John E. McMurry Paul D. Adams University of Arkansas Chapter 24 Amines and Heterocycles

 Organic derivatives of ammonia, NH 3  Nitrogen atom with a lone pair of electrons, making amines both basic and nucleophilic  Occur in plants and animals Amines – Organic Nitrogen Compounds

 Amines and carbonyl compounds are the most abundant and have rich chemistry  In addition to proteins and nucleic acids, a majority of pharmaceutical agents contain amine functional groups Why this Chapter?

 Alkyl-substituted (alkylamines) or aryl-substituted (arylamines)  Classified: 1° (RNH 2 ), methyl (CH 3 NH 2 ), 2° (R 2 NH), 3° (R 3 N) 24.1 Naming Amines

 A nitrogen atom with four attached groups is positively charged  Compounds are quaternary ammonium salts Quaternary Ammonium Ions

 For simple amines, the suffix -amine is added to the name of the alkyl substituent IUPAC Names – Simple Amines

 The suffix -amine can be used in place of the final -e in the name of the parent compound IUPAC Names – “-amine” Suffix

 Consider the –NH 2 as an amino substituent on the parent molecule IUPAC Names – Amines with More Than One Functional Group

 Symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group IUPAC Names – Multiple Alkyl Groups

 Named as N-substituted primary amines  Largest alkyl group is the parent name, and other alkyl groups are considered N-substituents IUPAC Names – Multiple, Different Alkyl Groups

 If the nitrogen atom occurs as part of a ring, the compound is designated as being heterocyclic  Each ring system has its own parent name Common Names of Heterocyclic Amines

 Bonding to N is similar to that in ammonia  N is sp 3 -hybridized  C–N–C bond angles are close to 109° tetrahedral value 24.2 Properties of Amines

 An amine with three different substituents on nitrogen is chiral (in principle but not in practice) : the lone pair of electrons is the fourth substituent  Most amines that have 3 different substituents on N cannot be resolved because the molecules interconvert by pyramidal inversion Chirality Is Possible (But Not Observed)

 Amines with fewer than five carbons are water-soluble  Primary and secondary amines form hydrogen bonds, increasing their boiling points Amines Form H-Bonds

 The lone pair of electrons on nitrogen makes amines basic and nucleophilic  They react with acids to form acid–base salts and they react with electrophiles 24.3 Basicity of Amines

 Amines are stronger bases than alcohols, ethers, or water  Amines establish an equilibrium with water in which the amine becomes protonated and hydroxide is produced  The most convenient way to measure the basicity of an amine (RNH 2 ) is to look at the acidity of the corresponding ammonium ion (RNH 3 + )  High pKa → weaker acid and stronger conjugate base. Relative Basicity

 Table 24.1: pK a values of ammonium ions  Most simple alkylammmonium ions have pK a 's of 10 to 11  Arylamines and heterocyclic aromatic amines are considerably less basic than alkylamines (conjugate acid pK a 5 or less) General Patterns of Basicity

 Amides (RCONH 2 ) in general are not proton acceptors except in very strong acid  The C=O group is strongly electron-withdrawing, making the N a very weak base  Addition of a proton occurs on O but this destroys the double bond character of C=O as a requirement of stabilization by N= Amides

 The N lone-pair electrons in arylamines are delocalized by interaction with the aromatic ring  electron system and are less able to accept H + than are alkylamines 24.4 Basicity of Arylamines

 Can be more basic or less basic than aniline  Electron-donating substituents (such as –CH 3, –NH 2, –OCH 3 ) increase the basicity of the corresponding arylamine  Electron-withdrawing substituents (such as –Cl, –NO 2, –CN) decrease arylamine basicity Substituted Arylamines

Substituted Arylamines (Cont’d)

Henderson-Hasselbalch Equation:  In what form do amines exist at physiological pH inside cells? 24.5 Biological Amines and the Henderson-Hasselbalch Equation

 Arylamines are prepared from nitration of an aromatic compound and reduction of the nitro group  Reduction by catalytic hydrogenation over platinum is suitable if no other groups can be reduced  Iron, zinc, tin, and tin(II) chloride are effective in acidic solution 24.6 Synthesis of Amines

 Ammonia and other amines are good nucleophiles S N 2 Reactions of Alkyl Halides

 Primary, secondary, and tertiary amines all have similar reactivity, the initially formed monoalkylated substance undergoes further reaction to yield a mixture of products Uncontrolled Multiple Alkylation

 Azide ion, N 3  displaces a halide ion from a primary or secondary alkyl halide to give an alkyl azide, RN 3  Alkyl azides are not nucleophilic (but they are explosive)  Reduction gives the primary amine Selective Preparation of Primary Amines: The Azide Synthesis

 A phthalimide alkylation for preparing a primary amine from an alkyl halide  The N-H in imides (–CONHCO–) can be removed by KOH followed by alkylation and hydrolysis Gabriel Synthesis of Primary Amines

 Treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent Reductive Amination of Aldehydes and Ketones

 Ammonia, primary amines, and secondary amines yield primary, secondary, and tertiary amines, respectively Reductive Amination Is Versatile

Mechanism of Reductive Amination

 Sodium cyanoborohydride, NaBH 3 CN, reduces C=N but not C=O  Stable in water Reducing Step

 Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement Hofmann and Curtius Rearrangements

 RCONH 2 reacts with Br 2 and base  Gives high yields of arylamines and alkylamines Hofmann Rearrangement

 Heating an acyl azide prepared from an acid chloride  Migration of –R from C=O to the neighboring nitrogen with simultaneous loss of a leaving group Curtius Rearrangement

 Alkylation and acylation have already been presented 24.7 Reactions of Amines

 Converts amines into alkenes  NH 2  is very a poor leaving group so it is converted to an alkylammonium ion, which is a good leaving group Hofmann Elimination

 Exchanges hydroxide ion for iodide ion in the quaternary ammonium salt, thus providing the base necessary to cause elimination Silver Oxide Is Used for the Elimination Step

 We would expect that the more highly substituted alkene product predominates in the E2 reaction of an alkyl halide (Zaitsev's rule)  However, the less highly substituted alkene predominates in the Hofmann elimination due to the large size of the trialkylamine leaving group  The base must abstract a hydrogen from the most sterically accessible, least hindered position Orientation in Hofmann Elimination

Steric Effects Control the Orientation

 Amino substituents are strongly activating, ortho- and para-directing groups in electrophilic aromatic substitution reactions  Reactions are controlled by conversion to amide 24.8 Reactions of Arylamines

 The amino group forms a Lewis acid–base complex with the AlCl 3 catalyst, preventing further reaction  Therefore we use the corresponding amide Arylamines Are Not Useful for Friedel-Crafts Reactions

 Primary arylamines react with HNO 2, yielding stable arenediazonium salts Diazonium Salts: The Sandmeyer Reaction

 The N 2 group can be replaced by a nucleophile Uses of Arenediazonium Salts

 Reaction of an arenediazonium salt with CuCl or CuBr gives aryl halides (Sandmeyer Reaction)  Aryl iodides form from reaction with NaI without a copper(I) salt Preparation of Aryl Halides

 An arenediazonium salt and CuCN yield the nitrile, ArCN, which can be hydrolyzed to ArCOOH Aryl Nitriles and Carboxylic Acids

 From reaction of the arenediazonium salt with copper(I) oxide in an aqueous solution of copper(II) nitrate Formation of Phenols (ArOH)

 By treatment of a diazonium salt with hypophosphorous acid, H 3 PO 2 Reduction to a Hydrocarbon

 Through radical (rather than polar or ionic) pathways Mechanism of Diazonium Replacement

 Arenediazonium salts undergo a coupling reaction with activated aromatic rings, such as phenols and arylamines, to yield brightly colored azo compounds, Ar–N=N–Ar Diazonium Coupling Reactions

 The electrophilic diazonium ion reacts with the electron- rich ring of a phenol or arylamine  Usually occurs at the para position but goes ortho if para is blocked How Diazonium Coupling Occurs

 Azo-coupled products have extended  conjugation that lead to low energy electronic transitions that occur in visible light (dyes) Azo Dyes

 A heterocycle is a cyclic compound that contains atoms of two or more elements in its ring, usually C along with N, O, or S 24.9 Heterocyclic Amines

 Pyrole is an amine and a conjugated diene, however its chemical properties are not consistent with either of these structural features Pyrole and Imidazole

 Electrophilic substitution reactions occur at C2 because it is position next to the N  A more stable intermediate cation having 3 resonance forms  At C3, only 2 resonance forms Chemistry of Pyrole

Polycyclic Heterocycles

Infrared Spectroscopy:  Characteristic N–H stretching absorptions 3300 to 3500 cm  1  Amine absorption bands are sharper and less intense than hydroxyl bands  Protonated amines show an ammonium band in the range 2200 to 3000 cm  Spectroscopy of Amines - Infrared

Examples of Infrared Spectra

 N–H hydrogens appear as broad signals without clear-cut coupling to neighboring C–H hydrogens  In D 2 O exchange of N–D for N–H occurs, and the N–H signal disappears Nuclear Magnetic Resonance Spectroscopy

 Hydrogens on C next to N absorb at lower field than alkane hydrogens  N-CH 3 gives a sharp three-H singlet at  2.2 to  2.6 Chemical Shift Effects

13 C NMR  Carbons next to amine N are slightly deshielded - about 20 ppm downfield from where they would absorb in an alkane

 A compound with an odd number of nitrogen atoms has an odd-numbered molecular weight and a corresponding parent ion  Alkylamines cleave at the C–C bond nearest the nitrogen to yield an alkyl radical and a nitrogen- containing cation Mass Spectrometry

 The two main modes of a cleavage give fragment ions at m/z = 58 and m/z = 72. Mass Spectrum of Ethylpropylamine

Let’s Work a Problem What are the major products that you might expect from Hofmann elimination of the following amine?

Answer The hydrogens that can be eliminated are covalently attached to the carbon bound to the Nitrogen. In this case, there are 2 such places where a hydrogen could be eliminated to give the cyclopentene