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Chapter 11

Chapter 11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations. Introduction. Alkyl halides – are polarized at the carbon- halide bond, making the carbon electrophilic – are electrophiles. Alkyl halides – react with nucleophiles and bases

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Chapter 11

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  1. Chapter 11 Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

  2. Introduction • Alkyl halides – are polarized at the carbon- halide bond, making the carbon electrophilic – are electrophiles

  3. Alkyl halides – react with nucleophiles and bases – undergo substitution of X by Nu – undergo elimination of HX to yield an alkene

  4. Substitution: Nucleophiles will replace the X in C-X bonds (act as Lewis bases) • Elimination: Nucleophiles that are Brønsted bases produce elimination

  5. A.The Discovery of the WaldenInversion • In 1896, Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagents

  6. Reactions of the Walden Inversions

  7. Discovery of the Walden Inversion • This established that optical rotation was directly related to chirality and that it changes with chemical alteration • Reaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acid • Further reaction with wet silver oxide gives (+)-malic acid • The reaction series starting with (+)-malic acid gives (-)-malic acid

  8. Significance of the Walden Inversion • The reactions alter the array at the chirality center • The reactions involve substitution at that center • Therefore, nucleophilic substitution can invert the configuration at a chirality center • The presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Walden’s cycle

  9. B.Stereochemistry of NucleophilicSubstitution

  10. Kenyon and Phillips, 1929, studied the interconversion of 1-phenyl-2-propanol enantiomers to isolate step: • Only the second and fifth steps are reactions at carbon • So inversion certainly occurs in the substitution step

  11. The inversion of stereochemical configuration takes place in the second step, the nucleophilic substitution of tosylate ion by acetate ion

  12. Practice Problem: What product would you expect to obtain from a nucleophilic substitution reaction of (S)-2- bromohexane with acetate ion, CH3CO2-? Assume that inversion of configuration occurs, and show the stereochemistry of both reactant and product

  13. C.Kinetics of Nucleophilic Substitution • Reaction rate – is the exact rate at which a reactant is converted into product • Kinetics – is useful for helping determine reaction mechanisms

  14. Definitions of Terms • Rate (V)- is change in concentration with time • - depends on concentration(s), temperature, inherent nature of reaction (barrier on energy surface) • A rate law - describes relationship between the concentration of reactants and conversion to products • A rate constant (k) - is the proportionality factor between concentration and rate • Example: for S converting to P • V = d[S]/dt = k [S]

  15. Kinetics– is the study of rates of reactions • Rates decrease as concentrations decrease but the rate constant does not • Rate units: [concentration]/time such as L/(mol x s) • The rate law– is a result of the mechanism • The orderof a reaction – is sum of the exponents of the concentrations in the rate law

  16. Second-order reaction –is a reaction in which the rate is linearly dependent on the concentration of two species Reaction rate = k x [RX]x[OH-] where [RX] = CH3Br concentration [OH-] = OH- concentration k = a constant value

  17. D.The SN2 Reaction • SN2 reaction – Substitution – Nucleophilic – Bimolecular • Bimolecular - Nu and RX take part in the step whose kinetics are measured • Second-orderkinetics: rate = k x [RX]x[Nu] • Inversion of stereochemistry at the carbon atom • No intermediate/ Single step

  18. The entering Nuapproaches the halide from a direction 180o away from the leaving group, resulting in an umbrella-like inversion

  19. The transition state is planar

  20. Practice Problem: What product would you expect to obtain from SN2 reaction of OH- with (R)-2-bromobutane? Show the stereochemistry of both reactant and product.

  21. Practice Problem: Assign configuration to the following substance, and draw the structure of the product that would result on nucleophilic substitution reaction with HS- (reddish-brown = Br)

  22. E.SN2 Reaction Characteristics • The effects of four variables on SN2 reactions: • Substrate: SN2 reactions are best for methyl and primary substrates • Nucleophile: Basic, negatively charged nucleophiles are more effective than neutral ones • Leaving group: Stable anions that are weak bases are good leaving groups • Solvent: Polar aprotic solvents

  23. Reactant and Transition-state Energy Levels Affect Rate • Higher reactant energy level (red curve) = faster reaction (smallerG‡). • Higher transition-state energy level (red curve) = slower reaction (largerG‡).

  24. The Substrate: Steric Effects in the SN2 Reaction • SN2 reactions are sensitive to steric effects • SN2 reactions occur only at relatively unhindered sites • Methyl halides are most reactive • Primary are next most reactive • Secondary might react • Tertiary are unreactive by this path • No reaction at C=C (vinyl halides) and aryl halides

  25. SN2 reactions are sensitive to steric effects The carbon atom in (a) bromomethane is readily accessible resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions.

  26. Order of Reactivity in SN2 • The more alkyl groups connected to the reacting carbon or near it, the slower the reaction • Methyl halides are most reactive • Primary are next most reactive • Secondary might react • Tertiary are unreactive by this path

  27. No reaction at C=C (vinyl halides) and aryl halides • This is due to steric factors

  28. The Substrate: Steric Effects in the SN2 Reaction • SN2 reactions are best for methyl and primary substrates • Steric Hindrance raises Transition State Energy, thus increasing G‡ and decreasing the reaction rate • Steric effects destabilize transition states • Severe steric effects can also destabilize ground state

  29. The Nucleophile • Neutral or negatively charged Lewis base • Reaction increases coordination at nucleophile • Neutral nucleophile acquires positive charge • Anionic nucleophile becomes neutral

  30. Relative Reactivity of Nucleophiles • It depends on substrate, solvent, and reactant concentration • More basic nucleophiles react faster (for similar structures) • Better nucleophiles are lower in a column of the periodic table • Anions are usually more reactive than neutrals

  31. Relative Reactivity of Nucleophiles • Nucleophilicity roughly parallels basicity • More basic nucleophiles react faster (for similar structures) • Nucleophilicity measures the affinity of a Lewis base for carbon atom • Basicity measures the affinity of a base for a proton

  32. Relative Reactivity of Nucleophiles • Nucleophilicity roughly parallels basicity • Nucleophilicity usually increases going down a column of the periodic table • Negatively charged Nu are usually more reactive than neutral ones

  33. Practice Problem: What product would you expect from SN2 reaction of 1-bromobutane with each of the following? • NaI • KOH • H-CΞC-Li • NH3

  34. Practice Problem: Which substance in each of the following pairs is more reactive as a nucleophile? • (CH3)2N- or (CH3)2NH • (CH3)3B or (CH3)3N • H2O or H2S

  35. The Leaving Group • A good leaving group • reduces the barrier to a reaction • stabilizes the negative charge well • is a weak base (i.e. anion derived from strong acids)

  36. Stable anions that are weak bases are usually excellent leaving groups • They can delocalize charge

  37. Stable anions that are weak bases are usually excellent leaving groups due to T.S formed • They distribute the negative charge over both the Nu and the leaving group • The greater the extent of charge stabilization, the lower the energy of the transition state and the more rapid the reaction

  38. Poor Leaving Groups • If a group is very basic or very small, it prevents reaction

  39. Practice Problem: Rank the following compounds in order of their expected reactivity toward SN2 reaction: CH3Br, CH3OTos, (CH3)3CCl, (CH3)2CHCl CH3Br CH3OTos (CH3)3CCl (CH3)2CHCl

  40. The Solvent • Protic solvents (with -OH or -NH groups) that can form hydrogen bonds slow SN2 reactions by associating with reactants(solvation) • Energy is required to break interactions between reactant and solvent • Polar aprotic solvents (no -NH, -OH, -SH) form weaker interactions with substrate and permit faster reaction

  41. Protic solvents i.e. solvents that can form hydrogen bonds (-OH or -NH) slow SN2 reactions • They cluster around or solvate the reactant nucleophile lowering its ground-state energy and reactivity

  42. Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction • They increase the rate of SN2 reactions by raising the ground-state energy of the Nu. HMPA = hexamethylphosphoramide

  43. Examples ofpolar aprotic solvents (no NH, OH, SH)include: • DMF= dimethyl formamide (CH3)2NCHO • DMSO= dimethyl sulfoxide (CH3)2SO • HMPA= hexamethylphosphoramide [(CH3)2N]3PO • acetonitrile CH3CN • Due to their high polarity, these solvents solvate metal cations rather than nucleophilic anions

  44. Practice Problem: Organic solvents such as benzene, ether, and chloroform are neither protic nor strongly polar. What effect would you expect these solvents to have on the reactivity of a nucleophile in SN2 reactions?

  45. SN2 Reaction Characteristics: Summary Substrate: SN2 reactions are best for methyl and primary substrates • Steric hindrance raises the energy of the transition state, thus increasing DG‡ and decreasing the reaction rate.

  46. Nucleophile: Basic, negatively charged nucleophiles are more effective than neutral ones • More reactive nucleophiles are less stable and have a higher ground-state energy, thereby decreasing DG‡ and increasing the reaction rate.

  47. Leaving group: Stable anions that are weak bases are good leaving groups • Good leaving groups (more stable anions) lower the energy of the transition state, thus decreasing DG‡ and increasing the reaction rate.

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