Bonding characteristics of nitrogen atoms in organic compounds
• We saw already that carbon atoms (Group 4A) form four bonds to other atoms in organic compounds.
• And oxygen atoms (Group 6A) form two bonds.
• Nitrogen atoms (Group 5A) require three bonds to give them octets. Normally, nitrogen atoms are involved in three covalent bonds to other atoms.
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The important arrangement for this chapter
Structure and classification of amines
• Amines are organic derivatives of ammonia (NH3), in which one or more alkyl, cycloalkyl, or aromatic groups replace hydrogen and bond to the nitrogen atom.
Ammonia (NH3) is a weak base. Amines are also weak bases.
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Structure and classification of amines
• Amines are classified as primary, secondary, and tertiary, as we have seen previously for alcohols.
• For alcohols, the type of carbon atom (1o, 2o, 3o) bound to the –OH group determined whether the alcohol was primary, secondary, or tertiary.
• For amines, it is the number of carbon groups that are bound to the nitrogen atom.
1o amine 2o amine 3o amine
Structure and classification of amines • This is an important difference in the way that 1o, 2o, and 3o
classification is given.
tert-butanola 3o alcohol
tert-butylaminea 1o amine
Nomenclature for amines
• Common and IUPAC systems are used extensively for naming amines.
• In the common system, rules similar to what we have seen for ethers are employed, naming the alkyl/aromatic groups attached to the functional group, and then following these with “amine”
Methylamine Trimethylamine Methylpropylamine
Methylphenylamine CyclohexyldimethylamineFor simple amines, this
is a good naming system
Nomenclature for amines
• The IUPAC system for naming amines is as follows:
– Select the longest carbon chain bound to the nitrogen as the parent chain
– Name the chain by changing the alkane name for this chain: drop the “e” and add “amine”
– Number the chain to give the nitrogen the lowest numbering
– The number and identity of other substituents (including any on the main chain) are indicated at the beginning of the amine name (some are attached to N)
For complicated amine structures, this is probably the better way of naming amines.
Structure and classification of amines
• Some examples. First, 1o amines
2-Butanamine
1-Butanamine
# to indicate placement of NH2 group 4-C chain (“butane”; - “e” + “amine”)
Structure and classification of amines
• For di- and trisubstituted amines, the non-parent chains are indicated as N-bonded:
N,N-Dimethyl-1-propanamine
N-Ethyl-N-methyl-2-butanamine
longest carbon chain = 4 carbons
longest carbon chain = 3 carbons
Structure and classification of amines
• For diamines, the molecule is named as an “alkane-diamine” with NH2 groups numbered.
• …and for cases where NH2-substituted alcohols or other compound cases are involved, the NH2-group is called an “amino” substituent.
1,4-Butanediamine
3-Aminobutanoic acid don’t need to name polyfunctional carboxylic acids
an example of an amino acid
Structure and classification of amines
• In cases where substituted parent chains are encountered, the substituents are named at the beginning of the compound’s name:
4,N-dimethyl-2-pentanamine
One CH3 substituent is on the amine’s N and one CH3
substituent is on C#4 of the 2-pentanamine chain.
Doesn’t matter if you write N or 4 first here
Structure and classification of amines
• Aromatic amines involve an amine-type nitrogen bound to an aromatic ring. The simplest case for these is aniline.
Aniline 3-Bromo-2-chloroaniline
phenol benzaldehyde benzoic acid
Remember: other aromatic compounds seen so far
Structure and classification of amines
• For substituted anilines, the substituent names are treated in a manner similar to what was shown for substituted parent chain cases:
Aniline 3,N-DimethylanilineN-Ethyl-N-methylaniline
Same idea as before. Now the benzene is treated as the “parent” part of the name.
Isomerism for amines
• Skeletal and positional isomers for amines are possible.
• In skeletal isomers, the carbon chain components of the amines differ
3-Hexanamine 2-Methyl-3-pentanamine
C6H15N
Physical properties of amines
• Amines tend to be gases for low molecular weight cases (e.g. up to (CH3)3N, trimethylamine) and many heavier ones are liquids at room temperature.
• One very noticeable thing about amines is that they tend to exhibit strong odors. For example, some have a “fishy” smell
Cadaverine(1,5-Pentanediamine)
Putrescine(1,4-Buntanediamine)
Physical properties of amines
• Amine boiling points are intermediate of those for alcohols and alkanes of similar molar mass.
• Because of the presence of N-H bond(s) in primary and secondary amines, hydrogen-bonding is sometimes possible; however, because N is not as electronegative as O, the N-H bond is not as polar as an O-H bond (weaker H-bonding).
H-bonding between tertiary amines not possible
Physical properties of amines
• Amines tend to be water-soluble because of H-bonding interactions with water molecules. In fact, amines having fewer than six carbon atoms are infinitely water-soluble.
