10. Organohalides

2 Why this Chapter? Reactions involving organohalides are less frequently encountered than other organic compounds, but reactions such as nucleophilic substitutions/eliminations that they undergo will be encountered Alkyl halide chemistry is model for mechanistically similar but more complex

3 What Is an Alkyl Halide An organic compound containing at least one carbon- halogen bond (C-X) X (F, Cl, Br, I) replaces H Can contain many C-X bonds Properties and some uses Fire-resistant solvents Refrigerants Pharmaceuticals and precursors

Naming Alkyl Halides Find longest chain, name it as parent chain (Contains double or triple bond if present) Number from end nearest any substituent (alkyl or halogen)

Number all halogens and list different in alphabetical order. 5

6 Naming if Two Halides or Alkyl Are Equally Distant from Ends of Chain Begin at the end nearer the substituent whose name comes first in the alphabet

Common Names Treat halogen as parent with alkyl side group 7

Learning Check: Give names for the following: 8

Solution: Give names for the following: 9 Iodobutane (butyl iodide) 1-chloro-3-methylbutane (isopentyl chloride) 1,5-dibromo-2,2-dimethylpentane 1,3-dichloro-3-methylbutane 1-chloro-3-ethyl-4-iodopentane 2-bromo-5-chlorohexane

Structure of Alkyl Halides C-X bond is longer as you go down periodic table C-X bond is weaker as you go down periodic table C-X bond is polarized with slight positive on carbon and slight negative on halogen

Preparing Alkyl Halides from Alkenes: Alkyl halide from addition of HCl, HBr, HI to alkenes to give Markovnikov product (see Alkenes chapter) Alkyl dihalide from anti addition of bromine or chlorine

Preparing Alkyl Halides from Alkanes: Radical Halogenation Alkane + Cl 2 or Br 2, heat or light replaces C-H with C- X but gives mixtures Hard to control Via free radical mechanism It is usually not a good idea to plan a synthesis that uses this method

13 Radical Halogenation of Alkanes If there is more than one type of hydrogen in an alkane, reactions favor replacing the hydrogen at the most highly substituted carbons (not absolute) 91 o H’s 1 3 o H So would expect 10:90 ratio if # of H’s was sole factor

14 Relative Reactivity: Chlorination Based on quantitative analysis of reaction products, relative reactivity is estimated Order parallels stability of radicals

15 Relative Reactivity: Chlorination 1 3 o H 9 1 o H’s So would expect 10:90 ratio if # of H’s was sole factor 1 3 o H 1 x 5 = o H’s 9 x 1 = 9 So would predict 5:9 ratio Or 5/14 : 9/14 = 35.7: 64.3

Learning Check: Predict ratio of mono-chlorinated butanes 16

Solution: Predict ratio of mono-chlorinated butanes o H’s 4 2 o H’s So would expect 60:40 ratio if # of H’s was sole factor 6 1 o H’s 6 x 1 = o H’s 4 x 3.5 = 14 So would predict 6:14 ratio Or 6/20 : 14/20 = 30: 70

Learning Check: 18 How many constitutional isomers will form in the radical mono-chlorination of 2,3-dimethylpentane?

Solution: 19 How many constitutional isomers will form in the radical mono-chlorination of 2,3-dimethylpentane?

Learning Check: 20 The selectivity of chlorine radical is 1.0 : 3.5 : 5.0 for 1°, 2° and 3° hydrogens, respectively. If only monochlorides were to form in the radical chlorination of 1,3-dimethylcyclobutane, what is the expected yield of the tertiary chloride? 1. 1/6 2. 1/5 3. 1/4 4. 1/3 5. 1/2

Solution: 21 The selectivity of chlorine radical is 1.0 : 3.5 : 5.0 for 1°, 2° and 3° hydrogens, respectively. If only monochlorides were to form in the radical chlorination of 1,3-dimethylcyclobutane, what is the expected yield of the tertiary chloride? 1. 1/6 2. 1/5 3. 1/4 4. 1/3 5. 1/2

22 Reaction distinction is more selective with bromine than chlorine Bromination Relative Reactivity: Bromination

23 Bromination Relative Reactivity: Bromination Formation of C radical more costly with Br. So Br more picky thus more selective.

