Amines and Amides Chapter 17 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. 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. 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-butylamine a 1o amine tert-butanol a 3o alcohol • The –NH2 group of a primary amine can be thought of as an “amino” group. Thus secondary and tertiary amines possess substituted amino groups. amino group 1o Monosubstituted amino group Disubstituted amino group 2o 3o Structure and classification of amines 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 Methylphenylamine Methylpropylamine Cyclohexyldimethylamine 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) Structure and classification of amines • Some examples. First, 1o amines 1-Butanamine 2-Butanamine 4-C chain (“butane”; - “e” + “amine”) # to indicate placement of NH2 group Structure and classification of amines • For di- and trisubstituted amines, the nonparent chains are indicated as N-bonded: N,N-Dimethyl-1-propanamine N-Ethyl-N-methyl-2-butanamine Structure and classification of amines • For diamines, the molecule is named as an “alkane-diamine” with NH2 groups numbered. 1,4-Butanediamine • And for cases where NH2-substituted alcohols or other compound cases are involved, the NH2-group is called an “amino” substituent. 3-Aminobutanoic acid 4-Amino-4-chloro-2-pentanone 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 Parent chain: pentane Amino-position: C-2 of parent chain CH3- substituents on parent chain (C-4) and N 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 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 N-Ethyl-N-methylaniline 3,N-Dimethylaniline 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 Isomerism for amines • Positional isomers differ in the placement of the –NH2 group along the parent chain. 3-Hexanamine 2-Hexanamine • Positional isomers are possible for substituted amines as well: N-Ethyl-1-propanamine N-Methyl-1-butanamine 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 Putrescine (1,4-Buntanediamine) Cadaverine (1,5-Pentanediamine) 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). 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: ammonium ion 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- .. .. . ... .. - Basicity of amines • A substituted ammonium ion results from the reaction between an amine and water. .. ... .. .. . - substituted ammonium ion Nitrogen tends to bond to three other atoms to get an octet; when it forms four bonds (in an ammonium salt), the nitrogen structure carries a positive charge Basicity of amines • Naming substituted ammonium ions: – Named similar to amine, but with the term “ammonium ion” instead of amine Methylammonium ion + Methylamine - Others: Trimethylammonium ion Anilinium ion Tetraethylammonium ion Basicity of amines • Amines are better bases than oxygencontaining compounds. • A comparison: A carboxylate ion Ethylamine: 0.1 M sol'n in water has pH ~ 11.9 Ethanoate ion: 0.1 M sol'n in water has pH ~ 8.9 (from ethanoic acid) • Ethers and alcohols have no significant basicity in water Amine salts • Amines, because they are basic, can react with acids in neutralization reactions. The reaction produces an amine salt, as follows: amine amine salt R-NH2 + H-Cl D R-NH3+ClNaming: 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 Amine salts • The neutral form of an amine drug is often called its “freebase” 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 Preparation of amines and quaternary ammonium salts • Preparation of amines from ammonia is possible under basic conditions: base NH3 + alkyl halide 1o amine base 1o amine + alkyl halide 2o amine base 2o amine + alkyl halide 3o amine base 3o amine + alkyl halide quaternary ammonium salt Preparation of amines and quaternary ammonium salts • When ammonia or an amine is treated with an alkyl halide in the presence of a strong base, the following reaction occurs: alkyl halide ammonia .. X- X- NaOH .. substituted amine NaCl H2O Preparation of amines and quaternary ammonium salts • When this reaction is being carried out, it is necessary to remove the amine as it is formed before a following alkylation step occurs: NaOH 1o amine NaCl NaOH NaOH H2O 2o amine NaCl H2O NaCl H2O 3o amine + Cl- 4o amine 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: Caffeine Nicotene 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. Selected biologically important amines Dopamine Norepinepherine + Acetylcholine Seratonin Selected biologically important