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1 SUBSTITUTION AND ELIMINATION REACTIONS OF ALKYL HALIDES S N 1, S N 2, E1 & E2 REACTIONS.

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Presentation on theme: "1 SUBSTITUTION AND ELIMINATION REACTIONS OF ALKYL HALIDES S N 1, S N 2, E1 & E2 REACTIONS."— Presentation transcript:

1 1 SUBSTITUTION AND ELIMINATION REACTIONS OF ALKYL HALIDES S N 1, S N 2, E1 & E2 REACTIONS

2 2 Reactions of Alkyl Halides (R-X): [SN1, SN2, E1, & E2 reactions] The  -carbon in an alkyl halide is electrophilic (electron accepting) for either or both of two reasons… a) the C to X (F, Cl, Br) bond is polar making carbon  + (4.0 – 2.5) = 1.5 (3.0 – 2.5) = 0.5 (2.8 – 2.5) = 0.3  EN (F-C) =  EN (Cl-C) =  EN (Br-C) =  EN (I-C) = (2.5 – 2.5) = 0.0 b) X (Cl, Br, I) is a leaving group decreasing basicity, increasing stability increasing leaving ability The best leaving groups are the weakest bases. The poorest leaving groups are the strongest bases.

3 3 Reactions of Alkyl Halides (R-X): [S N 1, S N 2, E1, & E2 reactions] When a nucleophile (electron donor, e.g., OH - ) reacts with an alkyl halide, the halogen leaves as a halide There are two competing reactions of alkyl halides with nucleophiles…. 1) substitution 2) elimination The Nu: - replaces the halogen on the  -carbon. The Nu: - removes an H + from a  -carbon & the halogen leaves forming an alkene.

4 4 There are two kinds of substitution reactions, called S N 1 and S N 2. As well as two kinds of elimination reactions, called E1 and E2. Let’s study S N 2 reactions first. S N 2 stands for Substitution, Nucleophilic, bimolecular. Another word for bimolecular is ‘2 nd order’.  Bimolecular (or 2 nd order) means that the rate of an S N 2 reaction is directly proportional to the molar concentration of two reacting molecules, the alkyl halide ‘substrate’ and the nucleophile: Rate = k [RX] [Nu: - ](This is a rate equation and k is a constant).  The mechanism of an S N 2 reaction is the one shown on slide #2: 2nd Order Nucleophilic Substitution Reactions, i.e., S N 2 reactions  Note that the nucleophile must hit the back side of the  -carbon. The nucleophile to C bond forms as the C to X bond breaks. No C + intermediate forms. An example is shown on the next slide.

5 5 2nd Order Nucleophilic Substitution Reactions, i.e., S N 2 reactions The rate of an S N 2 reaction depends upon 4 factors: 1. The nature of the substrate (the alkyl halide) 2. The power of the nucleophile 3. The ability of the leaving group to leave 4. The nature of the solvent 1. Consider the nature of the substrate :  Unhindered alkyl halides, those in which the back side of the  -carbon is not blocked, will react fastest in S N 2 reactions, that is: Me°>> 1°>> 2°>>3°  While a methyl halides reacts quickly in S N 2 reactions, a 3° does not react. The back side of an  -carbon in a 3° alkyl halide is completely blocked.

6 6 Me°>> 1°>> 2°>>3° Effect of nature of substrate on rate of S N 2 reactions: t-butyl bromidemethyl bromideethyl bromideisopropyl bromide Back side of  -C of a methyl halide is unhindered. Back side of  -C of a 1° alkyl halide is slightly hindered. Back side of  -C of a 2° alkyl halide is mostly hindered. Back side of  -C of a 3° alkyl halide is completely blocked. decreasing rate of S N 2 reactions SPACE FILLING MODELS SHOW ACTUAL SHAPES AND RELATIVE SIZES

7 7 The  -carbon in vinyl and aryl halides, as in 3° carbocations, is completely hindered and these alkyl halides do not undergo S N 2 reactions. Effect of the nucleophile on rate of S N 2 reactions: vinyl bromide bromobenzene The overlapping p-orbitals that form the  -bonds in vinyl and aryl halides completely block the access of a nucleophile to the back side of the  -carbon. Nu: -

