn is first order rxn in substrate no nucleophilic rxn possible for C 3 OTs both nucleophilic rxn and ionizing rxn possible if sp 2 -hybridized intermediate is formed racemization for chiral S.M. Sometimes partial inversion is observed (characteristic of S N 2) Solvated ions and ion pairs Solvated ion
First order in Cl 3 C C 3 independent of added Cl - no common ion effect chloride in B may come from the molecule itself ion-pair mechanism
Anchimeric assistance (Neighboring group participation) O Br ( )-threo Br + 3 C C 3 achiral if the S N 1 rxn has no anchimeric assistance, the product will contain meso-product in addition to the racemic 2,3-dibromobutane Br Br + Br dl B S -4.2 trans-tosylate rate of acetolysis for trans-tosylate cis-tosylate 10 3 1 Evidence of anchimeric assistance 1. stereochem. 2. rate O C 3 O OTs OTs 5 1 phenyl group participation through
S N 2 reaction backside attack with inversion at carbon from chiral iodide, the rate of racemization is twice the rate of incorporation of radioactive *I Solvent effect depend on solvation energy of reactants and transition state 1. negative nucleophile + neutral substrate rate increases with lower polarity, non-hydroxylic solvent 2. neutral nucleophile + neutral substrate rate increases with increasing polarity 3. negative nucleophile + positive substrate rate increases with lower polarity 4. neutral nucleophile + positive substrate rate increases with lower polarity Polar solvent can increase solubility of ionic nucleophile, less polar solvent increase the rate. use crown ether or special solvent to increase solubility / reactivity of nucleophile
C 3 I + Cl - C 3 Cl + I - 32.7 78.4 111 35.9 35.9 36.7 20.6 protic aprotic the nucleophilicity can change dramatically in different solvent in protic solvent I - > Br - > Cl - in aprotic solvent Cl - > Br - > I - strongly solvate in solvents with polarity lower than 2 O, the activation energy lies between that of gas phase and 2 O Substrate Effect Steric effect R-Br + *Br - *Br-R +Br - in acetone Increasing Steric hindrance
Electronic effect R-Cl + *I - R-I +Cl - in acetone dual attraction or stabilization of TS via -system Nucleophilicity relate to polarizability kinetic Nucleophilicity and Basicity are related but not necessarily equilibrium Brønsted correlation Nucleophilicity Basicity The correlation does not hold if the attacking atom is different, e.g. O - 103 mroe basic S - 104 more nucleophilic
Swain-Scott equation log(k n /k 0 ) = s n n nucleophilicity of a nucleophile s sensitivity of substrate to the nuclephile Edward s equation log(k n /k 0 ) = Eu + = pka + 1.74 Eu = E 0 + 2.60 relate to basicity relate to oxidization potent log(k n /k 0 ) = A P + B B basicity (from pk) P polarizability (from mole refractivity) Leaving group Effect The more stable the detached leaving group, the more stable the product system Leaving group ability (Nucleofugality) 2 O > C 3 O > Br - > NO 3- > I - > F - > Cl - > SCN - > (C 3 ) 2 S > C 6 5 O - > N 3 > C 6 5 S - > C 3 O - > CN - > > N 2- >> - > 3 C - Compare the basicity of the leaving group (or the acidity of the conjugate acid) Different solvent can change the leaving gp ability
Electrophilic Aromatic Substitution S E Ar Basic step General Mech. 1. generation of attacking species strong medium weak + NO 2 2 2 SO 4 + NO 3 + NO 2 + 2 SO - 4 + 3 O + Br 2 or Br 2 -MX n Br 2 + MX n Br 2 -MX n R 3 C + R 3 CX + MX n R 3 C + + [MX n+1 ] - O RC O + R CX + MX n RC O + + [MX n+1 ] - NO + NO 2 + + N O + + 2 O 2. Formation of encounter complex ( -complex) 3. Formation of -complex 4. Loss of proton Depending on the electrophile & substrate, rate-determining step can be either of these. Kinetic evidence for the mechanism reaction rate, kinetic isotope effect, Ipso substitution OC 3 OC 3 [NO 2 + ] ( not ) substitution of a substituent by another substituent.
