Post on 22-Feb-2018
145
286
Chapter 24: Amines
Amines: Nitrogen containing organic compounds
Organic derivatives of ammonia, NH3, Nitrogen atom have a lone pair of electrons, which potentially
make amines both basic and nucleophilicThere are many naturally occurring organic compounds that
contain nitrogen (alkaloids)
N
N
CH3
nicotine
N
H3C
CO2CH3
O Ph
O
cocaine
O
HO
N
CH3HH
HO
morphine
NH
N
HO
H3CO
H
quinine
NH2
OCH3
H3CO
H3CO
mescaline
NH
coniine
N
NH
HO2C
H
CH3
lysergic acid
N
CH3
N
CH3 CH3
OO
NHH3C
physostigmine
287
24.1: Naming AminesAlkyl-substituted (alkylamines) or aryl-substituted (arylamines)
Classified: 1° (RNH2), 2° (R2NH), 3° (R3N) and 4° (R4N+)
NC
H
sp3
NH
HH
alkylamines arylamines
primary (1°) amines
secondary (2°) amines
tertiary (4°) amines
quarternary (4°) ammonium ion
NH2
NH
N
H3CH2CNCH2CH3
CH2CH3H
H
N
H
H3C N
methanol primary secondary tertiary
Although the terminology is the same, this designation of amines is different from that of alcohols.
OC
H
HH H
OC
R
HH H
OC
R
HR H
OC
R
RR H
1° carbon 2° carbon 3° carbon
146
288
Amine nomenclature:The nomenclature for primary amines is similar to that of alcohols,
the suffix -amine can be used in place of the final -ol Consider the -NH2 group as an amino substituent on the parent
chainCH
3CH
2CH
2CH
3 CH
3CH
2CH
2CH
2OH
OH
CH3CH
2CH
2CH
2NH
2
NH2
butane 1-butanol 2-butanol
1-butanamine 2-butanamine(butylamine) (2-aminobutane)
CO2H
NH2NH2
cyclohexanamine 2-amino-3-phenyl-(cyclohexylamine) propanoic acid
H2NNH2
H2N NH2
1,4-diaminobutane 1,5-diaminopentane(putrescine) (cadaverine)
289
Symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group
Unsymmetrical secondary and tertiary amines are named as N-substituted primary amines. The largest alkyl group is the parent name, and other alkyl groups are considered N-substituents.
diphenylamine diisopropylamine triethylamine N,N-dimethyl- N-ethyl-N-methyl- propylamine cyclohexylamine
N
H
H3CH2CNCH2CH3
CH2CH3
N
H
NCH2CH3
CH3H3C
NCH3
CH2CH2CH3
Many arylamines go by non-systematic nomenclatureNH2 NH2
CH3
NH2
H2N
aniline o-toluidine p-phenylenediamine
147
290
The nomenclature of heterocyclic amines is highly specializedand often non-systematic
24.2 Structure and Bonding in AminesThe nitrogen of alkylamines is sp3 hybridized and
tetrahedral
pyridine pyrrole quinoline imidazole pyrimidine
indole quinoxoline pyrrolidine piperidine morpholine
N
N
NH
NH N
N
N
H
N
H
N
O
H
N
N
HN
N
291
In principle an amine with three different substituents on the nitrogen is chiral with the lone pair of electrons being the fourth substituent; however, for most amines the pyramidalinversion of nitrogen is a racemization mechanism
The barrier to nitrogen inversion is about 25 KJ/mol (very rapidat room temperature).
148
292
24.3 Properties and Aources of AminesPrimary and secondary amines, likes water and alcohols,can be hydrogen bond donors (N-H) and hydrogen bond acceptors (the lone pair)
24.5 Basicity of AminesThe chemistry of amines is dominated by the basicity of
the nitrogen lone pair
NO R
O
H N HO R
O
++
293
Alkyl amines are stronger bases than water, alcohols or ethers
R3N: + H2O R3NH + HO+ -
Kb = [R3NH+] [HO-][R3N]
pKb = - log Kb
pKb values are rarely used. Amines basicity is measured bythe pKa of the conjugate acid. (pKb + pKa = 14)
The conjugate base of a weak acid is a strong base:Higher pKa = weaker acid = stronger conjugate base
The conjugate base of a strong acid is a weak baseLower pKa = stronger acid = weaker conjugate base
R3NH+ + H2O H3O + R3N:+
lower pKaR3NH+ more acidicR3N less basic
higher pKaR3NH+ less acidicR3N more basic
149
294
Table 24.1 (p. 899): pKa values of ammonium ions Alkyl ammonium ions, R3NH+ X-, have pKa values in the range
of 10-11 (ammonium ion, H4N+ X-, has a pKa ~ 9.25) The ammonium ions of aryl amines and heterocyclic aromatic
amines are considerably less basic than alkyl amines (pKa ~ 5 or less). The nitrogen lone pair is less basic ifit is in an sp2 hybridized orbital (versus an sp3)
NH4+ pKa= 9.26
(H3CH2C)NH3+ 10.8
(H3CH2C)2NH2+ 10.7
(H3CH2C)3NH+ 11.0
pKa= 4.6
5.2
0.4
7.0
- 1.0
NH3
+
N H
+
NH
H+
NH2
+
NH3
O
+
295
24.5 Basicity of Substituted ArylaminesThe lone pair of electrons on the nitrogen of aniline are
conjugated to the π-electrons of the aromatic ringand are therefore less available for acid-base chemistry. Protonation disrupts the conjugation.
Substituents can greatly influence the basicity of the aniline. The effect is dependent upon the nature and position of the subtituent (recall the acidity of substituted phenols)
150
296
Electron-donating substituents (-CH3, -OH, -OCH3) make thesubstituted aniline more basic than aniline itself (the pKaof the anilinium ion is higher than 4.6)
Electron-withdrawing substituents (-Cl, -NO2) make thesubstituted aniline less basic than aniline itself (the pKaof the anilinium ion is lower than 4.6)
See Table 24.2 (p. 903)
NH2Y NH3 + H2O+ H3O
+Y
+
Y= -NH2 pKa= 6.15 -OCH3 pKa= 5.34 -CH3 pKa= 5.08 -H pKa= 4.63 -Cl pKa= 3.98 -CN pKa= 1.74 -NO2 pKa= 1.00
less acidic(more basic)
more acidic(less basic)
297
Problem 24.4: Which compound is more basic?a) b) c)
NaOH -or- H3C NH2N-or-(CH3)2NH
H3CH2C NH2H3CH2C NH2
C
O
-or-
Problem 24.6: Rank the following in order of increasing basicity?
a)
b)
c)
NH2O2N,
NH2,
NH2Br
NH2Cl, ,
NH2H3CNH2
O
NH2F3C, ,
NH2H2FCNH2H3C
O
H
151
298
24.6 Synthesis of AminesReduction of Nitriles, Amides and Nitro Compounds
R-BrMg(0), CO2
then H3O+
R NC
LiAlH4
ether R
N
CH R
N
C
H
H
2
H3O+
R
NH2
C
H
H
LiAlH4
R-BrNaCN
1° amine
1°, 2° or 3° amine
H3O+
-or-
NaOH, H2O
R OHC
O SOCl2
R ClC
O H3C-NH2
R NH
C
O
CH3
LiAlH4
R NH
C CH3
HH
-or-
BH3
HNO3, H2SO4NO2
H2O
H2, Pd/C
-or-
SnCl2
NH2
1° arylamines
299
SN2 reaction of alkyl halides and tosylates
Ammonia and other alkylamines are good nucleophiles andreact with 1° and 2° alkyl halides or tosylates viaand SN
2 reaction to give alkyl amines.
1°, 2°, and 3° amines all have similar reactivity; the initially formed monoalkylation product can undergo further reaction to yield a mixture of alkylated products
152
300
Synthesis of primary amines from the reaction of alkyl halides or tosylates with “ammonia equivalents”
Azide ion is a very strong nucleophile and react with 1° or 2° alkyl halides or tosylates via an SN
2 reaction. The resultingazide can be reduced to a 1° amine.
Gabriel amine synthesis: reaction of potassium phthalimide with alkyl halides or tosylates via an SN
2 reaction. The resultingN-substituted phthalimide can be hydrolyzed to a 1° amine.
XC
H
R1
R2
N N N
1° or 2° alkyl halideor tosylate
SN2
N C
H
R1
R2
NN N3 C
H
R1
R2
Alkyl azide
H2, Pd/C
-or-LiAlH4
H2N C
H
R1
R2
1° amine
azide
N
O
O
H
KOH
EtOH
N
O
O
K+
PhthalimidePotassiumphthalimide
XC
H
R1
H
H
R1
HN
O
O
C
N-substitutedphthalimide
NaOH/H2O
H2N C
H
R1
R2
1° amine
301
Reductive amination: synthesis of an amine by the reduction of an imine from the condenstion of an aldehyde or ketone with ammonia, 1° or 2° amine.
NH+ H3N
-H2O H2/ Pd/C NH2O
H
O
+ H3CNH2
-H2O NCH3
H2/ Pd/C HN
H
CH3
3-phenyl-2-propanone (P2P) amphetamine
methamphetamine
O
+ (H3C)2NH-H2O
NCH3H3C
H2/ Pd/CN H
CH3H3C
+
1° amine
2° amine
ammonia
1° amine
2° amine
3° amine
153
302
Sodium cyanoborohydride, Na+ N≡C-BH3– : the cyano ligand
makes cyanoborohydride a weak hydride source and itwill react with only the most easily reduced functional groups. such as an imine. Does not reduce ketones andreduced aldehydes slowly
Reductive amination with NaB(CN)H3: one-pot reaction
practice problem 24.1 (p. 908)
Hoffmann and Curtius rearrangements (please read)
CHO
+ H3C-NH2
NaB(CN)H3
CN
H
CH3
H
CNCH3
H
H H
NH2
+ H2C=ONaB(CN)H3
NCH2
H
CNCH3
H
H H
303
24.7: Reactions of AminesAcylation: ammonia, 1° and 2° amines react with acid chlorides
and anhydrides to give amides (Chapt. 21.4, 21.5 & 21.8)
R ClC
O
R NC
O
acid chloride
R'NH2
R OHC
O
carboxylic acid
SOCl2
R'2NH
NH3
di-substitiuted (3°) amide
R'
R'
R NH
C
O
R'
R NH2
C
O
mono-substitiuted (2°) amide
unsubstitiuted (1°) amide
154
304
Hofmann elimination: E2 elimination of a trimethyl ammoniumgroup to give an alkene
NH2
+ (H3C)3CO - K+ No reaction (H2N- is a very poor leaving group)
H3C-I
N(CH3)3I-
+ (H3C)3CO - K+ +
Hofmann elimination gives the less substituted alkene, whereE2 elimination of an alkyl halide or tosylate will followZaitsev rule to give the more substituted alkene
(major) (minor)
305
24.8 Reactions of ArylaminesElectrophilic aromatic substitution: an amino group is a
very strong activating group and an ortho/paradirector.