• Water-solubility decreases as: – Chain length increases, and,
– The degree of N-substitution increases
Basicity of amines • Ammonia is one of the few examples of a weak base we
looked at in the first semester. It reacts with water molecules to produce OH- ions, making the resulting solution basic:
NH3 + H2O D NH4+ + OH-
• The resulting ion (NH4+) is called an ammonium ion.
• Amines react with water to produce ammonium-like species.
CH3NH2 + H2O D CH3NH3+ + OH-
-. . ... .. . ... .
ammonium ion
Basicity of amines
• Naming substituted ammonium ions:
– Named similar to amine, but with the term “ammonium ion” instead of amine
-
+
Methylamine
Methylammonium ion
Others:
Trimethylammonium ion Anilinium ion
Tetraethylammonium ion
Basicity of amines
• Amines are better bases than oxygen-containing compounds.
• A comparison:
-
Ethanoate ion:0.1 M sol'n in water has pH ~ 8.9
Ethylamine:0.1 M sol'n in water has pH ~ 11.9
A carboxylate ion
(from ethanoic acid)
Organic bases • amines • conj. bases of carboxylic acids
Amine salts
• Amines, because they are basic, can react with acids in neutralization reactions. The reaction produces an amine salt, as follows:
R-NH2 + H-Cl D R-NH3+Cl-
amine amine salt
Naming: named as an ammonium chloride
Example: (CH3)3N+Cl- is Trimethylammonium chloride
Amine salts are ionic compounds in which the positive ion comes from the substituted ammonium and the negative ion comes from an acid used to react with the parent amine.
Amine salts
• Amine salts are water-soluble; many amines (having higher molar masses) are not. Thus, in order to introduce an amine-based drug into he body, it is often converted into the salt form.
• Many pharmaceuticals possess nitrogen centers that are protonated to the ammonium form, to make them water-soluble, or to stabilize them (they are often called “hydrochlorides”).
Paxil
·HCl Paxil hydrochloride
(water-soluble, shelf-stable)
Amine salts • The neutral form of an amine drug is often called its “free-
base” form.
• In this neutral form, the drug may be vaporized (because the intermolecular forces that keep it in a condensed state at room temperature can be overcome by heating).
• The ionic form has a very high boiling point and usually cannot be vaporized without decomposing the structure.
+Cl-
cocaine cocaine hydrochloride
free-base form ionic (salt) form
not water-soluble
water-soluble
Heterocyclic amines • Heterocylic compounds involve ring structures that possess
non-carbon atoms. We saw some examples in earlier chapters (cyclic ethers, cyclic esters, etc.)
• Nitrogen heterocycles are frequently encountered in biochemistry. Some examples are:
NicoteneCaffeine
Heterocyclic amines
• The following nitrogen heterocycles are found frequently in biologically relevant structures. For example, the purine structure is present in caffeine (drug), adenine and guanine (DNA).
Heterocyclic amines
• The nitrogen heterocycle shown below is used for oxygen transport in the body. The heme structure (right) is present in the bloodstream as a component of a much bigger molecule (hemoglobin) and acquires/releases O2.
porphyrin ring Heme, a component of hemoglobin
Selected biologically important amines
• Neurotransmitters: substances that are released at the end of a nerve which travel across the synaptic gap to another nerve and trigger a nerve impulse by binding to a chemical receptor site.
Alkaloids
• There are some very important nitrogen-containing plant extracts (alkaloids) that are used in medicinal science (all of which are amines):
Morphine Codeine
Heroin
Hydrocodone Oxycodone
Structure and classification of amides
• Amides possess a functional group that consists of a C=O (carbonyl) directly bound to a nitrogen:
• The amide functional group involves a nitrogen atom (and lone pair), but unlike an amine, the nitrogen center is not basic, due to the electron-withdrawing effect of the C=O group.
For amides, R, R’,, and R” can be • carbon-based, or • hydrogen
Structure and classification of amides • Amides may be primary, secondary, or teritary:
1o amide 3o amide2o amide
1o amine 2o amine 3o amine
Remember, for amines:
Structure and classification of amides
• In terms of their structure, amines may be aromatic (benzene substituents); for example, benzamide:
• They may also be cyclic, or even involve multiple amide groups in a single ring:
Structure and classification of amides
• In Ch-16, we looked at lactones, which were cyclic esters:
• Lactams are cyclic amides (and heterocycles)
-lactone -lactam -lactam-lactam
Lactams
Nomenclature of amides
• IUPAC system for naming amides:
– Like esters, amides are made using carboxylic acids. The portion that comes from the carboxylic acid is named as a carboxylic acid first, before dropping the “-oic acid” from the name and adding “-amide”
– Substituents attached to the nitrogen are prefixed with “N” to indicate their position; other substituents on the parent chain are named as part of the parent chain (unlike for amines)
Ethanoic acid(carboxylic acid)
N-methylethanamide(amide)
Methyl ethanoate(ester)
Ethanamide(amide)
Nomenclature of amides
• Some examples:
• For aromatic cases:
Butanamide N-Methylbutnamide
N,N-Diethyl-3-methylbutanamide
Benzamide N,N-Dimethylbenzamide
N,N,3,5-Tetramethylbenzamide
Ethyl and methyl substituents on a butanamide molecule
Selected amides and their uses
• Urea is one of the simplest amides, formed by reaction between CO2 and ammonia in a series of metabolic reactions.
