Download Amines and amino acids

Chemistry of Amines
Ch. 24 of McMurry
Classification: NH3= ammonia
IR:
N – H stretch:
NR4+ X- = quaternary ammonium salt
(tetraalkylammonium)
NH2R = 1o
NHR2 = 2o
2 bands
3250 – 3550 cm-1
1 band
~3400 cm-1
NR3 = 3o
no N-H, but adding
HCl
ammonium
2600 cm-1
N – H bending:
C – N stretch:
1580 – 1650
1515 cm-1
weak, 1020 – 1250 cm-1
NMR:Deshielding effect of N
shifts N-methyl to 2.42 ppm in
1
H NMR
20 ppm downfield shift of most
groups in 13C NMR
Mass spec: Odd-number of N atoms in a molecule produces an odd ion mass;
molecules w/ just C, H, O always give even masses.
α-cleavage:
RCH2 – CH2 – NR2
RCH2. + [CH2=NR2]+
Nomenclature
Primary amines: 1) Hydrocarbon portion is named with “amine” added as a suffix
2) When other FG present, name “amino” group as substituent
2o and 3o:
1) If symmetrical, use prefix “di” or “tri” before alkyl group name
2) Unsymmetrical: smaller groups are named as N-substituents
Aromatic amines: Named as derivatives of aniline with o, p system or with amino
group as C1
Heterocyclic amines,
common in nature have
specific skeletons
Nicotine and cocaine are
examples of plant-derived
amines, or “alkaloids”
Cocaine is a “piperidine
alkaloid”; nicotine contains
two heterocycles
Properties of amines
1) Physical:
Polarity: Due to polarity of N – H bonds, 1o and 2o amines can hydrogen-bond
Elevated boiling points: amines > alkanes
Water-solubility: 5C or smaller amines and ammonium salts are highly soluble,
aromatic are moderately soluble
Odor: fishy or rotten smell; diamines form from lysine in rotting flesh (cadaverine)
Pharmacological effects: Many amines resemble amine neurotransmitters and
affect nervous system functioning by mimicking or blocking these NTs
2) Chemical: Basicity and nucleophilicity
Due to lone pair of e- on N, amines are good electron-donors (nucleophilic)
and can accept protons (basic)
R3N:
+
H – Cl
NR3H+ Cl-
Relative basicities of amines are expressed based on the acidity of their conjugate
acids (the ammonium ions)
+
NR3H + H2O
+
NR3 + H3O
[amine] [H3O+]
Kb = Kw/Ka
Ka =
[ammonium salt]
Rule: The lower the pKa of the ammonium ion (more acidic), the weaker the base
How do substituents affect basicity?
 Nonaromatic amines: basicity isn’t affected much by the nature of alkyl groups
 Aromatic (anilines) & heterocyclic amines are much less basic than alkylamines
1) The hybridization of the N atom:
In heterocyclic aromatic amines the lone pair of e- may be part of the aromatic pi
electron system as in pyrrole, or held tightly in an sp2 orbital as in pyridine.
2) Resonance-stabilization of anilines
Arylamines (anilines) have delocalization of the N lone e- pair over the aromatic
ring, and there is therefore a greater loss of stability on protonation to the
arylammonium ion.
Substituent effects: See Table 24.2
E- donating groups on a ring increase basicity (alkyl, OR, OH, other NH2 groups)
EWG decrease basicity (NO2, CN, CHO, Br, Cl)
Preparation of Amines
1) Reduction of nitriles or amides using LiAlH4 gives 1o amines
H2
C
H 3C
H2
C
NaCN
Br
H2
C
1) LiAlH4, ether
H 3C
C
N
H3 C
2) H2O
NH2
C
H2
O
H3 C
1) LiAlH4, ether
C
C
H2
2) H2O
NH2
H2
C
H3 C
C
H2
NH2
2) Anilines can be prepared by reduction of nitrobenzenes
NO2
1) SnCl2 , H 3O +
2) NaOH
NH 2
or H2 , Pt
3) SN2 reactions with alkyl halides
Use of ammonia as Nu gives a mixture of mono, di, tri- and even tetra-substituted
amines (lesser amount of 3o amines, ammonium salts)
H2
C
H 3C
H2
C
NH3
Br
H 3C
H2
C
NH 2
H 3C
H2
C
H2
C
N
H
CH3
H 3C
H2
C
CH3
N
H 2C
o
Azide synthesis: ONLY makes 1 amines…but sometimes with a bang!
CH2
Br
NaN3
H2
C N N
CH 3
LiAlH 4, ether
CH2
NH2
NH
H2O
Gabriel amine synthesis: 1o amino group using an imide as nucleophile
• The acidic N of phthalimide can be deprotonated much like a β-diketone
• Alkylation occurs when treated with an alkyl halide
• Addition of base hydrolyzes the imide, releasing the amine as a product:
