Basic Organic Chemistry Course code : CHEM (Pre-requisites : CHEM 11122)

Transcription

1 Basic Organic Chemistry Course code : CHEM (Pre-requisites : CHEM 11122) Chapter 01 Mechanistic Aspects of S N2,S N1, E 2 & E 1 Reactions Dr. Dinesh R. Pandithavidana Office: B1 222/3 Phone: (+94) (Mobile) dinesh@kln.ac.lk

2 Introduction to Alkyl Halides Alkyl halides are 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 halogen atom in halides is often denoted by the symbol X. 2

3 Introduction to Alkyl Halides Examples of 1, 2, and 3 alkyl halides 3

4 Nomenclature 4

5 Physical Properties Alkyl halides are weak polar molecules. They exhibit dipole-dipole interactions because of their polar C X bond, but because the rest of the molecule contains only C C and C H bonds, they are incapable of intermolecular hydrogen bonding. 5

6 Some simple alkyl halides Interesting Alkyl Halides 6

7 Interesting Alkyl Halides 7

8 The Polar Carbon-Halogen Bond The electronegative halogen atom in alkyl halides creates a polar C X bond, making the carbon atom electron deficient. Electrostatic potential maps of four simple alkyl halides illustrate this point. Electrostatic potential maps of four halomethanes (CH 3 X) 8

9 Nucleophilic Substitution Vs Elimination 9

10 General Features of Nucleophilic Substitution Three components are necessary in any substitution reaction. 10

11 Mechanism of S N 2 (Substitution Nucleophilic Bimolecular) Reaction All S N 2 reactions proceed with backside attack of the nucleophile, resulting in inversion of configuration at a stereogenic center. 11

12 Mechanisms of Nucleophilic Substitution: Stereochemistry Two examples of S N 2 inversion of configuration: 12

13 Mechanisms of Nucleophilic Substitution: But what is the order of bond making and bond breaking? In theory, there are three possibilities. *** Bond making and bond breaking occur at the same time. 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. 13

14 An energy diagram for the S N 2 reaction: 14

15 General Features of Nucleophilic Substitution Negatively charged nucleophiles like HO and HS are used as salts with Li +, Na +, or K + counterions to balance the charge. Since the identity of the counterion is usually inconsequential, it is often omitted from the chemical equation. When a neutral nucleophile is used, the substitution product bears a positive charge. 15

16 The Leaving Group In a nucleophilic substitution reaction of R X, the C X bond is heterolytically cleaved, and the leaving group departs with the electron pair in that bond, forming X:. The more stable the leaving group X:, the better able it is to accept an electron pair. For example, H 2 O is a better leaving group than HO because H 2 O is a weaker base. 16

17 The Leaving Group (a review of basicity) There are periodic trends in leaving group ability: 17

18 Alkyl Halides and Nucleophilic Substitution The Leaving Group: Weak bases 18

19 Alkyl Halides and Nucleophilic Substitution The Leaving Group: Strong bases 19

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

21 The Nucleophile: Although nucleophilicity and basicity are interrelated, they are fundamentally different. Basicity is 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, so it is discussed in thermodynamic terms. Nucleophilicity is a measure of how readily an atom donates its electron pair to other atoms. It is characterized by a rate constant, k, and it is discussed in kinetic terms. 21

22 The Nucleophile: 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: 22

23 The Nucleophile: Nucleophilicity does not parallel basicity when steric hindrance becomes important. Steric hindrance is 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. 23

24 Alkyl Halides and Nucleophilic Substitution The Nucleophile: In the left box, all are strong nucleophiles except chloride and acetate which are medium. In the right box, HOH and ROH are weak, the others medium. 24

25 Alkyl Halides and Nucleophilic Substitution Mechanisms of Nucleophilic Substitution: 25

26 Mechanism of S N 1 (Substitution Nucleophilic Unimolecular) Reaction Loss of the leaving group in Step [1] generates a planar carbocation that is achiral. In Step [2], attack of the nucleophile can occur on either side to afford two products which are a pair of enantiomers. Because there is no preference for nucleophilic attack from either direction, an equal amount of the two enantiomers is formed called a racemic mixture. We say that racemization has occurred. 26

27 S N 1 (Substitution Nucleophilic Unimolecular) Reaction ** Bond breaking occurs before bond making. 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. 27

28 Energy Diagram for the S N 1 Reaction 28

29 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. 29

30 Alkyl Halides and Nucleophilic Substitution 30

31 Alkyl Halides and Nucleophilic Substitution Carbocation Stability: The effect of the type of alkyl halide on S N 1 reaction rates can be explained by considering carbocation stability. Carbocations are classified as primary (1 ), secondary (2 ), or tertiary (3 ), based on the number of R groups bonded to the charged carbon atom. As the number of R groups increases, carbocation stability increases. 31

32 Carbocation Stability The order of carbocation stability can be rationalized through inductive effects and hyperconjugation. Inductive effects are electronic effects that occur through σ bonds. Specifically, the inductive effect is the pull of electron density through σ bonds caused by electronegativity differences between atoms. Alkyl groups are electron donating groups that stabilize a positive charge. Since an alkyl group has several σ bonds, each containing electron density, it is more polarizable than a hydrogen atom, and better able to donate electron density. In general, the greater the number of alkyl groups attached to a carbon with a positive charge, the more stable will be the cation. 32

33 Carbocation Stability The order of carbocation stability is also a consequence of hyperconjugation. Hyperconjugation is the spreading out of charge by the overlap of an empty p orbital with an adjacent σ 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. 33

34 Rearrangements in S N1 Reactions In S N1 reactions, an intermediate carbocation appears. If a secondary carbocation is formed, a rearrangement may occur that results in a more stable tertiary carbocation by a 1,2-hydride shift. 34

35 Rearrangements in S N1 Reactions 1,2-methyl shift takes place if 3-bromo-2,2-dimethyl butane is applied to the same reaction. 35

36 Leaving Group in Predicting S N1 vs S N2 mechanisms: The leaving group is the third factor. A better leaving group increases the rate of both S N 1 and S N 2 reactions. 36

37 Solvent in predicting S N1 vs S N2 mechanisms: The nature of the solvent is a fourth factor. 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. 37

38 Factors in predicting S N1 vs S N2 mechanisms: 38

39 Factors in predicting S N1 vs S N2 mechanisms: Nucleophile: S 1 N S 2 N Substrate: S N 1 S 2 o o N CH 3 > 1 > 2 Solvent: S 1 N S 2 N Nucleophilic strength not important Needs a strong nucleophile 3 o > 2 o Enhanced by more polar solvent Enhanced by less polar solvent Leaving Group: S 1 N Good LG important to form C + S N 2 Not as important but enhances reaction 39

40 Results of S N1 vs S N2 mechanisms: Kinetics: S N 1 S N 2 rate = k[rx] rate = k[rx][nu:] Stereochemistry: S 1 N S 2 N both inversion and retention (racemic) inversion only Rearrangements: S 1 N S 2 N rearrangements common rearrangements not possible 40

41 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. 41

42 Alkyl Halides and Elimination Reactions Removal of the elements HX is called dehydrohalogenation. Dehydrohalogenation is an example of β elimination. The curved arrow formalism shown below illustrates how four bonds are broken or formed in the process. There are two mechanisms of elimination E 2 and E 1, just as there are two mechanisms of substitution, S N 2 and S N 1. E 2 mechanism bimolecular elimination E 1 mechanism unimolecular elimination 42

43 Alkene: Alkyl Halides and Elimination Reactions The Products of Elimination Recall that the double bond of an alkene consists of a σ bond and a π bond. 43

44 E 2 Mechanism The most common mechanism for dehydrohalogenation is the E 2 mechanism. It exhibits second-order kinetics, and both the alkyl halide and the base appear in the rate equation, i.e., Rate = k [ Alkyl halide ][ Base ] 44 The reaction is concerted all bonds are broken and formed in a single step.

45 Alkyl Halides and Elimination Reactions Mechanisms of Elimination: E2 Figure 8.3 An energy diagram for an E2 reaction: 45

46 Alkyl Halides and Elimination Reactions General Features of Elimination: The most common bases used in elimination reactions are negatively charged oxygen compounds, such as HO and its alkyl derivatives, RO, called alkoxides. 46

47 Alkyl Halides and Elimination Reactions Classification of Alkenes: Alkenes are classified according to the number of carbon atoms bonded to the carbons of the double bond. Classifying alkenes by the number of R groups bonded to the double bond 47

48 The Zaitsev (Saytzeff) Rule Recall that when alkyl halides have two or more different β carbons, more than one alkene product is formed. When this happens, one of the products usually predominates. The major product is the more stable product the one with the more substituted double bond. This phenomenon is called the Zaitsev rule. 48

49 The Zaitsev (Saytzeff) Rule A reaction is regioselective when it yields predominantly or exclusively one constitutional isomer when more than one is possible. Thus, the E2 reaction is regioselective. 49

50 Alkene: Alkyl Halides and Elimination Reactions The Products of Elimination The stability of an alkene increases as the number of R groups bonded to the double bond carbons increases. The higher the percent s-character, the more readily an atom accepts electron density. Thus, sp 2 carbons are more able to accept electron density and sp 3 carbons are more able to donate electron density. Consequently, increasing the number of electron donating groups on an sp 2 carbon atom makes the alkene more stable. 50

51 Mechanism of Elimination Bimolecular Reaction ( E 2 ) Increasing the number of R groups on the carbon with the leaving group forms more highly substituted, more stable alkenes in E 2 reactions. In the reactions below, since the disubstituted alkene is more stable, the 3 alkyl halide reacts faster than the 1 0 alkyl halide. 51

52 Alkene: Alkyl Halides and Elimination Reactions The Products of Elimination In general, trans alkenes are more stable than cis alkenes because the groups bonded to the double bond carbons are further apart, reducing steric interactions. 52

53 Stereochemistry of the E 2 Reaction The transition state of an E 2 reaction consists of four atoms from an alkyl halide one hydrogen atom, two carbon atoms, and the leaving group (X) all aligned in a plane. There are two ways for the C H and C X bonds to be coplanar. E 2 elimination occurs most often in the anti-coplanar geometry. This arrangement allows the molecule to react in the lower energy staggered conformation, and allows the incoming base and leaving group to be further away from each other. 53

54 Alkyl Halides and Elimination Reactions Stereochemistry of the E 2 Reaction: Two possible geometries for the E 2 reaction 54

55 Summery of the E 2 mechanism 55

56 Stereoisomeric Products E 2 When a mixture of stereoisomers is possible from a dehydrohalogenation, the major product is the more stable stereoisomer. A reaction is stereoselective when it forms predominantly or exclusively one stereoisomer when two or more are possible. The E 2 reaction is stereoselective because one stereoisomer is formed preferentially. 56

57 Mechanism of Elimination Unimolecular Reaction( E 1 ) The dehydrohalogenation of (CH 3 ) 3 CCI with H 2 O to form (CH 3 ) 2 C=CH 2 can be used to illustrate the second general mechanism of elimination, the E 1 mechanism. An E 1 reaction exhibits first-order kinetics: Rate = k [ Alkyl Halide] The E 1 reaction proceeds via a two-step mechanism: the bond to the leaving group breaks first before the π bond is formed. The slow step is unimolecular, involving only the alkyl halide. The E 1 and E 2 mechanisms both involve the same number of bonds broken and formed. The only difference is timing. In an E 1, the leaving group comes off before the β proton is removed, and the reaction occurs in two steps. In an E 2 reaction, the leaving group comes off as the β proton is removed, and the reaction occurs in one step. 57

58 Mechanism of Elimination: E 1 58

59 Energy Diagram for E 1 Reaction 59

60 The rate of an E 1 reaction increases as the number of R groups on the carbon with the leaving group increases. The strength of the base usually determines whether a reaction follows the E 1 or E 2 mechanism. Strong bases like OH and OR favor E 2 reactions, whereas weaker bases like H 2 O and ROH favor E 1 reactions. 60

61 Regioselectivity of E 1 Mechanism E 1 reactions are regioselective, favoring formation of the more substituted, more stable alkene. So, Zaitsev s rule applies to E 1 as well as E 2 reactions. 61

62 Summary of the E 1 Mechanism 62

63 S N1 and E 1 Reactions S N1 and E 1 reactions have exactly the same first step formation of a carbocation. They differ in what happens to the carbocation. Because E 1 reactions often occur with a competing S 1 N reaction, E 1 reactions of alkyl halides are much less useful than E 2 reactions. 63

64 Stereochemistry of the E 2 Reaction The stereochemical requirement of an anti-coplanar geometry in an E 2 reaction has important consequences for compounds containing sixmembered rings. Consider chlorocyclohexane which exists as two chair conformations. Conformation A is preferred since the bulkier Cl group is in the equatorial position. For E 2 elimination, the C-Cl bond must be anti-coplanar to the C H bond on a β carbon, and this occurs only when the H and Cl atoms are both in the axial position. The requirement for trans diaxial geometry means that elimination must occur from the less stable conformer, B. 64

65 Stereochemistry of the E 2 Reaction The trans diaxial geometry for the E 2 elimination in chlorocyclohexane 65

66 Now consider the E 2 dehydrohalogenation of cis- and trans-1- chloro-2-methylcyclohexane. This cis isomer exists as two conformations, A and B, each of which as one group axial and one group equatorial. E 2 reaction must occur from conformation B, which contains an axial Cl atom. 66

67 Because conformation B has two different axial β hydrogens, labeled H a and H b, E 2 reaction occurs in two different directions to afford two alkenes. The major product contains the more stable trisubstituted double bond, as predicted by the Zaitsev rule. 67

68 Summary for predicting S N1, S N2, E 1 & E 2 Halide Conditions Mechanism 1 o strong nucleophile S 2 N strong bulky base E 2 2 o strong base & nucleophile S N2 & E 2 strong bulky base E 2 weak base and nucleophile S N1 & E 1 3 o weak base and nucleophile S N1 & E 1 strong base E 2 Higher temp. favors elimination over substitution. 68