8 8 2. Consider the power of the nucleophile:  The better the nucleophile, the faster the rate of S N 2 reactions.  The table below show the relative power or various nucleophiles.  The best nucleophiles are the best electron donors. Effect of nature substrate on rate of S N 2 reactions:

9 9 3. Consider the nature of the leaving group : The leaving group usually has a negative charge  Groups which best stabilize a negative charge are the best leaving groups, i.e., the weakest bases are stable as anions and are the best leaving groups.  Weak bases are readily identified. They have high pKb values.  Iodine (-I) is a good leaving group because iodide (I - ) is non basic.  The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH - ) is a strong base. Effect of nature of the leaving group on rate of S N 2 reactions: Increasing leaving ability

10 10 4. Consider the nature of the solvent : There are 3 classes of organic solvents:  Protic solvents, which contain –OH or –NH 2 groups. Protic solvents slow down S N 2 reactions.  Polar aprotic solvents like acetone, which contain strong dipoles but no –OH or –NH 2 groups. Polar aprotic solvents speed up S N 2 reactions.  Non polar solvents, e.g., hydrocarbons. S N 2 reactions are relatively slow in non polar solvents. Effect of the solvent on rate of S N 2 reactions: Protic solvents (e.g., H 2 O, MeOH, EtOH, CH 3 COOH, etc.) cluster around the Nu:- (solvate it) and lower its energy (stabilize it) and reduce its reactivity via H-bonding. A solvated nucleophile has difficulty hitting the  -carbon.

11 11  Polar Aprotic Solvents solvate the cation counterion of the nucleophile but not the nucleophile.  Examples include acetonitrile (CH 3 CN), acetone (CH 3 COCH 3 ), dimethylformamide (DMF) [(CH 3 ) 2 NC=OH], dimethyl sulfoxide, DMSO [(CH 3 ) 2 SO], hexamethylphosphoramide, HMPA {[(CH 3 ) 2 N] 3 PO} and dimethylacetamide (DMA). Effect of the solvent on rate of S N 2 reactions:

12 12 Non polar solvents (benzene, carbon tetrachloride, hexane, etc.) do not solvate or stabilize nucleophiles.  S N 2 reactions are relatively slow in non polar solvents similar to that in protic solvents. Effect of the solvent on rate of S N 2 reactions:

13 13 1st Order Nucleophilic Substitution Reactions, i.e., S N 1 reactions  3  alkyl halides are essentially inert to substitution by the S N 2 mechanism because of steric hindrance at the back side of the  -carbon.  Despite this, 3  alkyl halides do undergo nucleophilic substitution reactions quite rapidly, but by a different mechanism, i.e., the S N 1 mechanism.  S N 1 = Substitution, Nucleophilic, 1st order (unimolecular). S N 1 reactions obey 1st order kinetics, i.e., Rate = k  [RX].  The rate depends upon the concentration of only 1 reactant, the alkyl halide-not the nucleophile  The order of reactivity of substrates for S N 1 reactions is the reverse of S N 2 3  > 2  >1  > vinyl > phenyl > Me° R 3 C-Br R 2 HC-Br RH 2 C-Br CH 2 =CH-Br  -Br H 3 C-Br increasing rate of S N 1 reactions

14 14 The mechanism of an S N 1 reaction occurs in 2 steps: Reaction Steps … 1.the slower, rate-limiting dissociation of the alkyl halide forming a C+ intermediate 2.a rapid nucleophilic attack on the C+ Mechanism of S N 1 reactions Note that the nucleophile is not involved in the slower, rate-limiting step.

15 15 The rate of an S N 1 reaction depends upon 3 factors: 1. The nature of the substrate (the alkyl halide) 2. The ability of the leaving group to leave 3. The nature of the solvent The rate is independent of the power of the nucleophile. 1. Consider the nature of the substrate : Highly substituted alkyl halides (substrates) form a more stable C+. The Rate of S N 1 reactions increasing rate of S N 1 reactions

16 16 Alkyl groups are weak electron donors.  They stabilize carbocations by donating electron density by induction (through  bonds)  They stabilize carbocations by hyperconjugation (by partial overlap of the alkyl C-to-H bonds with the empty p-orbital of the carbocation). Stability of Carbocations

17 17  Allyl and benzyl halides also react quickly by S N 1 reactions because their carbocations are unusually stable due to their resonance forms which delocalize charge over an extended  system Stability of Carbocations

