LARC

Chem 51C

[3] From amides (Section 20.7B) Preparation of Amines Primary (1), 2, and 3 amides are reduced to 1, 2, and 3 amines, respectively, by using Reduction (recap of old reactions) LiAlH4. O [1] LiAlH4 C RCH2 NH2 [2] H2O R NH2 1 amine 1 amide O [1] LiAlH4 C RCH2 N R' Direct Nucleophilic Substitution [2] H2O R NHR' H 2 amide 2 amine O [1] LiAlH4 C RCH2 Preparation N R' 25.7 of Amines 961 [2] H2O R NR'2 R' 3 amide 3 amine Useful SN2 Practice CH3CH2CH2 Br + NH3 CH3CH2CH2 NH2 + NH4+ Br substitutions Problem 25.14 What compound, nitrile, and amide are a reduced to eachtcompound? Which n itro nitro compound, nitrile, and amide nd r educed o e ach compound? excess 1 amine
a. CH3CHCH2NH2
CH3

Week 9 Worksheet 13

25.7

Preparation of Amines

963

b.

CH2NH2

c.

CH3 CH3 N
+

NH2

CH3 Br + CH3 N Problem 25.15 What amine is formed by reduction of each amide? CH 3 O CONH2 a. b. N Draw t he p roduct o f e ach r eaction. blem 25.11 Draw the product of each reaction.

+ Br

CH3
O quaternary ammonium salt

c.

NHCH3

Problem 25.16 a. Problem 25.17

Which amines cannot be prepared by reduction of an amide? NH2 The Gabriel Synthesis NH2 of 1 Amines N NH2 a. b. c. d. H To avoid polyalkylation, a nitrogen nucleophile can be used that reacts in a single nucleophilic substitution reactionthat is, the reaction forms a product that does not contain a nucleophilic Gabriel Synthesis nitrogen atom capable of reacting further. The Gabriel 25.7C Reductive Amination of Aldehydes andaKetones synthesis consists of two steps and uses resonance-stabilized nitrogen nucleo phile to synthesize 1 amines via nucleophilic substitution. The Gabriel synthesis begins with Reductive amination is a two-step method that converts aldehydes and ketones into 1, 2, phthalimide, of aLets grouprst ofexamine compounds called using imides. N H bond of an imide espeand 3 one amines. this method NHThe 1 amines. There areis two 3 to prepare cially acidic distinctbecause parts in reductive amination: the resulting anion is resonance stabilized by the two anking carbonyl groups. [1] Nucleophilic attack of NH3 on the carbonyl group forms an imine (Section 21.11A), which is not isolated; then, O O O O [2] Reduction of the imine forms an amine (Section 20.7B).
HO

CI isopropylamine + NH3 Explain why [(CH3)2CHNH2] can be prepared by reduction a nitro compound, but b. NH + of CH Br 2 3CH2 cannot be prepared by reduction of a nitrile, even though it is a 1 amine. (excess) (excess)

H N

Reductive amination A two-step process

R C O R'

N O

NH3

R C NH R'

N O

[H]

R R' C NH2 H 1 amine

N O

O phthalimide

R' = H or alkyl

imine resonance-stabilized anion

new bonds

Piperidine

OH

H 2O

CH3CH2 NH2

CO CH3CH 2 2Br

SN2
N H

Pyridine

CH3CH2 N O
N

OH

H 2O

CH3CH2 NH2

CO2 by-product

of Br by NH2

The lone pair is in an lone pair is in an The Overall result of Br by sp 3 hybrid orbital. Substitution sp 2 hybrid orbital.

by-pro NH2

Pyridine is a weaker base than piperidine because its nonbonded pair of electrons resides CH in anO 3 sp2 hybrid orbital. Although pyridine is an aromatic amine, its lone pair is not part of the delocalCHCH2CH2NH2 c. (CH3)2CHCH CH b.hybridization c. the NH2 2 As a result, ized a. system, so its basicity is determined by the of 2 its N2NH atom. Nomenclature pK is much a) a value for the conjugate acid of pyridine b) lower than that for the conjugate acid of piperidine, pyridine the weaker base. 25.41 Give a systematic or common making name for each compound. your el synthesis? Explain choices. Problem 25.13 Which amines cannot be prepared by a Gabriel synthesis? Explain your choices.
CH3O PROBLEMS NH2

Practice 994 Chapter 25 Amines The higher the percent s-character of the orbital containing the lone pair, the more Which alkyl halide 25.12 is needed to p repare p rimary amine by G abriel synthesis? tightly the lone pair e isach held, and the theeach base. Problem What alkyl halide is needed toweaker prepare 1 amine by a Gabriel synthesis? amine by a Gabriel synthesis? Reductive Amination

CH2CH3 CH3 e. (CH3CH2CH2)3N i. a. CH3NHCH2CH 2CH NH + + 2 2 NH2 N N N N N N N H H H N c. d. NH2H H H Reductive Amination pyridine piperidine a. b. c. d. H b. f. (C6H5)2NH j. CH3CH2CH2CH(NH2)CH(CH3)2 NH2 higher pKa lower pKa weaker base stronger base weaker acid stronger acid pKa = 5.3 Ka = 11.1 NH2 N C(CHp c. g. k. NH2 3)3 996 Chapter 25 Amines Groups That Contain Nitrogen CH2CH3 Problem 25.26 Which nitrogen atom in each compound is more basic? 25.7B Reduction of Other Functional Groups That Contain Nitrogen 25.57 Draw product of each reductive amination reaction. nitro compounds, nitriles, and amides. Because the CH3 the 996 they are Chapter CH3 sed previously, presented hereAmines inNsummary Amines can N(CH2CH3and )2 d. 25 h. l. NH3 NH2 O be NH prepared by reduction ofCHO nitro compounds, nitriles, amides. Becau Practice 2 N b. c. C6H5H a. a. C N N H5 6 NaBH3CN CH2CH2CH NaBH CN 3 3 CH details of CH these reactions have been discussed previously, they are presented here in sum 3 Predict the product. 3 O 25.57 Draw the product of each reductive amination reaction. N

DMAP form only. nicotine 25.42 Draw the structure that corresponds to each name. 4-(N,N -dimethylamino)pyridine NH2 NH3 a. cyclobutylamine NH2 f. N -methylcyclopentylamine (CH )26 NH H5 CHO c. 3C a. C6H5 NaBH CN NaBH O b. 3CN d.-2-aminocyclohexanol 3 b. N-isobutylcyclopentylamine g. cis NaBH NaBH3CN [1] From nitro compounds (Section 18.14C) ng a variety of reducing agents. 3CN O c. tritert -butylamine h. 3-methyl-2-hexanamine O a) b) 25.10F Summary d. N,N-diisopropylaniline i. 2sec-butylpiperidine 25.58 How would you prepare benzylamine (C6H5CH each compound? In some cases, more than one step is required. H2, Pd-C 2NH2) from 2 Nitro groups are reduced to 1 NH amines using a variety of reducing agents. Acidbase chemistry is central to many processes in organic e. N -methylpyrrole j. (2 S )-2-heptanamine (CH ) NH or 3 2 c. C6H5CONH2 e. C6H g. chemistry, C6H5NH2 so it has been a constant a. C6H5CH2Br 5CH3 R NH2 b. O d. Tables 25.2 and 25.3 organize and summarize the acidbase principles Fe, HCl NaBHb. Ctheme CNthroughout d.this C6text. H5CHO f. CN, COOH benzene name NaBH 6H5isomers 6H5 3CN H11 and give an h. acceptable for each amine. of molecular formula C4 3CN 1 amine 25.43 Draw all constitutional H2, Pd-C O or or Sn, HCl 25.2 Factors That Determine Amine Extraction NH2is required. R NO R step 25.58 Table How would you prepare benzylamine (C6H5CH ) from each compound? In some cases, more than one 2NH2Basicity Basicity of Amines 2 Chiral Compounds Fe, HCl 1 amine c. C e. C6Htoluene g. 3), Cbenzoic a. CFactor Example 6H5CH2Br 6H5CONH 5CH3 6H5NH2 acid (C6H5COOH), 25.59 How would 2 you separate (C6H5 CH and aniline (C 6H5NH2) by an extraction procedure? or How manyd. stereogenic present in each compound? stereoisomers. b.25.44 C6H5CN C6H5CHOcenters are f. C h. benzene Draw all possible 6H5COOH Sn, HCl [1] Inductive effects: Electron-donating groups bonded to N RNH2, R2NH, and R3N are more basic than NH3.

AlH4.
LiAlH4 H2O

CH by Ag and i. The product in (g), then [1] LiAlH4; [2] H2O 3COOH 2O pyridine. [3] Aromaticity: Having theb. lone pair on N as part of the f. CH3I (excess), Pyrrolefollowed is less basic than R CH2NH 2 c. (CH g. CH3CH2COCl j. The product in (h), then H2, Pd-C 3)2C O Reactions aromatic system decreases basicity. Nitriles are reduced to 1 amines with LiAlH4. d. CH2O, NaBH3CN 1 amine Basicity 25.60 What products are formed when N-ethylaniline (C6H5NHCH2CH3) isN treated with each reagent? 25.61 Draw products when p -methylaniline (p-CH3C6H4N NH )[1] is treated with each reagent. H LiAlH Which compound in the each pair is formed the stronger base? h. The2 product in a.25.45 HCl e. CH 4 (g), then HNO3, H2SO4 3I (excess) d by SN2 substitution of alkyl halides with a. CN, this less basic basic R 3C N R CH2NH )2more C O h. HCl e. (CH 2, HCl 2 NaNO b. CH COOH f. CH I (excess), followed by Ag O and i. The product in LiAlH [2] H2O (g), then [1] 3 3 2 4; [2] H2O alkyl halide to a 1 amine with one more carbon b. CH COCl f. CH COCl, AlCl i. Step (b), then CH3COCl, AlCl3 3 3 3 O(CHeffects: [4] (CH Hybridization Increasing the 2 percent is less piperidine. g. or CH3CH COCl s-character in Pyridine j. than The product in (h), then H2, Pd-C amine or 3)2C CH basic )2NH (ClCH NH a. c. (CH 2CH2)21 NH2 illustrates thisc. two-step sequence. 3CH2)2NH c. (CH g. 3CH32 COOH j. CH3CHO, NaBH3CN 3CO)2O basicity. the orbital with the lone pair decreases d. CH2O, NaBH3CN N d. excess CH 3I Because a(p cyano group is readily introduced by SN2 substitution of alkyl halides with C [1] LiAlH 4 25.61 Draw the products25.62 formed when p -methylaniline -CH NHNH treated with each reagent. 3C 6H4 2) is you convert CH CH CH CH into each compound? N N CH2NH2 3How CH3 C N CH or (CH 3 2 2 2 2 )2 would ) N b. d. 3 HCON(CH 3 3 provides a two-step an alkyl halide to a 1 amine with one more c [2] a. H2HCl O H or method to convert h. NaNO , HCl e. (CH 3)2C O 2 NH d. more CH3CH a. CH3CH2CH2CH2NHCOC 1 amine 6H5 2CH2CH2NHCH2C 6H5 less basic basic N b. CH3COCl CH CH COCl, AlCl i. 2NHCH Step (b), then CH3 COCl, atom. The of to CH3CH illustrates this two-step AlClsequence. f. conversion 3 CH3Br e. 3 2NH b. CH3CH2CH new C C bond 2CH2N C(CH23 3)2 2CH 2CH2 2CH3 H CH3CH + NaBH CN c. (CH3CO)2O j. 2N(CH CH3CHO, Practice 3 c. CH3CH2CH f. [CH3CH2CH2CH CH2 g. CH3COOH 3)3] I Rank the compounds in each group in order of increasing basicity. NaCN d.25.46 excess CH [1] LiAlH4 3I Rank the compound in the each group in o rder of amine increasing b asicity. Example 25.63 Draw products formed when each is treated with [1] CH3I (excess); major product when CH CH CH3 [2] C Ag N2O; [3] . Indicate the CH 3 Br 2NH2 NH NH NH2 3 SN2 2 2 [2] H2O 25.62 How would you convert CH mixture results. 3CH2CH 2CH2NH2 into each compound? 1 amine CH3 d. CH3CH2c. CH2CH2NHCH2C6H5 a. CH3CHa. NH2 3 2NHCOC6H5 NH2 2CHNH 2CH new C C bond b. e. CH3CH2CH2O c. d. e. 11:58:27 AM a. 2 b. CH CH CH NHCH CH CH smi75625_ch25_949-1001.indd 973 3CH2CH2CH2N 11/13/09 CH N C(CH 3)2 2)6NH2 2 2 3 N Cl 3(CH 3 2 H NH2 N c. CH3CH2CH f. [CH3CH2CH2CH2N(CH3)3]+ I CH2

CH3 + Extraction N products N 6H CH CH CH 22 CH CH a. b.pair 25.60 Delocalizing What are formed N-ethylaniline NHCH CH ) is3treated with each reagent? 5 3CH 2CHCH 2CH 2CH2 (C 2 23 ) are less basic than alkylamines (RNH2). [2] Resonance effects: the lone on Nwhen Arylamines (C 6H 5NH2 I (excess) h. The product a. HCl e. CH 25.59 How would you separate toluene (C H CH ), benzoic acid (C H COOH), and aniline (C H NH ) by an extraction procedure? decreases basicity. Amides (RCONH ) are much less basic than amines (RNH ). (g), then HNO3, H2SO4 CH CH CH 3 CH [2] From nitriles (Section 22.18B) 2 2in 3 6 5 6 5 2 3 2 3 6 5 3 CI

Reactions increase basicity.

CH2CH3

25.63 Draw the products formed when each amine is treated with [1] CH3I (excess); [2] Ag2O; [3] . Indicate the major product when a b. d. C6H5NH2 (C6H5)2NH NH2 to convert acetophenone (C6H5COCH3) into each compound? In some cases, more than one step mixture results. 25.64 What reagents are needed N N N required. H H CH
NH2 N(CH3)2 b. c. e. OH a. CH3(CH N 25.47 2)6NH 2 How does the p Ka of the conjugate of AM benzylamine (C6H5CH2NHd. 2) compare to the pKas of the conjugate acids of 11/13/09 acid 11:58:22 H c. e. a. NH N NHCH3 2 cyclohexanamine (10.7) (4.6)? Explain your choice. C6H5 C6H5 and aniline NH C6H5 H
2

NH2

CH3

CH3

25.64 What reagents are needed to convert acetophenone (C6H5COCH3) into each compound? In some cases, more than one step is NHCH2CH2CH2CH3 b. d. C6H5 f. required. C6H5 NCH2CH2CH3 C6H5
smi75625_ch25_949-1001.indd 962

N(CH3)2

a.

NH2 OH 25.65 Answer the following questions about benzphetamine, a habit-forming diet pill sold under the trade name Didrex. c. e. NHCH