aq.
NaOH
4) Reductive amination of aldehydes & ketones: 1o, 2o & 3o amines
C
O
:NH3
H2
C
NH
CH
Raney
nickel
NH 2
Raney Ni = fine Ni particles with adsorbed H2
Another common reducing agent for this reaction is NaBH3CN in CH3OH
5) Rearrangements: Decarbonylation of amides to make 1o amines
Work well for both alkyl and aryl amines:
Hofmann rearrangement uses base
to brominate the amide, followed by
a migration of the R group to the nitrogen
(Fig 24.5)
In the Curtius rearrangement, an acyl
azide forms, rearranges to isocyanate by
migration of R, then decarbonylates
O
NaOH, Br 2
C
R
NH2
O
R
NH 2
R
NH 2
1) NaN 3 , heat
C
R
H 2O
Cl
2) H 2 O
Many common amine stimulant drugs are structurally similar to, and raise the
levels of natural neurotransmitters including norephinephrine and dopamine.
Some drugs prepared by the methods shown here include:
Amphetamines
(reductive amination)
“Fen-Phen”
(Hofmann rearr.)
Reactions of Amines
1) Alkylation: Reaction of amines with alkyl halides results in substitution of alkyl
groups for the H atoms.
Tertiary amines can be used to prepare quaternary ammonium salts in this way:
CH3CH2Cl
:N(CH2CH3)3
(CH3CH2)4N+ Cl-
2) Amide formation: Reaction of carboxylic acids or acyl chlorides with amines
O
O
H2NCH3
C
C
H 3C
H2 N
Cl
N
H
CH3
3) Hofmann eliminations: Alkenes from quaternary ammonium salts
 Quaternary ammonium salts can be prepared from amines using alkyl halides,
such as an excess of CH3I.
 NR3+ becomes a leaving group
 In the presence of base ( – OH or Ag2O), β-elimination by E2 pathway occurs
 This reaction was more commonly used to identify amines than to make
alkenes
H2
C
H 3C
C
H2
CH3
CH3
heat
N
H3 C
CH3
CH 2
H 3C
C
H
+ H 3C
N
CH 3
Regiochemistry: When there is more than one set of β-hydrogens, elimination
occurs from the less substituted carbon (“anti-Zaitsev” orientation). The tertiary
amine is a bulky leaving group, so the less hindered position is favored.
Mechanism of Hoffmann Rearrangement
Arylamine reactions
Electrophilic aromatic substitution (Review):
In general, amines are activators and direct substitution at the ortho & para
positions
Reactivity is enhanced so much that multiple
substitutions often occur:
Diazonium Salts, Azo compounds and
Color
Although electrophilic aromatic substitution is a versatile procedure, not all
substituted aromatics can be made directly (fluorobenzenes, phenols)
Transformation of aniline to give a good leaving group provides a route to a variety
of substituents: the diazonium salt is such a group
NaNO2 or HNO2
H 2 SO 4
NH 2
N N
Cl-
0o C
NaNO2 and acid produce HNO2,
which eliminates water to form
nitrosonium ion (NO+)
Aryl diazonium salts can react with nucleophiles to release stable N2; this is the
driving force behind many useful substitutions:
HBr, CuBr
Br
N N
or HCl, CuCl
+ N2
(Sandmeyer reaction)
or Cl
KCN
C
N N
Cl
-
N
CuCN
+ N2
NaI
I + N2
N N
Cl
-
N N
Cl-
HBF4
Heat
Cu 2O
N N
Cl-
Cu(NO3 )2 ,
H 2O
F + N2 + BF3 + HCl
OH
+ N2
(Schiemann rxn)
When you need an o, p director on a temporary basis:
An amino group may be gotten rid of entirely by conversion to an azo group
followed by reaction with hypophosphorous acid:
NaNO2 or HNO2
H3PO 2
H 2 SO 4
NH 2
0o C
N N
Cl
+ N2
-
Azo compounds…to dye for!
The diazonium salt makes a “cool” electrophile (only stable at low temps) and is
particularly effective in coupling reactions with activated benzenes such as
phenols.
Example: the ingrain dyeing process used to make colorfast azo dyes inside
cotton fibers:
Reaction between a phenol and a diazonium salt prepared from a substituted
aniline
Azo dyes are molecules containing aromatic rings conjugated together by azo
linkages and often having various substituents at different positions
 The extended conjugated pi system absorbs light in the visible range
 These pi systems, referred to as “chromophores,” are necessary for color