18 18 Relative Stability of All Types of Carbocations Increasing C+ stability and rate of S N 1 reaction Note that 1° allylic and 1° benzylic C+’s are about as stable as 2°alkyl C+’s. Note that 2° allylic and 2° benzylic C+’s are about as stable as 3° alkyl C+’s. Note that 3° allylic and 3° benzlic C+’s are more stable than 3° alkyl C+’s Note that phenyl and vinyl C+’s are unstable. Phenyl and vinyl halides do not usually react by S N 1 or S N 2 reactions

19 19 2. Consider the nature of the leaving group : The nature of the leaving group has the same effect on both S N 1 and S N 2 reactions. The better the leaving group, the faster a C+ can form and hence the faster will be the S N 1 reaction. The leaving group usually has a negative charge  Groups which best stabilize a negative charge are the best leaving groups, i.e., the weakest bases are stable as anions and are the best leaving groups.  Weak bases are readily identified. They have high pKb values. Effect of nature of the leaving group on rate of S N 1 reactions: Increasing leaving ability  Iodine (-I) is a good leaving group because iodide (I - ) is non basic.  The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH - ) is a strong base.

20 20 3. Consider the nature of the solvent:  For S N 1 reactions, the solvent affects the rate only if it influences the stability of the charged transition state, i.e., the C+. The Nu: - is not involved in the rate determining step so solvent effects on the Nu: - do not affect the rate of S N 1 reactions.  Polar solvents, both protic and aprotic, will solvate and stabilize the charged transition state (C+ intermediate), lowering the activation energy and accelerating S N 1 reactions.  Nonpolar solvents do not lower the activation energy and thus make S N 1 reactions relatively slower Effect of the solvent on rate of S N 1 reactions: reaction rate increases with polarity of solvent The relative rates of an S N 1 reaction due to solvent effects are given (CH 3 ) 3 C-Cl + ROH  (CH 3 ) 3 C-OR + HCl H 2 O 20% EtOH (aq) 40% EtOH (aq) EtOH 100,000 14,

21 21  Solvent polarity is usually expressed by the “dielectric constant”, , which is a measure of the ability of a solvent to act as an electric insulator.  Polar solvents are good electric insulators because their dipoles surround and associate with charged species.  Dielectric constants of some common solvents are given in the following table Effect of the solvent on rate of S N 1 reactions:

22 22 Consider the nature of the Nucleophile:  Recall again that the nature of the nucleophile has no effect on the rate of S N 1 reactions because the slowest (rate-determining) step of an S N 1 reaction is the dissociation of the leaving group and formation of the carbocation.  All carbocations are very good electrophiles (electron acceptors) and even weak nucleophiles, like H 2 O and methanol, will react quickly with them.  The two S N 1 reactions will proceed at essentially the same rate since the only difference is the nucleophile. Effect of the nucleophile on rate of S N 1 reactions:

23 23 We have seen that alkyl halides may react with basic nucleophiles such as NaOH via substitution reactions. Also recall our study of the preparation of alkenes. When a 2° or 3° alkyl halide is treated with a strong base such as NaOH, dehydrohalogenation occurs producing an alkene – an elimination (E2) reaction. bromocyclohexane + KOH  cyclohexene (80 % yield) Substitution and elimination reactions are often in competition. We shall consider the determining factors after studying the mechanisms of elimination. Elimination Reactions, E1 and E2:

24 24 There are 2 kinds of elimination reactions, E1 and E2. E2 = Elimination, Bimolecular (2nd order). Rate = k [RX] [Nu: - ]  E2 reactions occur when a 2° or 3° alkyl halide is treated with a strong base such as OH -, OR -, NH 2 -, H -, etc. E2 Reaction Mechanism The Nu: - removes an H + from a  -carbon & the halogen leaves forming an alkene.  All strong bases, like OH -, are good nucleophiles. In 2° and 3° alkyl halides the  -carbon in the alkyl halide is hindered. In such cases, a strong base will ‘abstract’ (remove) a hydrogen ion (H+) from a  -carbon, before it hits the  -carbon. Thus strong bases cause elimination (E2) in 2° and 3° alkyl halides and cause substitution (S N 2) in unhindered methyl° and 1° alkyl halides.

25 25 In E2 reactions, the Base to H  bond formation, the C to H  bond breaking, the C to C  bond formation, and the C to Br  bond breaking all occur simultaneously. No carbocation intermediate forms. Reactions in which several steps occur simultaneously are called ‘concerted’ reactions. Zaitsev’s Rule: Recall that in elimination of HX from alkenes, the more highly substituted (more stable) alkene product predominates. E2 Reaction Mechanism

26 26  E2 reactions, do not always follow Zaitsev’s rule.  E2 eliminations occur with anti-periplanar geometry, i.e., periplanar means that all 4 reacting atoms - H, C, C, & X - all lie in the same plane. Anti means that H and X (the eliminated atoms) are on opposite sides of the molecules.  Look at the mechanism again and note the opposite side & same plane orientation of the mechanism: E2 Reactions are ‘antiperiplanar’

27 27 Antiperiplanar E2 Reactions in Cyclic Alkyl Halides  When E2 reactions occur in open chain alkyl halides, the Zaitsev product is usually the major product. Single bonds can rotate to the proper alignment to allow the antiperiplanar elimination.  In cyclic structures, however, single bonds cannot rotate. We need to be mindful of the stereochemistry in cyclic alkyl halides undergoing E2 reactions. See the following example.  Trans –1-chloro-2-methylcyclopentane undergoes E2 elimination with NaOH. Draw and name the major product.

28 28  Just as S N 2 reactions are analogous to E 2 reactions, so S N 1 reactions have an analog, E1 reaction.  E1 = Elimination, unimolecular (1st order); Rate = k  [RX]  E1 eliminations, like S N 1 substitutions, begin with unimolecular dissociation, but the dissociation is followed by loss of a proton from the  -carbon (attached to the C + ) rather than by substitution.  E1 & S N 1 normally occur in competition, whenever an alkyl halide is treated in a protic solvent with a nonbasic, poor nucleophile.  Note: The best E1 substrates are also the best S N 1 substrates, and mixtures of products are usually obtained. E1 Reactions

29 29  As with E2 reactions, E1 reactions also produce the more highly substituted alkene (Zaitsev’s rule). However, unlike E2 reactions where no C + is produced, C + rearrangements can occur in E1 reactions.  e.g., t-butyl chloride + H 2 O (in EtOH) at 65  C  t-butanol + 2-methylpropene  In most unimolecular reactions, S N 1 is favored over E1, especially at low temperature. Such reactions with mixed products are not often used in synthetic chemistry.  If the E1 product is desired, it is better to use a strong base and force the E2 reaction.  Note that increasing the strength of the nucleophile favors S N 1 over E1. Can you postulate an explanation? E1 Reactions

30 30 1.Non basic, good nucleophiles, like Br - and I - will cause substitution not elimination. In 3° substrates, only S N 1 is possible. In Me° and 1° substrates, S N 2 is faster. For 2° substrates, the mechanism of substitution depends upon the solvent. 2.Strong bases, like OH - and OR -, are also good nucleophiles. Substitution and elimination compete. In 3° and 2° alkyl halides, E2 is faster. In 1° and Me° alkyl halides, S N 2 occurs. 3.Weakly basic, weak nucleophiles, like H 2 O, EtOH, CH 3 COOH, etc., cannot react unless a C+ forms. This only occurs with 2° or 3° substrates. Once the C+ forms, both S N 1 and E1 occur in competition. The substitution product is usually predominant. 4.High temperatures increase the yield of elimination product over substitution product. (  G =  H –T  S) Elimination produces more products than substitution, hence creates greater entropy (disorder). 5.Polar solvents, both protic and aprotic, like H 2 O and CH 3 CN, respectively, favor unimolecular reactions (S N 1 and E1) by stabilizing the C+ intermediate. Polar aprotic solvents enhance bimolecular reactions (S N 2 and E2) by activating the nucleophile. Predicting Reaction Mechanisms

31 31 Predicting Reaction Mechanisms S N 1, E1 SN2SN2 E2E2 SN2SN2 SN2SN2 SN1SN1 SN2SN2 SN2SN2 E2E2 E2E2 SN2SN2 E2 (S N 2) E2E2 no reaction S N 1, E1 Strong bulky bases like t-butoxide are hindered. They have difficulty hitting the  -carbon in a 1° alkyl halide. As a result, they favor E2 over S N 2 products.

32 32 The nucleophiles in the table on slide 30 are extremes. Some nucleophiles have basicity and nucleophilicity in between these extremes. The reaction mechanisms that they will predominate can be interpolated with good success. Predict the predominant reaction mechanisms the following table. Predicting Reaction Mechanisms 4.7 v. gd. moderate SN2SN2 SN2SN2 SN2SN2 E2E2 6.0 / 7.0 moderate v. gd. SN2SN2 SN2SN2 E2E2 SN2SN2 9 weak fair SN2SN2 SN2SN2 E2E2 E2E2 SN2SN2 SN2SN2 SN1SN1 SN1SN1 HCl, HBr and HI are assumed to be in aqueous solution, a protic solvent.

33 33 Recall the preparation of long alkynes. 1.A terminal alkyne (pKa = 25) is deprotonated with a very strong base… R-C  C-H + NaNH 2  R-C  C: - Na + + NH 3 2.An alkynide anion is a good Nu: - which can substitute (replace) halogen atoms in methyl or 1  alkyl halides producing longer terminal alkynes  R-C  C: - Na + + CH 3 CH 2 -X  R-C  C-CH 2 CH 3 + NaX  The reaction is straightforward with Me and 1  alkyl halides and proceeds via an S N 2 mechanism  Alkynide anions are also strong bases (pKb = -11) as well as good Nu: -’ s, so E2 competes with S N 2 for 2  and 3  alkyl halides CH 3 (CH 2 ) 3 C  C: - Na+ + CH 3 -CH(Br)-CH 3  CH 3 (CH 2 ) 3 C  CCH(CH 3 ) 2 (7% S N 2) + CH 3 (CH 2 ) 3 C  CH + CH 3 CH=CH 2 (93% E2) Alkylation of Alkynides

34 34 Alkyl halides can be prepared from alcohols by reaction with HX, i.e., the substitution of a halide on a protonated alcohol. Preparation of Alkyl Halides from Alcohols Very slow. Protic solvent inhibits the nucleophile. Rapid. 3° C+ is stabilized by protic sovent (H 2 O)  Draw the mechanism of the reaction of isopropyl alcohol with HBr.  What products form if concentrated H 2 SO 4 is used in place of aq. HCl?  OH - is a poor leaving group, i.e., is not displaced directly by nucleophiles. Reaction in acid media protonates the OH group producing a better leaving group (H 2 O). 2  and 3  alcohols react by S N 1 but Me° and 1  alcohols react by S N 2.

35 35 Alternative to using hydrohalic acids (HCl, HBr, HI), alcohols can be converted to alkyl halides by reaction with PBr 3 which transforms OH - into a better leaving group allowing substitution (S N 2) to occur without rearrangement. Preparation of Alkyl Halides from Alcohols

36 36 On Slide 22 we noted that 2° and 3° alkyl halides can be dehydrohalogenated with a strong base such as OH - producing an alkene. bromocyclohexane + KOH  cyclohexene (80 % yield) Clearly, this is an E2 reaction. Preparation of Alkenes from Alkyl Halides  Predict the mechanism that occurs with a Me° or 1° alkyl halide.  Predict the products and mechanism that occur with isopentyl chloride and KOH

37 37 Alkyl Halide Substrate Reactivity: Summary of S N /Elimination Reactions

38 38 Reactivity of Nucleophiles: Note that poor nucleophiles that are also weak bases (H 2 O, ROH, CH 3 COOH, etc.) do not undergo any reaction unless a C + is formed first. If a C + can form (as with a 2º, 3º, any benzylic, or any allylic halides), then E1 and S N 1 generally occur together. Leaving Group Activity: Summary of S N /Elimination Reactions

39 39  Draw the mechanism of the reaction of isopropyl alcohol with 48% HBr (aq.) Reactions of Alkyl Halides  What products form if concentrated H 2 SO 4 is used in place of aq. HBr or HCl?  HSO 4 - is a non basic, very weak Nu: -, E1 and S N 1 should compete. Only E1 product forms because H 2 SO 4 has strong affinity for H 2 O.

40 40  Predict the products and mechanism that occur with isopentyl chloride and KOH Reactions of Alkyl Halides  Predict the products and mechanism that occur with isopentyl chloride and KCN.


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