The amino group is incompatible with the Friedel-Craftsreactions (Ch. 16.3).
Electrophilic aromatic substitution of phenyl acetamides(amides of aniline).
NH2
CH3
HN
CH3
CH3
O
(H3CCO)2O,pyridine Br2
HN
CH3
CH3
O
BrNaOH, H2O
NH2
CH3
Br
The acetamide group is still a strong activator and an ortho/paradirector. (see Fig. 16.10, page 541)
155
306
Advantages of the acetamide over the amino group forelectrophilic aromatic substitution:Anilines are so activated that multiple substitution
reactions can be a problem. The reactivity of theacetamide is attenuated so that mono substitution is achieved.
The acetamide group is compatiable with the Friedel-Crafts reactions.
NH2
Br2, H2O
NH2
Br Br
Br
NH2
HN CH3
O
(H3CCO)2O,pyridine
H3CCOCl
AlCl3
HN CH3
O
O CH3
(H3C)3C-Cl
AlCl3
HN CH3
O
NaOH, H2O
NH2
O CH3
NH2 NaOH, H2O
307
Diazonium salts: The Sandmeyer reactionprimary arylamines (anilines) react with nitrous acid (HNO2,generated from the reaction of NaNO2 and H2SO4) to forma stable aryl diazonium salt.
N
OH
O
H+
N
OH2
O
- H2O N
O
HNNO
- H
NNOH
H+ NNOH2
NN
HSO3
H2N
Aryl diazonium salts react with nucleophiles in a substitutionreaction. N2 is one of the best leaving groups.
NN
+ Nu:
Nu
N N+
NN
NN
+
NN
What is the mechanism? rate= k [Ar-N≡N+]
156
308
Synthesize 3,5-dibromotoluene from bromobenzene or toluene
BrBr
CH3
CH3
Br
Some reactions of aryl diazonium salts I
- N2
NN
- N2
F
- N2
HH3PO2
HBF4
NaI
309
Some more reactions of aryl diazonium substitution reactions promoted by Cu(I) salts (Sandmeyer reaction).
Cl
- N2
NN
- N2
Br
- N2
CNCu(CN)
HBr, CuBr
HCl, CuCl
- N2
Cu2O, H2OOH
The mechanism of the Sandmeyer reaction (Cu+ promoted) involves an aryl radical intermediate.
157
310
Diazonium coupling reaction (please read)
24.9 Tetraalkylammonium Salts as Phase-Transfer Catalysts (please read)
Synthesize 2-iodoethylbenzene from benzene:
I CH2CH3
311
24.10 Spectroscopy of AminesIR: N-H stretches in the range of 3300 - 3500 cm-1
same range as O-H stretch, but N-H stretches are sharperand less intense.
OH
158
312
Mass Spectrum: Nitrogen rule: small organic compounds with an odd number of
nitrogen atoms have an odd mass; compounds with an even number of nitrogen atoms have an even mass
NMR: Hydrogens on the carbon attached to a nitrogen of an amine have a chemical shift of δ 2.2 - 3.0
CH2 N
H
CH2CH3
1H, m-N-H
2H, q-N-CH2-CH3
5H, mC6H5- 2H, s
Ph-CH2-N-
3H, t-CH2-CH3
313
13C NMR: Carbons attached to a nitrogen of an amine are deshielded about 20 ppm downfield from where they would absorb in an alkane
140.6
128.3 128.0
126.8
54.0 43.7 15.3
CDCl3
CH2 N
H
CH2CH3
38.224.213.7
CH2 CH2 CH3
159
314
C9H13NO[α]D +23°
13C NMR: 138.6, 129.1, 128.5, 126.3, 65.9, 54.2, 40.6
7.21-7.32 (m, 2H)7.15-7.21 (m, 3H)
3.60 (1H, dd, J= 10.7, 4.1)
3.38 (1H, dd, J= 10.7, 7.0)
3.05-3.12 (1H, m)
2.77 (1H, dd, J= 13.3, 5.0)
2.49 (1H, dd, J= 13.3, 8.8)
2.35-2.45 (3H, br s)
IR: