Advanced Organic Chemistry Chm 512/412 Spring Handout IX Nucleophilic Substitution Reactions Part 2

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1 Advanced Organic Chemistry Chm 512/412 Spring 2010 Handout IX Nucleophilic Substitution Reactions Part 2 Solvent Effects Gas Phase S N 2 Reactions Nucleophlicity Scales 1

2 RX Nu Type I: neutral neutral Types of S N 2 Reactions!+!- Y: + R-X Y R X Y R + X - Example: n-bu X + N X - N Bu Menshutkin Reaction => Charge increases (but neutral TS) Type II: neutral anionic!-!- Y: + R-X Y R X Y R + X - Example: Cl + Na + I - I + NaCl Finkelstein Reaction => Charge more dispersed in TS 2

3 Types of S N 2 Reactions RX Nu Type III: cationic neutral!+!+ Y: + R-X Y R X Y R + X Example: S Br - + N( ) 3 S + N( ) 3 Br - => Charge more dispersed in TS Type IV: cationic anionic!-!+ Y: + R-X Y R X Y R + X Example: N S S + -N 3 => Charge decreases in TS; neutral TS 3

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5 polar protic H 2 O MeOH EtOH COOH dielectric constant ε large (H 2 O 78.5; MeOH 32.6) solvate cations & anions X - H O M H-bonding H O ion-dipole Solvents for S N 2 Reactions dipolar aprotic S DMSO O N N P O N CH3 HMPA DMF ε large: ( ) 2 C=O CN large molar polarizability => good interaction with dispersed charges and non-polar TS * large dipole moments (2-3 times larger than H 2 O/MeOH) * - pole exposed; + pole shielded very strong solvation of cations poor solvation of anions S H O N O M + O O N DMA S non-polar hexane ether benzene CHCl 3 thf ([(CH 2 ) 4 ]O ε < 10 Not suitable ions/ion-pairs are poorly solvated 5

6 Solvation of Anions and Cations in Water 1. Hydration energies for anions are high. 2. Hydration energy increases with increasing ratio of charge/radius. 3. Hydration energy of anion higher than that of cation with same charge/radius ratio. 4. Similar trends in other protic polar solvents. 5. Strong solvation of anionic nucleophiles reduces their reactivity (nucleophilicity). 6

7 Effect of Solvent on Rates of S N 2 Reactions Examples from Parker, Chem. Rev. 69, 1-32 (1969). Type I: neutral n e u t r a l X - n-bu X + N N Bu X log(k DMF /k MeOH ) I 1.5 Br 0.8 Cl -0.2 Br + S S Br - log(k DMA /k MeOH ) = 0.5 M S log! = -0.3 RX S = DMA M = MeOH M S log! = -0.4 Y M S log! = -1.5 M S! X M S log! X S M (X) S S (X) transfer activivity coefficient of species X: change of the activity coefficient of X, if it is transfered from MeOH into Solvent S log S M (X) - log S S (X) solubility of species X in MeOH solubility of X in solvent S 7

8 2. Type II : neutral anionic Relative Rate Constants (k rel ) for the Reaction of Chloride with Methyl Iodide Solvent k rel Methanol 0.9 Water 1.0 Formamide 14.1 Nitromethane Acetonitrile DMF Acetone (A. Parker, Chem. Rev. 1969, 69, 1) 1. Nucleophile negatively charged; negative charge more dispersed in TS 2. Dipolar aprotic solvents are superior to protic solvents: log(k acetone /k MeOH ) = 6.2 Strong solvation of nucleophile by protic polar solvents TS slighly better stabilized by dipolar aprotic solvent 8

9 Type III: neutral cationic S Br - + N( ) 3 S + N( ) 3 Br - Solvent log(k solv /k MeOH ) H 2 O -0.8 EtOH 0.2 DMSO 0.8 DMF 0.8 Nucleophile lone pair stronger solvated in protic solvent Type IV: anionic cationic N S + -N 3 S Solvent log(k solv /k MeOH ) EtOH 1.0 DMF 3. 1 CN 3.7 ( ) 2 C=O 4.9 Nucleophile stronger solvated in protic solvent Situation similar to Type II reactions 9

10 Gas phase Nucleophilic Substitutions Literature: 1. Gas-phase Nucleophilic Displacement Reactions J. M. Riveros, S. M. Jose and K. Takashima, Adv. Phys. Org. Chem. 1985, 21, (available in Chemistry library; location:stacks -- QD476.A45) 2. Gas-Phase Ionic Reactions: Dynamics and Mechanism of Nucleophilic Displacements Michael L. Chabinyc, Stephen L. Craig, Colleen K. Regan, John I. Brauman Science 1995, Gas-Phase Nucleophilic Displacement Reactions. William N. Olmstead and John I. Brauman, JACS 1977, 99, Intrinsic Barriers in Nucleophilic Displacements. Mark J. Pellerite and John I. Brauman, J. Am. Chem. Soc. 1980, 102, Gas-phase nucleophilic displacement reactions John I. Brauman, William N. Olmstead, and Charles A. Lieder, JACS (1974) 96, Jayaraman Chandrasekhar, Scott F. Smith, and William L. Jorgensen J. Am. Chem. Soc. 1984, 106,

11 Gas Phase S N 2 Reactions: Thermodynamic considerations - usually only if exothermic or thermoneutral -limited dynamic range (must have small E a ) Gas Phase Reaction Rates From rates of substitution reactions (Reference 5): X - + -Y -X + Y - X = F, Cl, S; Y = Cl, Br X Y k rxn /10-10 k rel k coll /10-10 ΔH rxn /kcal/mol F Cl F Br Cl Cl 0.06 ~ Cl Br S Cl S Br k rel : F - > S - > Cl - Extended study: OH - > F - ~ O - > S - >> Cl - > CN - > Br - 11

12 Mechanism of Gas Phase S N 2 reactions (references 1 and 3) Cl - + Cl* Cl - Cl* Cl *Cl - ClCH *Cl E!E E o E o ' Reaction Coordinate E o = -8.0 kcal/mol; E o = 11.6 kcal/mol; ΔE = 3.6 kcal/mol; exothermicity = 0 kcal/mol Support for double-well potential from efficiency of reaction X = Cl: efficiency = k rxn /k coll =

13 Mechanism of Gas Phase S N 2 reactions (references 1 and 3) Cl - + Br Cl - Br Cl Br - ClCH Br E!E E o '' E o E o ' Reaction Coordinate E o = -10.3; E o = 7.8 kcal/mol; ΔE = -2.5 kcal/mol; exothermicity = -8 kcal/mol 13

14 Efficiencies of Nucleophiles in S N 2 Gas Phase Reactions (from ref 1 & 3) Ion-Molecule Complex Stabilities in the Gas Phase (from ref. 1) - 14

15 Effect of Solvation on Rate of S N 2 Reactions OH - (H 2 O) n + Br Br - (H 2 O) n + OH n = 0 k = (6.0 ± 0.12) M -1 s -1 n = 1 k = (3.8 ± 1.5) M -1 s -1 n = 2 k = (1.2 ± 0.6) 10 9 M -1 s -1 n = 3 k < M -1 s -1 n = k aq = M -1 s -1 15

16 Calculated Potential Energy Surface of a degenerated Halide Exchange Reaction. (from ref. 6) 1) Solvation flattens ion-dipole minima and increases barrier of activation 2) Sharp onset of activation barrier 3) Enhanced barrier due to less solute-solvent attraction of charge-delocalized TS compared to separated reactants. up to here, desolvation of the ion is offset by ion-dipole interactions 16

17 Effect of nucleophile on rate of S N 2 reaction Nucleophile Nucleophilicity Classical: electron donor in subst. Lewis base good donor => good nucleophile Nucleophilicity Basicity tendency to bond to C tendency to bond to H + kinetic property thermodynamic property (related to rate of substitution react.) (realated to equilibrium of a reaction with H + ) Nucleophilicity is influenced by: 1. Solvation 2. Strength of bond formed to carbon (C-Nu bond) 3. Size of Nu 4. Electronegativity of donor atom 5. Polarizability of donor atom 17

18 Empirical Rules (a) Nuc: - > Nuc-H HO - /H 2 O (b) Nucleophilicity increases from right to left within raw of periodic table (PTE) R 3 C - > R 2 N: - > RO: - > F - (c) Nucleophilicity increases within column of PTE by going downwards F - < Cl - < Br - < I -!!! Solvent dependent & only true in polar protic solvents (ROH; H 2 O) Nucleophilicity in DMSO: F - > Cl - > Br - > I - 18

19 Empirical Methods to Quantify Nucleophilicity Swain-Scott-nucleophilicity constant n (see also A & D p ) Standard reaction at 25 o -I + OH k CH3OH OH -O- + HI log k Nu /k CH3OH = n CH3I x S k Nu CH-I + Nu - -Nu + I - OH S is sensitivity of substrate to Nu (S = 1 for I) S can be determined for other reactions. e.g. R-X + Nu - R-Nu + X - log k(nu + RX) k(nu + I) vers n CH3I gives S of above reaction as slope e.g. S CH3CH2OTs =

20 Swain Scott nucleophilicicty Values, n CH3I ( OH) protic solvents (see also A & D p ) 20

21 Nucleophilicy Basicity Correlation Bronsted Relationship: Log(k) = β Nuc pk a (Nu-H) + log(c) DMSO PhCH 2 -Cl + Nu - 25 o PhCH 2 -Nu Cl - N N N S Y Y Z Y Z Z

22 Steric Requirements of Nucleophile PhNO 2 R-I + R' 3 N R' 3 NR I - N Et 3 N R-I k rel I ( ) 2 CH-I N N N N k rel with I 22

23 Counterion Effect on Nucleophilicity Aggregation (ion-pairing) with nucleophile reduces reactivity (nucleophilicity) O Bu 4 N X + n-bu-o S Br acetone N-Bu-X + - OBs O OBs Cl > Br > I with Li X Cl < Br < I 23 16

Nucleophilic Substitution and Elimination

Nucleophilic Substitution and Elimination What does the term "nucleophilic substitution" imply? A nucleophile is an the electron rich species that will react with an electron poor species A substitution