amines • Epinepherine (adrenaline): a central nervous system stimulant. Its release causes blood glucose levels to rise, blood pressure to increase, increased heart rate and muscle strength. Epinepherine Selected biologically important amines • Histamine: responsible for the symptoms experienced during hay fever. The body stores histamines, which are released in the presence of pollen/dust/allergens. The response is produced when histamines bind to receptor sites in complex molecules. • Antihistamines (present in a medication) bind to these same receptor sites, and block the histamine response. Histamine Alkaloids • There are some very important nitrogencontaining 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. Structure and classification of amides • Amides may be primary, secondary, or teritary: 1o amine 2o amine 3o amine 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: A d-lactam Structure and classification of amides • In Ch-16, we looked at lactones, which were cyclic esters: -lactone -lactam -lactam d-lactam Lactams • Lactams are cyclic amides (and heterocycles) 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) Methyl ethanoate (ester) Ethanamide (amide) Nomenclature of amides • Some examples: Propanamide N-Methylbutnamide N,N-Diethyl-3-methylbutanamide • For aromatic cases: Benzamide N,N-Dimethylbenzamide N,N,3,5-Tetramethylbenzamide 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 Urea • Barbiturates derive from barbituric acid (sedatives/tranquilizers) are cyclic amides, made from urea and malonic acid: 2H2O Urea Pentanedioic acid Malonic acid Barbituric acid Physical properties of amides • Amides do not have a basic non-bonding pair of electrons, like amines (as mentioned) • The simplest amides (methanamide, N-methyl, and N,Ndimethyl derivatives) are liquids at room temperature, and all unbranched amides having 2 or more carbons on their C-chain side are solids. Methanamide N-Methylmethanamide N,N-Dimethylmethanamide • The secondary and teritary amides have lower melting points, with tertiary amides having lower melting points than secondary amides (less opportunity for H-bonding). Physical properties of amides 4 locations on a primary amide group that may participate in intermolecular H-bonding 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: 100 oC catalyst H2O Preparation of amides • For amide formation to happen, the temperature must be high (at room temperature, an acid-base neutralization reaction happens instead). Room Temp. acid base carboxylate salt • Also, the amine used in the reaction must be either a primary or secondary amine (can’t be a tertiary amine). 100 oC catalyst Preparation of amides Ammonia + carboxylic acid 1o amide 100oC .. H2O catalyst 1o amine + carboxylic acid 2o amide 100oC .. catalyst H2O 2o amine + carboxylic acid 3o amide 100oC .. catalyst H2O 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: 100 oC catalyst H2O 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: Amidification carboxylic acid amine amide Amide hydrolysis carboxylic acid amine amide Hydrolysis of amides • The products of the hydrolysis reaction will depend on the acidity/basicity of the reaction conditions. Amide hydrolysis heat amide acidic/basic conditions used carboxylic acid (derivative?) amine (derivative?) 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: Amide hydrolysis H2O basic pH heat amide carboxylic acid amine NaOH Remember,: carboxylic acids are acids amines are bases Amide hydrolysis carried out under basic conditions is called amide saponification. - Na+ carboxylic acid salt H2O Hydrolysis of amides • Overall, the reaction would look like this: NaOH - Na+ H2O heat carboxylic acid salt amide amine • Example: NaOH - Na+ H2O heat amide carboxylic acid salt amine Hydrolysis of amides • Under acidic conditions, the amine is produced as an ammonium salt: Amide hydrolysis acidic pH H2O heat amide carboxylic acid amine HCl Remember,: carboxylic acids are acids amines are bases Cl- ammonium salt Hydrolysis of amides • Overall, under acidic conditions, the reaction would look like this: HCl H2O Clheat carboxylic acid amide • Example: ammonium salt HCl H2O Clheat amide carboxylic acid ammonium salt 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): heat a dicarboxylic acid a diamine ... ... a polyamide n Polyamides • Nylon-6,6 is a polyamide. It can be synthesized from Hexanedioic acid and 1,6-Hexanediamine: n Nylon-6,6 a polyamide Polyamides • Kevlar (bullet-proof vests) is also a polyamide:
