Chapter 7 Haloalkanes PDF

Chapter 7 Haloalkanes (Structure and Reactivity) Structure Haloalkane (alkyl halide): Contains a halogen atom covalently -bonded to an sp3 hybridized carbon. Given the symbol RX where X = F, Cl, Br, or I and R is the organic framework The reactivity we will look at is...

Chapter 7 Haloalkanes (Structure and Reactivity) Structure Haloalkane (alkyl halide): Contains a halogen atom covalently -bonded to an sp3 hybridized carbon. Given the symbol RX where X = F, Cl, Br, or I and R is the organic framework The reactivity we will look at is due to the nature of the C-X bond.  Nomenclature - IUPAC Halogen groups are named as substituents, similar to alkyl sidechains Halogen substituent names: fluoro- (F), chloro- (Cl), bromo- (Br), iodo- (I) Numbering should give the first substituent the lowest possible number. Listed in alphabetical order with other substituents. This is actually a pair of enantiomers  Common Haloalkanes Polyhaloalkanes: Are often solvents and are generally referred to by their common or trivial names (in brackets).  Freons & Their Alternatives Freons are chlorofluorocarbons (CFCs) Among the most widely used are/were: Less ozone-depleting alternatives: hydrofluorocarbons (HFCs) or hydrochlorofluorocarbons (HCFCs)  Reactivity: Substitution & Elimination In this chapter we concentrate on two types of reactions: nucleophilic substitution: replacement of a halogen substituent with a nucleophile -elimination: loss of a halogen substituent and an adjacent H atom to form a C-C -bond  Nucleophilic Substitutions Substitution takes place on sp3 hybridized carbon. A nucleophile replaces the leaving group (halogen atom) Halides are very good leaving groups because they form stable anions. The nucleophile reacts with the carbon atom because it is electrophilic due to the polarity of the C-X bond. + –  Many types of functional groups can be formed by using different nucleophiles Nucleophiles are not all charged, but all have a lone pair. Mechanisms Two limiting mechanisms are proposed for nucleophilic substitutions They differ in the timing of: The C-X bond breaking The C-Nu bond forming SN2 Mechanism At one extreme, the C-X bond breaks and the C-Nu bond forms simultaneously in one step. Designated SN2. S = substitution N = nucleophilic 2 = bimolecular (two species are involved in the rate-determining step) rate = k[R-X][Nucleophile] SN2 Mechanism Both the nucleophile and haloalkane are involved in the transition state of the rate-determining step. The nucleophile attacks the reactive center from the side opposite the leaving group. Pattern: Reaction of a nucleophile and an electrophile to form a new covalent bond. The reaction has one mechanistic step. Stereochemistry at the reacting carbon is inverted.  SN2 Mechanism There is one transition state and no reactive intermediate. ΔG Figure 7.1 An energy diagram for an SN2 reaction SN1 Mechanism The other limiting mechanism has two steps: Step 1: The C-X bond breaks forming a carbocation intermediate and halide ion. (slow, rate determining step (RDS) ) Step 2: The nucleophile reacts with the carbocation to form a C-Nu bond.(fast) This mechanism is designated SN1 where S = substitution N = nucleophilic 1 = unimolecular (only one species, R-X, is involved in the rate-determining step, Step 1) rate = k[R-X] SN1: tert-Butyl bromide + CH3OH Step 1: Break a bond to form a stable ion or molecule.(slow) Ionization of the C-X bond gives a 3° carbocation intermediate and bromide ion. SN1: tert-Butyl bromide + CH3OH Step 2: Reaction of a nucleophile and an electrophile (carbocation) forming a new covalent bond. (fast) The carbocation has an empty p-orbital which is available to form a bond with the nucleophile. If the product has a stereocentre formed in this step, both the R and S forms will be produced in equal amounts. (racemate) SN1: tert-Butyl bromide + CH3OH Step 3: Take a proton away to form a neutral product. Proton transfer to methanol completes the reaction. This is generally going to occur for neutral nucleophiles.  SN1 Mechanism Two transition states (‡) ‡ ‡ One reactive intermediate (carbocation) ΔG The first step determines the rate of reaction Figure 7.2 An energy diagram for an SN1 reaction. SN1: Carbocation Rearrangements SN1 reactions form a carbocation, so rearrangements are possible. This can occur with a 2° carbocation, which is prone to rearrange to a more stable 3° carbocation (Section 5.4). Stereochemistry For an SN1 reaction at a stereocentre, the product is a racemic mixture. For an SN2 reaction at a stereocentre, the product is an inverted stereocentre. SN1 vs. SN2 Mechanisms Factors Affecting Reaction Rates  SN1 vs. SN2 Mechanisms To determine which mechanism is likely to be in effect, we consider the following questions: What effect does the structure of the nucleophile have on the rate of reaction? What effect does the structure of the haloalkane have on the rate of reaction? What effect does the structure of the leaving group have on the rate of reaction? What is the role of the solvent? Nucleophilicity A kinetic property related to how a nucleophile influences the rate of reaction. Evaluated by comparing the reaction rates for various nucleophiles (Nu:) reacting with a reference compound under a standard set of SN2 experimental conditions. SN2 experimental conditions are necessary since the Nu: does not affect the rate of SN1 reactions For example, Table 7.2 lists the relative rates at which a set of nucleophiles displaces bromide ion from bromoethane in ethanol at 25 °C. Table 7.2 Relative Nucleophilicity of Common Nucleophiles Size, charge and electronegativity all affect the nucleophilicity of the the nucleophilic atom  Structure of the Haloalkane The substitution (3°, 2°, 1°, methyl) of the carbon atom attached to the halogen has a major influence on the rate of each mechanism SN1 reactions Governed by electronic factors, namely the relative stabilities of carbocation intermediates. Relative SN1 rates: 3° > 2° > 1° > methyl Generally not observed SN2 reactions Governed by steric factors, namely the relative ease of approach of the nucleophile to the site of reaction. Relative SN2 rates: methyl > 1° > 2° > 3° Generally not observed Structure of the Haloalkane Steric factors Compare access to the reaction center in bromoethane and 2-bromo-2-methylpropane (tert-butyl bromide). The SN2 transition state would be difficult to achieve for tert-butyl bromide This is why 3° carbon centres do not react via SN2 mechanisms.  Structure of the Haloalkane Electronic factors Only 3° and 2° alkyl halides can form stable carbocation intermediates in an SN1 mechanism. Only 2° alkyl halides have the possibility of reacting via either mechanism for simple haloalkanes Figure 7.3 Effect of electronic and steric factors in competition between SN1 and SN2 reactions of haloalkanes. The Leaving Group The best leaving groups form stable species, e.g., I–, Br–, Cl–, and H2O These are all conjugate bases of strong acids OH–, RO–, and NH2– rarely, if ever, act as leaving groups in nucleophilic substitutions.  The OH– Leaving Group (Ch 8) Hydroxide ion, OH–, is a poor leaving group. Alcohols can undergo nucleophilic substitution by first protonating the –OH group by an acid This forms –OH2+, a better leaving group. Both SN1 and SN2 reactivity is enhanced in this fashion.  The Solvent: Protic Solvents Protic solvent: a solvent that contains a hydrogen bond donor. Many common protic solvents contain –OH groups. Protic solvents favour SN1 reactions  The Solvent: Protic Solvents Protic solvents strongly associate (solvate) with cations and anions in solution. This stabilizes carbocations and charged leaving groups, promoting SN1 type reations. They also solvate charged Nu-, reducing their effectiveness in SN2 reactions by increasing their steric bulk.  The Solvent: Aprotic Solvents Aprotic solvent: A solvent that does not contain an –OH group and is not a hydrogen bond donor. Aprotic solvents favor SN2 reactions. Formation of carbocations in them is more difficult than in protic solvents. (Et2O) Copyright © 2016 John Wiley & Sons, Inc. All rights reserved.  The Solvent: Aprotic Solvents Not as as effective in solvating anions (leaving groups or negatively charged nucleophiles) Therefore, formation of carbocations (SN1) in aprotic solvents is more difficult than in protic solvents Unsolvated nucleophiles are more effective since solvation increases their steric size SN1 vs. SN2 in Haloalkanes Aprotic solvents & good Protic solvents and poor nucleophiles favor SN2 nucleophiles favor SN1 Example: Predict the product of each reaction, the reaction mechanism, and the stereochemistry of the product. SN1 2° RX: SN1 or SN2? Poor nucleophile racemate Protic solvent SN2 No stereochemistry to consider 1° RX: so SN2 Good nucleophile Aprotic solvent Copyright © 2016 John Wiley & Sons, Inc. All rights reserved. Example: Predict the product of each reaction, the reaction mechanism, and the stereochemistry of the product. SN 2 Inverted stereochemistry 2° RX: SN1 or SN2? Good nucleophile Aprotic solvent SN 2 Inverted stereochemistry 2° RX: SN1 or SN2? Good nucleophile Aprotic solvent Copyright © 2016 John Wiley & Sons, Inc. All rights reserved. SN1 vs. SN2 in Haloalkanes Aprotic solvents & good Protic solvents and poor nucleophiles favor SN2 nucleophiles favor SN1  -Elimination (Formation of Alkenes)  -Elimination β-Elimination: In general, this is the removal of atoms or groups of atoms from adjacent carbons One type of -elimination is dehydrohalogenation (the elimination of H–X). A halogen atom and a hydrogen atom on an adjacent carbon are lost to form a -bond, creating an alkene.  -Elimination Selectivity Zaitsev’s rule: The most stable alkene is formed The major product of a -elimination is the more highly substituted alkene. (most stable) When cis-trans isomerism is possible, trans is favored (less steric strain).  -Elimination Mechanisms There are two limiting mechanisms for -elimination reactions. E1 mechanism: Step 1(slow): The C-X bond breaks to form a carbocation Step 2: The base removes an H atom on an adjacent carbon atom. Only R-X is involved in the rate-determining step. The first step is identical to the first step in SN1 E2 mechanism: In one step the C-X and C-H bonds are broken and the alkene is formed. This is a concerted reaction. Both R-X and base are involved in the rate-determining step. No carbocation is formed.  E1 Mechanism Step 1: Break a bond to give a stable molecule or ion. Ionization of the C-X bond gives a carbocation intermediate and halide ion. (rate determining step) methanol Step 2: Take a proton away. (fast) Proton transfer from the carbocation to a base (in this case, the solvent methanol) gives the alkene.  E2 Mechanism One-step mechanism: Loss of leaving group and removal of -hydrogen are concerted. Both processes happen simultaneously to form a C-C -bond  Elimination Reactions E1 is favoured with weak bases since the carbocation enhances the acidity of the -H. E2 is favoured by strong bases able to remove the -H. E1 is only possible for 2° and 3° alkyl halides. E2 is possible for 3° alkyl halides since -H are not sterically hindered in most cases. Substitution versus Elimination Many nucleophiles are also strong bases (OH– and RO–) SN and E reactions will be competing pathways. The ratio of SN/E products depends on the relative rates of the two reactions.  SN1 versus E1 Reactions of 2° and 3° haloalkanes in polar protic solvents (e.g. 80% aqueous ethanol) give mixtures of substitution and elimination products. Poor base/nucleophile and solvent favours carbocation formation. Product ratios are difficult to predict.  SN2 versus E2 It is considerably easier to predict the ratio of SN2 to E2 products. Here the base/nucleophile is a major factor. Large strong bases favour E2 for steric reasons. Small good nucleophiles favour SN2.  SN versus E for Methyl and 1° Haloalkanes For Methyl and Primary Haloalkanes  SN versus E for 2°,3° Haloalkanes For Secondary and Tertiary Haloalkanes Strong bases favour E2 reactions. Good nucleophiles that are not strong bases favour SN2 reactions Poor nucleophiles that are weak bases result in SN1/E1 reactions, particularly in protic solvents. SN versus E for Haloalkanes Examples: Predict the major product and the mechanism for each reaction. Strong base/good nucleophile Most stable alkene SN2 not possible so E2 Major product Weak base/ok nucleophile Quaternary nitrogen is positively charged E1/SN1 not possible (check formal charges) SN2 is the only likely mechanism Copyright © 2016 John Wiley & Sons, Inc. All rights reserved. SN versus E for Haloalkanes Predict the major product and the mechanism for each reaction. Strong base/good nucleophile Both SN2 and E2 can occur E2 is probably favoured by strong base + Strong base/good nucleophile Both SN2 and E2 can occur Racemate inversion E2 is probably favoured by strong base Major product Haloalkanes Practice problems: 7.9, 7.11, 7.15, 7.19, 7.21, 7.23(b)(c)(f), 7.25, 7.27(a)(b)(e)(f), 7.31, 7.35, 7.37, 7.39, 7.43 End Chapter 7