1 Chapter 7 Alkyl Halides and Nucleophilic Substitution

2 Alkyl halides : organic molecules containing a halogen atom bonded to an sp 3 hybridized carbon atom. Alkyl halides are classified as primary (1 ° ), secondary (2 ° ), or tertiary (3 ° ), depending on the number of carbons bonded to the carbon with the halogen atom. The single most important factor that determines the reactivity of alkyl haide. Introduction to Alkyl Halides Alkyl Halides and Nucleophilic Substitution

3 Allylic halides : X bonded to the carbon atom adjacent to a C—C double bond. Benzylic halides have X bonded to the carbon atom adjacent to a benzene ring. Introduction to Alkyl Halides

4 Alkyl Halides and Nucleophilic Substitution Vinyl halides have a halogen atom (X) bonded to a C—C double bond. Aryl halides have a halogen atom bonded to a benzene ring. Introduction to Alkyl Halides

5 Alkyl Halides and Nucleophilic Substitution Nomenclature F: fluoro Cl: chloro Br: bromo I: iodo

6  Common names are often used for simple alkyl halides. Nomenclature Alkyl Halides and Nucleophilic Substitution 2-iodo-2-methylpropane chloroethane

7 weak polar molecules dipole-dipole interactions incapable of intermolecular hydrogen bonding. Physical Properties Alkyl Halides

8 Physical Properties Alkyl Halides

9 Interesting Alkyl Halides Alkyl Halides

10 Alkyl Halides Interesting Alkyl Halides DichloroDiphenylTrichloroethane

11 The Polar Carbon-Halogen Bond

12 Alkyl Halides and Nucleophilic Substitution Three components are necessary in any substitution reaction. General Features of Nucleophilic Substitution Lewis acid Lewis base

13 Alkyl Halides and Nucleophilic Substitution Since the identity of the counterion is usually inconsequential, it is often omitted from the chemical equation. General Features of Nucleophilic Substitution When a neutral nucleophile is used, the substitution product bears a positive charge.

14 Alkyl Halides and Nucleophilic Substitution when the substitution product bears a positive charge and also contains a proton bonded to O or N, General Features of Nucleophilic Substitution To draw any nucleophilic substitution product: Find the sp 3 hybridized carbon with the leaving group. Identify the nucleophile, the species with a lone pair or  bond. Substitute the nucleophile for the leaving group and assign charges (if necessary) to any atom that is involved in bond breaking or bond formation. the initially formed substitution product readily loses a proton in a BrØnsted-Lowry acid-base reaction, forming a neutral product.

15 The Leaving Group For example, H 2 O is a better leaving group than HO ¯ because H 2 O is a weaker base. Alkyl Halides and Nucleophilic Substitution The more stable the leaving group X:¯, the better able it is to accept (accommodate) an electron pair.

16 There are periodic trends in leaving group ability: The Leaving Group Equilibrium will favor products of nucleophilic substitution when the leaving group is a weaker base than the in-coming nucleophile.

17 The Leaving Group Alkyl Halides and Nucleophilic Substitution

18 Alkyl Halides and Nucleophilic Substitution The Leaving Group

19 Alkyl Halides and Nucleophilic Substitution The Leaving Group

20 Alkyl Halides and Nucleophilic Substitution Nucleophiles v.s. bases structurally similar: both have a lone pair or a  bond. They differ in what they attack. The Nucleophile

22 Basicity : a measure of how readily an atom donates its electron pair to a proton. It is characterized by an equilibrium constant, K a in an acid-base reaction, making it a thermodynamic property. Nucleophilicity: a measure of how readily an atom donates its electron pair to other atoms. It is characterized by a rate constant, k, making it a kinetic property. Alkyl Halides and Nucleophilic Substitution The Nucleophile

23 Alkyl Halides and Nucleophilic Substitution Nucleophilicity parallels basicity in three instances: 1.For two nucleophiles with the same nucleophilic atom, the stronger base is the stronger nucleophile. The relative nucleophilicity of HO ¯ and CH 3 COO ¯, two oxygen nucleophiles, is determined by comparing the pK a values of their conjugate acids (H 2 O = 15.7, and CH 3 COOH = 4.8). HO ¯ is a stronger base and stronger nucleophile than CH 3 COO ¯. 2.A negatively charged nucleophile is always a stronger nucleophile than its conjugate acid. HO ¯ is a stronger base and stronger nucleophile than H 2 O. 3.Right-to-left-across a row of the periodic table, nucleophilicity increases as basicity increases: The Nucleophile