resemble reactant positive charge is small on the ring less sensitive to substituent low and low positional selectivity highly reactive electrophile positive charge is substantial on the ring resemble -complex high and high positional selectivity relative to late transition state middle T.S. early transition state
r.d.s. less reactive substrate rate depend on substrate conc n as well as electrophile r.d.s. more reactive substrate rate independent of subst. conc n the deprotonation step is not shown if r.d.s. a primary KIE will be observed Evidence of -complex C 3 C 3 + C 2 3 F + BF 3 BF 4-8.40 C 2 5 3.30 C 3 C 3 SO 2 + F-SbF - 5 SbF 6 9.38 5.05 C 3 C 3 salt isolated at low temp. m.p.(dec.) -70, elem. anal. NMR temp. dependent C 3 C 3
For Substituted aromatics, the reaction sites are non-equivalent. activating & ortho, para-directing gp alkyl, OC 3, -NR, deactivating & meta-directing gp -NO 2, - + NR 3 deactivating & ortho, para-directing gp Cl, Br C 3 Y E C 3 more stabilized by alkyl group E Y more stabilized by lone pair E more stabilized by conjugation E E - O N O Cl E E strongly destabilized Partial Rate factors E k rate for the rxn of substituted derivative k rate for the rxn of benzene if f Z > 0 activating f Z <0 deactivating f Z o Z,f Z p Z > f o, p directing Z m Z
low selective Partial rate factors relate 1. substrate selectivity 2. positional selectivity high substrate selectivity large differences in rate of rxn low reactivity of electrophile low substrate selectivity high reactivity of electrophile positional selectivity relates to substrate selectivity In general Electrophilie with high substrate selectivity will have low ortho para ratio and negligible meta Electrophiles of low substrate selectivity low position selectivity Selectivity factor S = log f f f P m for toluene for toluene strongly correlate with f P high substrate selective high positional selective intermediate highly selective
PMO Theory of directing effect if the T.S. is similar to the intermediate -complex E a pentadienyl cation with 4e - (late T.S.) The cation charge is on C 1, C 3, C 5 for a substituent with positive charge on atom directly bond to the ring, there will be electrostatic repulsion. meta-directing for C=O, C N, NO 2 Nucleophilic Aromatic Substitution S N Ar First order ψ 5 7 1. ψ 4 ψ 3 ψ 2 + ψ1 7 +1. 0.57 0 0.57 E 0.57 0 coefficients of MOψ 3 a substituent will have little effect if at meta-position, since it s a node there Second order good leaving gp Driving force 1. The site of reaction is the leaving group position, as is not a good leaving group no isomeric mixture formation. 2. a strong e - -withdrawing NO 2, -CN at ortho, para-position is needed to stabilize the adduct Br N Br NO 2 N NO 2
Benzyne OC 3 OC 3 NaN 2 liq. N 3 N 2 Br CF 3 CF 3 Cl amino is at the site of leaving gp or one carbon away the S.M. or product does not isomerize under same rxn condition reactivity Br > I > Cl >> F *C-labeling expt. N 2 proposed rxn mech. same intermediate or mechanism for the formation of both product trapping exp. concerted + stepwise D-labeling expt. D KN D F 2 /N 3 D D F D D F D Cl D 100% loss of D 0% Anilinar formation 100% 0% 100% 0% 13% 28% stepwise
Product Distribution in Benzyne Rxns considered as e-withdrawing since the anion is in sp 2, orthogonal to the -system relative stability determines the prod. distribution R = CF 3, m-product favored C 3, ~ equal mixture meta- if R = e - -donating group if R = e - -withdrawing ortho- meta- if R = e - -donating group if R = e - -withdrawing