Learning Check: 24 Which of these radicals is expected to be the least selective? 1. HO 2. F 3. Cl 4. Br 5. I

Solution: 25 Which of these radicals is expected to be the least selective? 1. HO 2. F 3. Cl 4. Br 5. I

Allylic position more reactive ,5 Preparing Alkyl Halides from Alkenes: Allylic Bromination Allylic radical stabilized by resonance

27 Allylic Stabilization Allyl radical is delocalized More stable than typical alkyl radical by 40 kJ/mol (9 kcal/mol) Allylic radical is more stable than tertiary alkyl radical

28 Allylic Bromination: NBS N-bromosuccinimide (NBS) selectively brominates allylic positions Requires light Requires light for activation A source of dilute bromine atoms

29 Allylic Bromination: NBS

Product mix favors more substituted C=C and less hindered Br 30 Allylic Bromination: NBS

Examples: 31 NBS

32 Use of Allylic Bromination Allylic bromination with NBS creates an allylic bromide Reaction of an allylic bromide with base produces a conjugated diene, useful in synthesis of complex molecules

Learning Check: Predict the products of allylic bromination w/ NBS 33 NBS

Solution: Predict the products of allylic bromination w/ NBS 34 NBS

Preparing Alkyl Halides from Alcohols Reaction of tertiary C-OH with HX is fast and effective Add HCl or HBr gas into ether solution of tertiary alcohol Primary and secondary alcohols react very slowly and often rearrange, so alternative methods are used

Example: 36

Alkyl Halides from Alcohols 37 Alternative methods for slow primary and secondary alcohols to avoid rearrangements.

Learning Check: Prepare the following from alcohols 38

Solution: Prepare the following from alcohols 39 HCl PBr 3

Reactions of Alkyl Halides: Grignard Reagents Reaction of RX with Mg in ether or THF Product is RMgX – an organometallic compound (alkyl-metal bond) R is alkyl 1°, 2°, 3°, aryl, alkenyl X = Cl, Br, I

Grignard Reagents Forms a basic/nucleophilic Carbon 41 Example:

Organometallic Coupling Reactions Alkyllithium (RLi) forms from RBr and Li metal RLi reacts with copper iodide to give lithium dialkylcopper (Gilman reagents) Lithium dialkylcopper reagents react with alkyl halides to give alkanes

Examples: 43

44 Utility of Organometallic Coupling in Synthesis Coupling of two organometallic molecules produces larger molecules of defined structure Aryl and vinyl organometallics also effective Coupling of lithium dialkylcopper molecules proceeds through trialkylcopper intermediate

Palladium-catalyzed Tributyltin chloride Works well with aryl or vinyl halides 45

Oxidation and Reduction in Organic Chemistry In organic chemistry, we say that oxidation occurs when a carbon or hydrogen that is connected to a carbon atom in a structure is replaced by oxygen, nitrogen, or halogen Oxidation is a reaction that results in loss of electron density at carbon (as more electronegative atoms replace hydrogen or carbon) Oxidation: break C-H (or C-C) and form C-O, C-N, C-X Oxidation = LEO Gaining an Oxygen Or Losing a Hydrogen

47 Reduction Reactions Organic reduction is the opposite of oxidation Results in gain of electron density at carbon (replacement of electronegative atoms by hydrogen or carbon) Reduction: form C-H (or C-C) and break C-O, C-N, C-X Reduction = GER Losing an Oxygen Or Gaining a Hydrogen

48 Oxidation Levels Functional groups are associated with specific levels CH

Examples: 49

Examples: 50

Learning Check: 51 Which of these is not a redox reaction? 1. x 2. x 3. x 4. x 5. x

Solution: 52 Which of these is not a redox reaction? 1. x 2. x 3. x 4. x 5. x

Biological Halides 53

Learning Check: 54 Radical chlorination of (2R)-fluorobutane yields 2-chloro-3- fluorobutane as one of the products. Which is the best prediction for the stereochemistry of this product? 1. two enantiomers in equal amounts 2. two diastereomers in different amounts 3. two diastereomers in equal amounts 4. four stereoisomers, in different amount each 5. four stereoisomers, with enantiomeric pairs in equal amounts, but diastereomeric pairs in non-equal amounts

1. two enantiomers in equal amounts 2. two diastereomers in different amounts 3. two diastereomers in equal amounts 4. four stereoisomers, in different amount each 5. four stereoisomers, with enantiomeric pairs in equal amounts, but diastereomeric pairs in non-equal amounts Solution: 55 Radical chlorination of (2R)-fluorobutane yields 2-chloro-3- fluorobutane as one of the products. Which is the best prediction for the stereochemistry of this product?

Learning Check: 56 Which mechanistic step determines the regiochemistry of the radical-chain chlorination of 2-methylpropane? 1. protonation step 2. hydrogen abstraction step 3. chlorine abstraction step 4. chloride addition step 5. initiation step

Solution: 57 Which mechanistic step determines the regiochemistry of the radical-chain chlorination of 2-methylpropane? 1. protonation step 2. hydrogen abstraction step 3. chlorine abstraction step 4. chloride addition step 5. initiation step

1. The electronegativity of halogens in alkyl halides is nearly constant. 2. The inductive effects are counterbalanced by hyperconjugation. 3. The electronegativity effects are counterbalanced by bond strengths. 4. Lone-electron pairs are more delocalized on smaller halogens. 5. The charge-separation and bond-lengths trends have opposite effects. Learning Check: 58 Dipole moments of CH 3 –X are 1.85, 1.87, 1.81, and 1.62 D for F, Cl, Br, and I, respectively. What is the best explanation of the small differences in dipole moments?

1. The electronegativity of halogens in alkyl halides is nearly constant. 2. The inductive effects are counterbalanced by hyperconjugation. 3. The electronegativity effects are counterbalanced by bond strengths. 4. Lone-electron pairs are more delocalized on smaller halogens. 5. The charge-separation and bond-lengths trends have opposite effects. Solution: 59 Dipole moments of CH 3 –X are 1.85, 1.87, 1.81, and 1.62 D for F, Cl, Br, and I, respectively. What is the best explanation of the small differences in dipole moments?

Learning Check: 60 Which of the following is not the product of the radical chain-reaction of 2-pentene with NBS?

Solution: 61 Which of the following is not a product of the radical chain-reaction of 2-pentene with NBS?

Learning Check: 62 What is the best reagent to carry out the following transformation? 1. PBr 3 2. HBr 3. NBS/hv/CCl 4 4. Br 2 /hv 5. NBS/H 2 O/DMSO

Solution: 63 What is the best reagent to carry out the following transformation? 1. PBr 3 2. HBr 3. NBS/hv/CCl 4 4. Br 2 /hv 5. NBS/H 2 O/DMSO

Learning Check: 64 What is the best reagent to carry out the following transformation? 1. PBr 3 2. HBr/ether 3. NBS/hv/CCl 4 4. Br 2 /hv 5. NBS/H 2 O/DMSO

Solution: 65 What is the best reagent to carry out the following transformation? 1. PBr 3 2. HBr/ether 3. NBS/hv/CCl 4 4. Br 2 /hv 5. NBS/H 2 O/DMSO

Learning Check: 66 Which sequence of reagents is best to accomplish the following transformation? 1. KOH followed by BD 3 /THF 2. KOH followed by NaBH 4 3. Mg/ether followed by D 2 O 4. Li/pentane followed by D 2 /CuI 5. NaNH 2 followed by D 2 /Pd

Solution: 67 Which sequence of reagents is best to accomplish the following transformation? 1. KOH followed by BD 3 /THF 2. KOH followed by NaBH 4 3. Mg/ether followed by D 2 O 4. Li/pentane followed by D 2 /CuI 5. NaNH 2 followed by D 2 /Pd

Learning Check: 68 The selectivity of chlorine radical is 1.0 : 3.5 : 5.0 for 1°, 2° and 3° hydrogens, respectively. Assuming that only monochlorides are produced in the radical chain chlorination of 2,3-dimethybutane, what would be the expected ratio of the two isomeric alkyl chlorides formed in the reaction? 1. 1/6 2. 1/4 3. 1/2 4. 3/5 5. 5/6

Solution: 69 The selectivity of chlorine radical is 1.0 : 3.5 : 5.0 for 1°, 2° and 3° hydrogens, respectively. Assuming that only monochlorides are produced in the radical chain chlorination of 2,3-dimethybutane, what would be the expected ratio of the two isomeric alkyl chlorides formed in the reaction? 1. 1/6 2. 1/4 3. 1/2 4. 3/5 5. 5/6

Learning Check: 70 The reaction shown produces 5 different bromides. Which of the compounds listed is one of the expected products?

Solution: 71 The reaction shown produces 5 different bromides. Which of the compounds listed is one of the expected products?

Learning Check: 72 Which of the following molecules would not yield an organolithium reagent when treated with Li in pentane? 1. iododecane 2. 4-bromo-1-pentanol 3. phenyl bromide 4. 4-bromobutyl methyl ether 5. cyclohexylbromide

Solution: 73 Which of the following molecules would not yield an organolithium reagent when treated with Li in pentane? 1. iododecane 2. 4-bromo-1-pentanol 3. phenyl bromide 4. 4-bromobutyl methyl ether 5. cyclohexylbromide

Learning Check: 74 What is the IUPAC name of the following molecule? 1. 2,4-dimethylheptyl-6-chloride 2. 2,4,6-trimethyl-6-chlorohexane 3. 2-chloro-4,6-dimethylheptane 4. 1-chloro-1,3,5-trimethylhexane 5. 2-chloro-4-methyl-isoheptane

Solution: 75 What is the IUPAC name of the following molecule? 1. 2,4-dimethylheptyl-6-chloride 2. 2,4,6-trimethyl-6-chlorohexane 3. 2-chloro-4,6-dimethylheptane 4. 1-chloro-1,3,5-trimethylhexane 5. 2-chloro-4-methyl-isoheptane

Learning Check: 76 What is the product of the following sequence of reactions?

Solution: 77 What is the product of the following sequence of reactions?