24 Alkyl Halides and Nucleophilic Substitution Nucleophilicity does not parallel basicity when steric hindrance becomes important. Steric hindrance : a decrease in reactivity resulting from the presence of bulky groups at the site of a reaction. Steric hindrance decreases nucleophilicity but not basicity. Sterically hindered bases that are poor nucleophiles are called nonnucleophilic bases. The Nucleophile – steric factor

25 Alkyl Halides and Nucleophilic Substitution If the salt NaBr is used as a source of the nucleophile Br ¯ in H 2 O, the Na + cations are solvated by ion-dipole interactions with H 2 O molecules, and the Br ¯ anions are solvated by strong hydrogen bonding interactions. The Nucleophile – solvent effect

26 Alkyl Halides and Nucleophilic Substitution In polar protic solvents, nucleophilicity increases down a column of the periodic table as the size of the anion increases. This is the opposite of basicity. The Nucleophile – solvent effect protic solvents : compounds with OH or NH bond polar protic solvents

27 Alkyl Halides and Nucleophilic Substitution Polar aprotic solvents also exhibit dipole—dipole interactions, but they have no O—H or N—H bonds. Thus, they are incapable of hydrogen bonding. The Nucleophile – solvent effect

28 Alkyl Halides and Nucleophilic Substitution Polar aprotic solvents solvate cations by ion—dipole interactions. Anions are not well solvated because the solvent cannot hydrogen bond to them. These anions are said to be “naked”. The Nucleophile – solvent effect

29 Alkyl Halides and Nucleophilic Substitution In polar aprotic solvents, nucleophilicity parallels basicity, and the stronger base is the stronger nucleophile. Because basicity decreases as size increases down a column, nucleophilicity decreases as well. CH 3 CH 2 CH 2 CH 2 -Br + N 3 -  CH 3 CH 2 CH 2 CH 2 N 3 + Br - Solvent CH 3 OH H 2 O DMSO DMF CH 3 CN HMPA Rel. rate x10 5 example

30 Alkyl Halides and Nucleophilic Substitution The Nucleophile

31 Alkyl Halides and Nucleophilic Substitution In a nucleophilic substitution: Mechanisms of Nucleophilic Substitution Possible mechanisms In this scenario, the mechanism is comprised of one step. In such a bimolecular reaction, the rate depends upon the concentration of both reactants, that is, the rate equation is second order. [1] Bond making and bond breaking occur at the same time.

32 Alkyl Halides and Nucleophilic Substitution Mechanisms of Nucleophilic Substitution In this scenario, the mechanism has two steps and a carbocation is formed as an intermediate. Because the first step is rate-determining, the rate depends on the concentration of RX only; that is, the rate equation is first order. [2] Bond breaking occurs before bond making.

33 Alkyl Halides and Nucleophilic Substitution Mechanisms of Nucleophilic Substitution This mechanism has an inherent problem. The intermediate generated in the first step has 10 electrons around carbon, violating the octet rule. Because two other mechanistic possibilities do not violate a fundamental rule, this last possibility can be disregarded. [3] Bond making occurs before bond breaking.

34 Alkyl Halides and Nucleophilic Substitution Mechanisms of Nucleophilic Substitution Kinetic data show that the rate of reaction [1] depends on the concentration of both reactants, which suggests a bimolecular reaction with a one-step mechanism. S N 2 (substitution nucleophilic bimolecular) mechanism.

35 Kinetic data show that the rate of reaction [2] depends on the concentration of only the alkyl halide. This suggests a two-step mechanism in which the rate-determining step involves the alkyl halide only. S N 1 (substitution nucleophilic unimolecular) mechanism. Alkyl Halides and Nucleophilic Substitution Mechanisms of Nucleophilic Substitution

36 Alkyl Halides and Nucleophilic Substitution S N 2 Mechanism Kinetics Rate = k[CH 3 Br][CH 3 COO - ] one step mechanism

37 Alkyl Halides and Nucleophilic Substitution S N 2 Mechanism backside attack

38 Alkyl Halides and Nucleophilic Substitution S N 2 Mechanism -- stereochemistry Frontside attack : Nu approaches from the same side as the leaving group Backside attack : Nu approaches from the opposite side as the leaving group

39 Alkyl Halides and Nucleophilic Substitution All S N 2 reactions proceed with backside attack of the nucleophile, resulting in inversion of configuration at a stereogenic center. S N 2 Mechanism -- stereochemistry

40 Alkyl Halides and Nucleophilic Substitution S N 2 Mechanism -- stereochemistry S R S R

41 Alkyl Halides and Nucleophilic Substitution S N 2 Mechanism -- stereochemistry

42 Influence of Identity of R group on S N 2 reactions Methyl and 1° alkyl halides undergo S N 2 reactions with ease. 2° Alkyl halides react more slowly. 3° Alkyl halides do not undergo S N 2 reactions. This order of reactivity can be explained by steric effects. Steric hindrance caused by bulky R groups makes nucleophilic attack from the backside more difficult, slowing the reaction rate. Alkyl Halides and Nucleophilic Substitution

43 Alkyl Halides and Nucleophilic Substitution Influence of Identity of R group on S N 2 reactions Substrate (CH 3 ) 3 CBr (CH 3 ) 3 CCH 2 Br (CH 3 ) 2 CHBr CH 3 CH 2 Br CH 3 Br 3 o hindered 1 o 2 o 1 o methyl (neopentyl) Rel. rate < x x 10 6

44 Alkyl Halides and Nucleophilic Substitution Influence of Identity of R group on S N 2 reactions

45 Alkyl Halides and Nucleophilic Substitution

46 Alkyl Halides and Nucleophilic Substitution Application: Useful S N 2 Reactions

47 S N 2 reaction in Nature Nucleophilic substitution reactions are important in biological systems as well. methylation Alkyl Halides and Nucleophilic Substitution Application: Useful S N 2 Reactions

48 Alkyl Halides and Nucleophilic Substitution two step mechanism, carbocations -- reactive intermediates. S N 1 Mechanism

49 Alkyl Halides and Nucleophilic Substitution S N 1 Mechanism

50 Alkyl Halides and Nucleophilic Substitution geometry of the carbocation intermediate. S N 1 Mechanism -- stereochemistry

51 Alkyl Halides and Nucleophilic Substitution racemic mixture S N 1 Mechanism -- stereochemistry 1 : 1 mixture racemization

52 Alkyl Halides and Nucleophilic Substitution S N 1 Mechanism -- stereochemistry

53 Alkyl Halides and Nucleophilic Substitution The rate of an S N 1 reaction is affected by the type of alkyl halide involved. This trend is exactly opposite to that observed in S N 2 reactions. Influence of Identity of R group on S N 1 reactions

54 Alkyl Halides and Nucleophilic Substitution S N 1 Mechanism

55 Alkyl Halides and Nucleophilic Substitution Carbocation Stability i.e. alkyl groups act as electron donor

56 Alkyl Halides and Nucleophilic Substitution Carbocation Stability

57 Alkyl Halides and Nucleophilic Substitution Carbocation Stability The order of carbocation stability can be rationalized through inductive effects and hyperconjugation. Inductive effects : electronic effects that occur through  bonds -- the pull of electron density through  bonds caused by electronegativity differences between atoms. Alkyl groups are electron donating groups that stabilize a positive charge. In general, the greater the number of alkyl groups attached to a carbon with a positive charge, the more stable will be the cation.

58 Alkyl Halides and Nucleophilic Substitution Carbocation Stability Hyperconjugation : the spreading out of charge by the overlap of an empty p orbital with an adjacent  bond. This overlap (hyperconjugation) delocalizes the positive charge on the carbocation, spreading it over a larger volume, and this stabilizes the carbocation. Example: CH 3 + cannot be stabilized by hyperconjugation, but (CH 3 ) 2 CH + can.

59 Alkyl Halides and Nucleophilic Substitution Carbocation Stability

60 Alkyl Halides and Nucleophilic Substitution The rate of an S N 1 reaction

61 Alkyl Halides and Nucleophilic Substitution The Hammond postulate relates reaction rate to stability. It provides a quantitative estimate of the energy of a transition state. The Hammond postulate : the transition state of a reaction resembles the structure of the species (reactant or product) to which it is closer in energy. in an endothermic step, TS resembles the products, in an exothermic step, TS resembles the reactants.

62 Alkyl Halides and Nucleophilic Substitution The Hammond Postulate

63 Alkyl Halides and Nucleophilic Substitution The Hammond Postulate endothermic reaction the transition state resembles the products more than the reactants --- anything that stabilizes the product stabilizes the transition state also. i.e. lowering the energy of the transition state decreases E a, which increases the reaction rate.

64 Alkyl Halides and Nucleophilic Substitution The Hammond Postulate If there are two possible products in an endothermic reaction, but one is more stable than the other, the transition state that leads to the formation of the more stable product is lower in energy, so this reaction should occur faster.

65 Alkyl Halides and Nucleophilic Substitution The Hammond Postulate exothermic reaction the transition state resembles the reactants more than the products. lowering the energy of the products has little or no effect on the energy of the transition state. Since E a is unaffected, the reaction rate is unaffected. The conclusion is that in an exothermic reaction, the more stable product may or may not form faster, since E a is similar for both products.

66 Alkyl Halides and Nucleophilic Substitution The Hammond Postulate In an exothermic reaction, the more stable product may or may not form faster, since E a is similar for both products.

67 Alkyl Halides and Nucleophilic Substitution The Hammond Postulate and S N 1 reaction The stability of the carbocation determines the rate of its formation.

68 Alkyl Halides and Nucleophilic Substitution S N 1 Reactions, Nitrosamines and Cancer S N 1 reactions are thought to play a role in how nitrosamines act as toxins and carcinogens.

69 Alkyl Halides and Nucleophilic Substitution Predicting the Likely Mechanism of a Substitution Reaction. When is the mechanism S N 1 or S N 2 ? 1. Allkyl halides

70 Alkyl Halides and Nucleophilic Substitution Strong nucleophiles (which usually bear a negative charge) present in high concentrations favor S N 2 reactions. Weak nucleophiles, such as H 2 O and ROH favor S N 1 reactions by decreasing the rate of any competing S N 2 reaction. When is the mechanism S N 1 or S N 2 ? 2. Nucleophile

71 Alkyl Halides and Nucleophilic Substitution The strong nucleophile favors an S N 2 mechanism. The weak nucleophile favors an S N 1 mechanism.

72 Alkyl Halides and Nucleophilic Substitution A better leaving group increases the rate of both S N 1 and S N 2 reactions. When is the mechanism S N 1 or S N 2 ? 3. Leaving group

73 Alkyl Halides and Nucleophilic Substitution Polar protic solvents like H 2 O and ROH favor S N 1 reactions because the ionic intermediates (both cations and anions) are stabilized by solvation. Polar aprotic solvents favor S N 2 reactions because nucleophiles are not well solvated, and therefore, are more nucleophilic. When is the mechanism S N 1 or S N 2 ? 4. Solvent

74 Alkyl Halides and Nucleophilic Substitution

75 Alkyl Halides and Nucleophilic Substitution

77 Alkyl Halides and Nucleophilic Substitution Vinyl Halides and Aryl Halides. Vinyl and aryl halides do not undergo S N 1 or S N 2 reactions, because heterolysis of the C—X bond would form a highly unstable vinyl or aryl cation. SN1 and SN2 reactions occur only at sp3 hybridized carbon atoms. for now!

78 Alkyl Halides and Nucleophilic Substitution In organic synthesis

79 Alkyl Halides and Nucleophilic Substitution In organic synthesis Organic synthesis : systematic preparation of a compound (the target molecule, TM) from readily available starting material. main goals of synthetic organic chemistry : to prepare physiologically active natural products (or their analogs) from simpler starting materials Taxol aspirin

80 Alkyl Halides and Nucleophilic Substitution Nucleophilic Substitution and Organic Synthesis. To carry out the synthesis of a particular compound, we must think backwards, and ask ourselves the question: What starting material and reagents are needed to make it? “retrosynthesis”

81 Alkyl Halides and Nucleophilic Substitution Nucleophilic Substitution and Organic Synthesis.

7.47, 7.51, 7.52, 7.54, 7.55, 7.57, 7.61, 7.63, 7,.67, 7.68, 7.71, 7.73, 7.76, 7.79 Homework

Preview of Chapter 8 Alkyl Halides and Elimination reactions Alkyl Halides : R-X Alkenes Substitution reaction - mechanism E1 v.s. E2 - When is the reaction S N 1, S N 2, E1 or E2?

1.What is Zaitsev rule ? 2.Which halide undergo elimination reaction faster than others a) under E1 mechanism? b) under E2 mechanism? R 3 CX,, R 2 CHX, RCH 2 X And there will be the 2nd Quiz On March 21 st (Saturday)! 1:00 p.m. Preview of Chapter 8 Alkyl Halides and Elimination reactions