• Acetominophen is an aromatic amide
• Barbiturates derive from barbituric acid (sedatives/tranquilizers) are cyclic amides, made from urea and malonic acid:
Urea
Barbituric acid
UreaPentanedioic acid
Malonic acid
2H2O
Preparation of amides
• Amides are prepared in a manner similar to what we’ve already seen for esters. A condensation reaction involving a carboxylic acid is needed, this time with an amine:
H2O100 oC
catalyst
amidification (like esterification)
amide functional group
Preparation of amides
• For amide formation to happen, the temperature must be high (at room temperature, an acid-base neutralization reaction happens instead).
• Also, the amine used in the reaction must be either a primary or secondary amine (can’t be a tertiary amine).
100 oC
catalyst
Room Temp. -
acid base carboxylate salt
Preparation of amides
Ammonia + carboxylic acid 1o amide
1o amine + carboxylic acid 2o amide
2o amine + carboxylic acid 3o amide
H2O100oC
catalyst..
100oCH2O
catalyst..
100oCH2O
catalyst..
Preparation of amides • Reactions that make esters from carboxylic acids and alcohols
are called esterification reactions.
• Reactions that make amides from carboxylic acids and amines (or ammonia) are called amidification reactions. Thus amidification reactions are condensation reactions.
• In the condensation, the carboxylic acid loses the OH and the amine loses a H atom:
carboxylic acid amine amide
H2O100 oC
catalyst
H+(cat)
H2O
alcoholcarboxylic acid ester
amidification
esterification
Hydrolysis of amides
• Like esters, amides can undergo hydrolysis. This reaction results in the amide being broken up into amine and carboxylic acid starting materials:
carboxylic acid amine amide
Amidification
Amide hydrolysis
carboxylic acid amine amide
hydrolysis and saponification of amides
This bond was created by amidification. The same one breaks during hydrolysis.
Hydrolysis of amides
• The products of the hydrolysis reaction will depend on the acidity/basicity of the reaction conditions.
heat
Amide hydrolysis
carboxylic acid(derivative?)
amine(derivative?)
amide acidic/basic conditions used
Remember what an acid does: donates protons (H+ ions); bases accept protons. Acids react with bases, not with other acids.
Hydrolysis of amides
• Under basic conditions, the carboxylic acid is produced as an carboxylic acid salt:
H2Obasic pH (NaOH)
heat
Amide hydrolysis
carboxylic acid amineamide
Remember,: carboxylic acids are acids amines are bases
Amide hydrolysis carried out under basic conditions is called amide saponification.
H2O
NaOH
-Na+
carboxylic acid salt
Hydrolysis of amides
• Overall, the reaction would look like this:
• Example:
H2O
NaOH
Na+-heat
carboxylic acid salt amineamide
NaOH
H2ONa+-heat
carboxylic acid salt amineamide
Hydrolysis of amides • Under acidic conditions, the amine is produced as an
ammonium salt:
H2Oacidic pH (HCl)
heat
Amide hydrolysis
carboxylic acid amineamide
Remember,: carboxylic acids are acids amines are bases
HCl
Cl-
ammonium salt
Hydrolysis of amides
• Overall, under acidic conditions, the reaction would look like this:
• Example:
H2O Cl-HCl
heat
carboxylic acid
ammonium salt
amide
H2O Cl-HCl
heat
carboxylic acid
ammonium salt
amide
Physical properties of amides
• The simplest amides (methanamide, N-methyl, and N,N-dimethyl derivatives) are liquids at room temperature, and all unbranched amides having 2 or more carbons on their C-chain side are solids.
• The secondary and teritary amides have lower melting points, with tertiary amides having lower melting points than secondary amides (less opportunity for H-bonding).
Methanamide
N-Methylmethanamide N,N-Dimethylmethanamide
Primary amides have higher boiling points than carboxylic acids that have the same number of carbons. In order of increasing amide boiling points (for a given molar mass): 3o < 2o < 1o.
Boiling points
Polyamides • Like we saw for esters, amide condensation reactions can be
used to make polymers (another polycondensation reaction).
• As for polyesters, di-functional reactants are needed for polymerization (i.e. a diamine and a dicarboxylic acid):
......
n
a dicarboxylic acid a diamine
a polyamide
heat
Polyamides
• Nylon-6,6 is a polyamide. It can be synthesized from Hexanedioic acid and 1,6-Hexanediamine:
Nylon-6,6a polyamide
n