 The nitro, amino, chloro, bromo & hydroxy groups found as ring substituents
are called “auxochromes” and cause variations in the basic color of the dyes
 Phenols are particularly useful for dyeing cotton because their OH groups can
hydrogen-bond with cotton fibers (cellulose)
Physiological roles of amines: Neurotransmitters and amines that mimic them
Amphetamines
CNS stimulants
Opiates (psychoactives)
Problems
How could these amines be prepared using reductive amination?
Predict the products that would form in a Hofmann elimination:
Compound A, C6H12O, has an IR absorption at 1715 cm-1 and gives compound B,
C6H15N, when treated with NH3 and NaBH3CN. The IR and 1H NMR spectra of B
are shown. What are the structures of A and B?
How would you prepare these compounds from benzene using a diazonium
replacement?
a. p-bromobenzoic acid
b. m-bromochlorobenzene
c. p-methylbenzoic acid
Amino Acids and Proteins
Peptides & proteins = natural “polymers” made up of amino acid units (“residues”)
Peptides are generally < 40 amino acids; proteins range in size from 40 aa's to
several thousand
Roles of proteins:
 Major structural component in animal kingdom:
--skin, bones, muscles, tendons contain mostly collagen
--hair, fur, nails, feathers, hooves mostly keratin
 Enzymes are primarily proteins; some hormones are proteins or peptides
Structure is vitally important to function. There are several levels of protein
structure:
 Primary structure: sequence of amino acids in the protein chain
 Secondary structure: folding or twisting of the protein backbone
 Tertiary structure: 3-D structure of the entire protein chain
 Quarternary structure: In proteins composed of more than one chain, how
these chains associate with each other
The primary structure of a protein determines the other levels of structure. Thus,
a good understanding of the units that make up the protein chain is important.
Unlike polysaccharides, which are composed of the same type of unit linked in
different ways, protein chains can contain any or all of the naturally-occurring
amino acids
 Table 20.1: each amino acid makes up somewhere between 1.1 and 9.0 % of
the average protein
 Variety in amino acid structure leads to tremendous variety in protein aa
sequences
 These sequences determine protein properties & 3-D structure.
Amino acids:
Bifunctional molecules
O
General structure:
O
H
C
NH 3
R
where R = “side chains” of varying structure
All a.a’s except glycine have a chiral center
At physiological pH, both amino & acid
groups are charged
Stereochemistry: Unlike sugars, all amino acids in nature have the
L-configuration defined by glyceraldehyde:
COOH
NH3
R +
CHO
H
OH
CH2OH
CHO
HO
H
CH2OH
COOH3N
H
+
R
D-amino acids
D-glyceraldehyde
L-glyceraldehyde
L-amino acids
All amino acid groups have the 1o amine and carboxylic acid functionality, which
join together in amide linkages to make peptides and proteins.
Side chain structure varies greatly:
1) Aliphatic amino acids: Contain alkyl side chains, all hydrocarbon, neutral &
nonpolar (“hydrophobic”) side chains:
Gly, Ala, Val, Leu, Ile
2) Hydroxy-amino acids: Contain alcohol side chains, polar
Ser, Thr
3) Sulfur-containing: Contain thiol or thioether side chains, less polar than OH
Cys, Met
4) Acidic: Contains a second carboxylic acid group, very polar
These side chains may be negatively charged at basic pH:
Asp, Glu
5) Amides: Contain an amide of the acid groups noted above, also polar
Asn, Gln
6) Basic: Contain a second amine group
These side chains may be positively charged at acidic pH
Arg, Lys, His
7) Aromatic: Contain a benzene ring
Tyr (Trp)
8) Heterocyclic: Contain a heterocyclic amine ring
Trp (His) Pro (side chain and amino group are together in a ring)
Acid-base properties of amino acids
At pH = 7.4, both acid & amino groups are charged; typical amino acid is a
zwitterion:
Amino group
Acid group
Side chains
pKa = 9
pKa = 2
pKa varies (table 26.1)




At pH < 2, the acid group is protonated and so is the amino group.
At pH > 2, the acid group loses its proton
At pH > 9, the amino group loses its proton and becomes uncharged
Under no condition does the molecule exist with both groups uncharged
Those amino acids with acidic or basic side groups may have an additional
charge depending on the relationship between pKa and pH.
In general: when pH < pKa, the group is protonated
when pH > pKa, the group loses the proton
Example: histidine, with a weakly basic side group has a pKa of 6.04
Amino acids can be identified by titration curves: illustrates pKa values of the
groups
 Plot of pH vs. equivalents of added base
 pH at each inflection point on the curve corresponds to pKa of an ionizable
group
 titration curve for alanine shown
Isoelectric point (pI): Useful property in identification and separation of
amino acids
pI = pH at which a sample of amino acid has no net charge (the charges cancel)
For aa’s with neutral side chains:
pI
= pKa (acid) + pKa (base)
2
For amino acids with ionizable side chains:
Basic: pI = average of the
side chain pKa + amino group pKa
Acidic: pI = average of the
side chain pKa + acid group pKa
How pI affects behavior: using charge to separate amino acids

When solution pH < pI, protonation predominates: aa is positively charged overall

When solution pH > pI, deprotonation predominates: aa is negatively charged overall

The charge on an amino acid affects its response to an electric field at a given pH

This property can be used to separate and identify amino acids in a mixture (electrophoresis)

It can also be used preparatively in ion-exchange chromatography: Ion exchange resins
have charged side chains that either repel or attract amino acids depending on the buffer pH

TLC or paper chromatography can be used to separate amino acids by polarity
Electrophoresis:
 An electric
field is applied
to a buffered
solution
containing
paper or gel
 Amino acids are applied to the gel
 They migrate towards either positive or negative electrode depending on pI
If pI is below pH, aa will have (-) charge, migrates to positive
If pI is above pH, aa will have (+) charge, migrates to negative
 If pI values are close, the larger the molecule the slower it moves
 This principle can be applied to separation of peptides and proteins too, since
overall charge depends on charges of aa constituents as well as size
 Amino acids are detected by staining with ninhydrin, an imine-formation
reaction
Peptide bonds
Peptides and proteins are composed of amino acids joined together by "peptide
bonds": The reaction is essentially formation of an amide from a carboxylic acid
and a 1o amine
Ex:
A tripeptide of valine, cysteine and serine: Val-Cys-Ser (valylcysteylserine)
CH 3
H 3N
HS
C
H
O
H 3N
H 2 C OH
CH 2
C
H
O
H 3N
C
H
O
O
O
O
H3 C
O
H
H 2C
H
N
C
H 3N
H
C
H
O
N
H
C
O
OH
CH 2
O
HS
Val
Cys
Ser
 Direction & sequence matters: Val-Cys-Ser
is different from Ser-Cys-Val
 Peptide bonds have partial double bond
character
 No free rotation about the C - N bond
 The peptide group is planar
 α- carbons of adjacent aa are
trans to each other
Disulfide bonds are another type of covalent bonds found in peptides & proteins
A mild oxidizing agent can link 2 thiols such as cysteine side chains by forming
disulfide bridges which hold the cysteines together: