Chapter 5: Amines and Heterocycles PDF

Chapter 5. Amines and Heterocycles Based on McMurry’s Organic Chemistry, 7th edition Amines – Organic Nitrogen Compounds Organic derivatives of ammonia, NH , 3 Nitrogen atom with a lone pair of electrons, making amines both basic and nucleophilic Oc...

Chapter 5. Amines and Heterocycles Based on McMurry’s Organic Chemistry, 7th edition Amines – Organic Nitrogen Compounds 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 2 Why this Chapter? 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 3 24.1 Naming Amines Alkyl-substituted (alkylamines) or aryl-substituted (arylamines) Classified: 1° (RNH ), methyl (CH NH ), 2° (R NH), 3° 2 3 2 2 (R3N) 4 Quaternary Ammonium Ions A nitrogen atom with four attached groups is positively charged Compounds are quaternary ammonium salts 5 IUPAC Names – Simple Amines For simple amines, the suffix -amine is added to the name of the alkyl substituent 6 IUPAC Names – “-amine” Suffix The suffix -amine can be used in place of the final -e in the name of the parent compound 7 IUPAC Names – Amines With More Than One Functional Group Consider the NH2 as an amino substituent on the parent molecule 8 IUPAC Names – Multiple Alkyl Groups Symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group 9 IUPAC Names – Multiple, Different Alkyl Groups Named as N-substituted primary amines Largest alkyl group is the parent name, and other alkyl groups are considered N-substituents 10 Common Names of Heterocyclic Amines 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 11 24.2 Properties of Amines Bonding to N is similar to that in ammonia N is sp3-hybridized C–N–C bond angles are close to 109° tetrahedral value 12 Chirality Is Possible (But Not Observed) 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 are not resolved because the molecules interconvert by pyramidal inversion 13 Amines Form H-Bonds Amines with fewer than five carbons are water- soluble Primary and secondary amines form hydrogen bonds, increasing their boiling points 14 24.3 Basicity of Amines 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 15 Relative Basicity 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 (RNH2) is to look at the acidity of the corresponding ammonium ion (RNH3+) High pKa → weaker acid and stronger conjugate base. 16 17 General Patterns of Basicity Table 24.1: pKa values of ammonium ions Most simple alkylammmonium ions have pKa's of 10 to 11 Arylamines and heterocyclic aromatic amines are considerably less basic than alkylamines (conjugate acid pKa 5 or less) 18 Amides Amides (RCONH ) in general are not proton acceptors except in 2 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 19 24.4 Basicity of Substituted Arylamines 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 20 Substituted Arylamines Can be more basic or less basic than aniline Electron-donating substituents (such as CH , NH , 3 2 OCH3) increase the basicity of the corresponding arylamine Electron-withdrawing substituents (such as Cl, NO , 2 CN) decrease arylamine basicity 21 22 24.5 Biological Amines and the Henderson-Hasselbalch Equation What form do amines exist at physiological pH inside cells 23 24.6 Synthesis of Amines 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 SN2 Reactions of Alkyl Halides Ammonia and other amines are good nucleophiles 25 Uncontrolled Multiple Alkylation Primary, secondary, and tertiary amines all have similar reactivity, the initially formed monoalkylated substance undergoes further reaction to yield a mixture of products 26 + Br + NH3 NH2 + H NH2 N Br + + H Br + N N + Br + N N+ 27 Selective Preparation of Primary Amines: the Azide Synthesis Azide ion, N  displaces a halide ion from a primary or 3 secondary alkyl halide to give an alkyl azide, RN3 Alkyl azides are not nucleophilic (but they are explosive) Reduction gives the primary amine 28 Gabriel Synthesis of Primary Amines 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 29 Reductive Amination of Aldehydes and Ketones Treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent 30 Reductive Amination Is Versatile Ammonia, primary amines, and secondary amines yield primary, secondary, and tertiary amines, respectively 31 Mechanism of Reductive Amination 32 Reducing Step Sodium cyanoborohydride, NaBH CN, reduces C=N 3 but not C=O Stable in water 33 Hofmann and Curtius Rearrangements Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement 34 Hofmann Rearrangement RCONH reacts with Br and base 2 2 Gives high yields of arylamines and alkylamines Figure 24.5 See Mechanism 35 Curtius 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 36 24.7 Reactions of Amines Alkylation and acylation have already been presented 37 Hofmann Elimination Converts amines into alkenes NH2 is very a poor leaving group so it converted to an alkylammonium ion, which is a good leaving group 38 Silver Oxide Is Used for the Elimination Step Exchanges hydroxide ion for iodide ion in the quaternary ammonium salt, thus providing the base necessary to cause elimination 39 Orientation in Hofmann Elimination 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 40 Steric Effects Control the Orientation 41 24.8 Reactions of Arylamines Amino substituents are strongly activating, ortho- and para-directing groups in electrophilic aromatic substitution reactions Reactions are controlled by conversion to amide 42 Arylamines Are Not Useful for Friedel-Crafts Reactions The amino group forms a Lewis acid–base complex with the AlCl3 catalyst, preventing further reaction Therefore we use the corresponding amide O O Cl O O acetic anhydride benzoyl chloride 43 Diazonium Salts: The Sandmeyer Reaction Primary arylamines react with HNO2, yielding stable arenediazonium salts 44 Uses of Arenediazonium Salts The N2 group can be replaced by a nucleophile 45 Preparation of Aryl Halides 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 46 Aryl Nitriles and Carboxylic Acids An arenediazonium salt and CuCN yield the nitrile, ArCN, which can be hydrolyzed to ArCOOH 47 Formation of Phenols (ArOH) From reaction of the arenediazonium salt with copper(I) oxide in an aqueous solution of copper(II) nitrate 48 Reduction to a Hydrocarbon By treatment of a diazonium salt with hypophosphorous acid, H3PO2 49 Mechanism of Diazonium Replacement Through radical (rather than polar or ionic) pathways 50 Diazonium Coupling Reactions 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 51 How Diazonium Coupling Occurs 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 52 Azo Dyes Azo-coupled products have extended  conjugation that lead to low energy electronic transitions that occur in visible light (dyes) 53 24.9 Heterocycles 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 54 Pyrole and Imidazole Pyrole is an amine and a conjugated diene, however its chemical properties are not consistent with either of structural features 55  Chemistry of Pyrole Electrophilic substitution reactions occur at C2 b/c it is position next to the N A more stable intermediate cation having 3 resonance forms At C3, only 2 resonance forms 56 Polycyclic Heterocycles 57 24.10 Spectroscopy of Amines - Infrared 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1 58 Examples of Infrared Spectra 59 Nuclear Magnetic Resonance Spectroscopy N–H hydrogens appear as broad signals without clear-cut coupling to neighboring C–H hydrogens In D2O exchange of N–D for N–H occurs, and the N– H signal disappears 60 Chemical Shift Effects Hydrogens on C next to N and absorb at lower field than alkane hydrogens N-CH gives a sharp three-H singlet at  2.2 to  2.6 3 61 13 C NMR Carbons next to amine N are slightly deshielded - about 20 ppm downfield from where they would absorb in an alkane 62 Mass Spectrometry 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 63  Mass Spectrum of N- Ethylpropylamine The two modes of a cleavage give fragment ions at m/z = 58 and m/z = 72. 64