Amines. Chapter 2

Biologically Active Amines The alkaloids are an important group of biologically active amines, mostly synthesized by plants to protect them from being eaten by insects and other animals. Many drugs of addiction are classified as alkaloids. Chapter 2 Dr. EEY 2 2 5/6/2020 Biological Activity of Amines Dopamine is a neurotransmitter. Epinephrine is a bioregulator. Niacin, Vitamin B6, is an amine. Alkaloids: nicotine, morphine, cocaine Amino acids Chapter 2 Dr. EEY 3 3 5/6/2020 Classes of Amines Primary (1): Has one alkyl group bonded to the nitrogen (RNH2). Secondary (2): Has two alkyl groups bonded to the nitrogen (R2NH). Tertiary (3): Has three alkyl groups bonded to the nitrogen (R3N). Quaternary (4): Has four alkyl groups bonded to the nitrogen and the nitrogen bears a positive charge(R4N+). Chapter 2 Dr. EEY 4 4 5/6/2020 Examples of Amines Primary (1º) Secondary (2º) Chapter 2 Dr. EEY Tertiary (3º) 5 5 5/6/2020 Common Names Chapter 2 Dr. EEY 6 6 5/6/2020 Amine as Substituent On a molecule with a higher priority functional group, the amine is named as a substituent. Chapter 2 Dr. EEY 7 7 5/6/2020 A saturated cyclic amine- a cyclic amine without any double bondscan be named as a cycloalkane, using the prefix aza to denote the nitrogen atom Chapter 2 Dr. EEY 8 8 5/6/2020 Heterocycles with oxygen and sulfur heteroatoms are named similarly. The prefix for oxygen is oxa and that for sulfur is thia. Chapter 2 Dr. EEY 9 9 5/6/2020 Chapter 2 Dr. EEY 10 10 5/6/2020 IUPAC Names Name is based on longest carbon chain. -e of alkane is replaced with -amine. Substituents on nitrogen have N- prefix. Br N(CH3)2 NH2CH2CH2CHCH2CH3 CH3CH2CHCH2CH2CH3 3-bromo-1-pentanamine N,N-dimethyl-3-hexanamine Chapter 2 Dr. EEY 11 11 5/6/2020 Aromatic Amines In aromatic amines, the amino group is bonded to a benzene ring. Parent compound is called aniline. Chapter 2 Dr. EEY 12 12 5/6/2020 More about amines Chapter 2 Dr. EEY 13 13 5/6/2020 Structure of Amines Nitrogen is sp3 hybridized with a lone pair of electrons. The angle is less than 109.5º. Chapter 2 Dr. EEY 14 14 5/6/2020 Interconversion of Chiral Amines Nitrogen may have three different groups and a lone pair, but enantiomers cannot be isolated due to inversion around N. Chapter 2 Dr. EEY 15 15 5/6/2020 Chiral Amines Amines whose chirality stems from the presence of chiral carbon atoms. Inversion of the nitrogen is not relevant because it will not affect the chiral carbon. Chapter 2 Dr. EEY 16 16 5/6/2020 Chiral Amines (Continued) Quaternary ammonium salts may have a chiral nitrogen atom if the four substituents are different. Inversion of configuration is not possible because there is no lone pair to undergo nitrogen inversion. Chapter 2 Dr. EEY 17 17 5/6/2020 Boiling Points N—H less polar than O—H. Weaker hydrogen bonds, so amines will have a lower boiling point than the corresponding alcohol. Tertiary amines cannot hydrogen-bond, so they have lower boiling points than primary and secondary amines. Chapter 2 Dr. EEY 18 18 5/6/2020 Solubility and Odor Small amines (< 6 Cs) are soluble in water. All amines accept hydrogen bonds from water and alcohol. Branching increases solubility. Most amines smell like rotting fish. NH2CH2CH2CH2CH2CH2NH2 1,5-pentanediamine or cadaverine Chapter 2 Dr. EEY 19 19 5/6/2020 Basicity of Amines Lone pair of electrons on nitrogen can accept a proton from an acid. Aqueous solutions are basic to litmus. Ammonia pKb = 4.74 Alkyl amines are usually stronger bases than ammonia. Increasing the number of alkyl groups decreases solvation of ion, so 2 and 3 amines are similar to 1 amines in basicity. Chapter 2 Dr. EEY 20 20 5/6/2020 AMINES REACT AS BASES AND AS NUCLEOPHILES Chapter 2 Dr. EEY 21 21 5/6/2020 AMINES REACT AS BASES AND AS NUCLEOPHILES Chapter 2 Dr. EEY 22 22 5/6/2020 AMINES REACT AS BASES AND AS NUCLEOPHILES Conjugate addition Chapter 2 Dr. EEY 23 23 5/6/2020 Chapter 2 Dr. EEY 24 24 5/6/2020 Base-Dissociation Constant of Amines An amine can abstract a proton from water, giving an ammonium ion and a hydroxide ion. The equilibrium constant for this reaction is called the base-dissociation constant for the amine, symbolized by Kb. Chapter 2 Dr. EEY 25 25 5/6/2020 Base Dissociation of an Amine Chapter 2 Dr. EEY 26 26 5/6/2020 Alkyl Group Stabilization of Amines Alkyl groups make the nitrogen a stronger base than ammonia. Chapter 2 Dr. EEY 27 27 5/6/2020 Resonance Effects Any delocalization of the electron pair weakens the base. Chapter 2 Dr. EEY 28 28 5/6/2020 Protonation of Pyrrole When the pyrrole nitrogen is protonated, pyrrole loses its aromatic stabilization. Therefore, protonation on nitrogen is unfavorable and pyrrole is a very weak base. Chapter 2 Dr. EEY 29 29 5/6/2020 H N pKb= 13.6 Hybridization Effects Pyridine is less basic than aliphatic amines, but it is more basic than pyrrole because it does not lose its aromaticity on protonation. Chapter 2 Dr. EEY 30 30 5/6/2020 Compare basicity Chapter 2 Dr. EEY 31 31 5/6/2020 Reaction of Amines with Carbonyl Compounds Chapter 2 Dr. EEY 32 32 5/6/2020 Electrophilic Substitution of Aniline —NH2 is strong activator, ortho- and para-directing. Multiple alkylation is a problem. Attempt to nitrate aniline may burn or explode. Chapter 2 Dr. EEY 33 33 5/6/2020 Protonation of Aniline in Substitution Reactions Strongly acidic reagents protonate the amino group, giving an ammonium salt. The —NH3+ group is strongly deactivating (and metaallowing). Therefore, strongly acidic reagents are unsuitable for substitution of anilines. Chapter 2 Dr. EEY 34 34 5/6/2020 Electrophilic Substitution of Pyridine Strongly deactivated by electronegative N. Substitutes in the 3-position. Chapter 2 Dr. EEY 35 35 5/6/2020 Electrophilic Aromatic Substitution of Pyridine Chapter 2 Dr. EEY 36 36 5/6/2020 Electrophilic Aromatic Substitution of Pyridine (Continued) Attack at the 2-position would have an unfavorable resonance structure in which the positive charge is localized on the nitrogen. Substitution at the 2-position is not observed. Chapter 2 Dr. EEY 37 37 5/6/2020 Chapter 2 Dr. EEY 38 38 5/6/2020 Electrophilic Aromatic Substitution of Pyrrole Substitution occurs preferentially at C-2 because the intermediate obtained by attaching a substituent at this position is more stable than the intermediate obtained by attaching a substituent at C-3 Chapter 2 Dr. EEY 39 39 5/6/2020 • oxygen of furan is more electronegative than the nitrogen of pyrrole so is not as effective as nitrogen in stabilizing the carbocation. oxygen •Thiophene is less reactive than furan because sulfur s electrons are in a 3p orbital, which overlaps less effectively than the 2p orbital Chapter 2 Dr. EEY 40 40 5/6/2020 Nucleophilic Substitution of Pyridine Deactivated toward electrophilic attack. Activated toward nucleophilic attack. Nucleophile will replace a good leaving group in the 2- or 4-position. Chapter 2 Dr. EEY 41 41 5/6/2020 Mechanism for Nucleophilic Substitution Attack at the 3-position does not have the negative charge on the nitrogen, so substitution at the 3-position is not observed. Chapter 2 Dr. EEY 42 42 5/6/2020 Alkylation of Amines by Alkyl Halides Disadvantage of direct alkylation ……difficulty of stopping Even if just one equivalent of the halide is added, some amine molecules will react once, some will react twice, and some will react three times (to give the tetraalkylammonium salt). Chapter 2 Dr. EEY 43 43 5/6/2020 Examples of Useful Alkylations Exhaustive alkylation to form the tetraalkylammonium salt. NH2 CH3CH2CHCH2CH2CH3 3 CH3I NaHCO3 _ + N(CH3)3 I CH3CH2CHCH2CH2CH3 Reaction with large excess of NH3 to form the primary amine. CH3CH2CH2Br NH3 (xs) Chapter 2 CH3CH2CH2NH2 + NH4Br Dr. EEY 44 44 5/6/2020 Acylation of Amines amide Primary and secondary amines react with acid halides to form amides. This reaction is a nucleophilic acyl substitution. Chapter 2 Dr. EEY 45 45 5/6/2020 Acylation of Aromatic Amines When the amino group of aniline is acetylated, the resulting amide is still activating and ortho, paradirecting. Acetanilide may be treated with acidic (and mild oxidizing) reagents to further substitute the ring. The acyl group can be removed later by acidic or Dr. EEY basic hydrolysis. Chapter 2 46 46 5/6/2020 Solved Problem 1 Show how you would accomplish the following synthetic conversion in good yield. Solution An attempted Friedel–Crafts acylation on aniline would likely meet with disaster. The free amino group would attack both the acid chloride and the Lewis acid catalyst. Chapter 2 Dr. EEY 47 47 5/6/2020 Solved Problem 1 (Continued) Solution (Continued) We can control the nucleophilicity of aniline’s amino group by converting it to an amide, which is still activating and ortho, para directing for the Friedel–Crafts reaction. Acylation, followed by hydrolysis of the amide, gives the desired product. Chapter 2 Dr. EEY 48 48 5/6/2020 Hofmann Elimination A quaternary ammonium salt has a good leaving group—a neutral amine. Heating the hydroxide salt produces the least substituted alkene. Chapter 2 Dr. EEY 49 49 5/6/2020 Mechanism of the Hofmann Elimination The Hofmann elimination is a one-step, concerted E2 reaction using an amine as the leaving group. Chapter 2 Dr. EEY 50 50 5/6/2020 Regioselectivity of the Hofmann Elimination The least substituted product is the major product of the reaction—Hofmann product. Chapter 2 Dr. EEY 51 51 5/6/2020 Solved Problem 2 Predict the major product(s) formed when the following amine is treated with excess iodomethane, followed by heating with silver oxide. Solution Solving this type of problem requires finding every possible elimination of the methylated salt. In this case, the salt has the following structure: Chapter 2 Dr. EEY 52 52 5/6/2020 Solved Problem 2 (Continued) Solution (Continued) The green, blue, and red arrows show the three possible elimination routes. The corresponding products are The first (green) alkene has a disubstituted double bond. The second (blue) alkene is monosubstituted, and the red alkene (ethylene) has an unsubstituted double bond. We predict that the red products will be favored. Chapter 2 Dr. EEY 53 53 5/6/2020 Oxidation of Amines Amines are easily oxidized, even in air. Common oxidizing agents: H2O2 , MCPBA. 2 Amines oxidize to hydroxylamine (—NOH) 3 Amines oxidize to amine oxide (R3N+—O-) Chapter 2 Dr. EEY 54 54 5/6/2020 Preparation of Amine Oxides Tertiary amines are oxidized to amine oxides, often in good yields. Either H2O2 or peroxyacid may be used for this oxidation. Chapter 2 Dr. EEY 55 55 5/6/2020 Cope Rearrangement E2 mechanism. The amine oxide acts as its own base through a cyclic transition state, so a strong base is not needed. Chapter 2 Dr. EEY 56 56 5/6/2020 Solved Problem 3 Predict the products expected when the following compound is treated with H2O2 and heated. Solution Oxidation converts the tertiary amine to an amine oxide. Cope elimination can give either of two alkenes. We expect the less hindered elimination to be favored, giving the Hofmann product. Chapter 2 Dr. EEY 57 57 5/6/2020 Formation of Diazonium Salts R NH2 + NaNO2 + 2 HCl R N N R N N Cl- + 2 H2O + NaCl R + N N Primary amines react with nitrous acid (HNO2) to form alkyldiazonium salts. The diazonium salts are unstable and decompose into carbocations and nitrogen. Chapter 2 Dr. EEY 58 58 5/6/2020 Arenediazonium Salts By forming and diazotizing an amine, an activated aromatic position can be converted into a wide variety of functional groups. Chapter 2 Dr. EEY 59 59 5/6/2020 Reactions of Arenediazonium Salts Chapter 2 Dr. EEY 60 60 5/6/2020 The Sandmeyer Reaction Chapter 2 Dr. EEY 61 61 5/6/2020 Reductive Amination: 1º Amines Primary amines result from the condensation of hydroxylamine (zero alkyl groups) with a ketone or an aldehyde, followed by reduction of the oxime. LiAlH4 or NaBH3CN can be used to reduce the oxime. Chapter 2 Dr. EEY 62 62 5/6/2020 Reductive Amination: 2º Amines imine Condensation of a ketone or an aldehyde with a primary amine forms an N-substituted imine (a Schiff base). Reduction of the N-substituted imine gives a secondary amine. Chapter 2 Dr. EEY 63 63 5/6/2020 Reductive Amination: 3º Amines Condensation of a ketone or an aldehyde with a secondary amine gives an iminium salt. Iminium salts are frequently unstable, so they are rarely isolated. A reducing agent in the solution reduces the iminium salt to a tertiary amine. Chapter 2 Dr. EEY 64 64 5/6/2020 Solved Problem 3 Show how to synthesize the following amines from the indicated starting materials. (a) N-cyclopentylaniline from aniline (b) N-ethylpyrrolidine from pyrrolidine Solution (a) This synthesis requires adding a cyclopentyl group to aniline (primary) to make a secondary amine. Cyclopentanone is the carbonyl compound. (b) This synthesis requires adding an ethyl group to a secondary amine to make a tertiary amine. The carbonyl compound is acetaldehyde. Formation of a tertiary amine by Na(AcO)3BH reductive amination involves an iminium intermediate, which is reduced by (sodium triacetoxyborohydride). Chapter 2 Dr. EEY 65 65 5/6/2020 Synthesis of 1º Amines by Acylation–Reduction Acylation of the starting amine by an acid chloride gives an amide with no tendency toward overacylation. Reduction of the amide by LiAlH4 gives the corresponding amine. Chapter 2 Dr. EEY 66 66 5/6/2020 Synthesis of 2º Amines by Acylation–Reduction Acylation–reduction converts a primary amine to a secondary amine. LiAlH4, followed by hydrolysis, can easily reduce the intermediate amide to the amine. Chapter 2 Dr. EEY 67 67 5/6/2020 Synthesis of 3º Amines by Acylation–Reduction Acylation–reduction converts a secondary amine to a tertiary amine. Reduction of the intermediate amide is accomplished with LiAlH4. Chapter 2 Dr. EEY 68 68 5/6/2020 The Gabriel Synthesis The phthalimide ion is a strong nucleophile, displacing the halide or tosylate ion from a good SN2 substrate. Heating the N-alkyl phthalimide with hydrazine displaces the primary amine, giving the very stable hydrazide of phthalimide. Chapter 2 Dr. EEY 69 69 5/6/2020 Mechanism Chapter 2 Dr. EEY 70 70 5/6/2020 Reduction of Azides Azide ion, N3-, is a good nucleophile. React azide with unhindered 1 or 2 halide or tosylate (SN2). Alkyl azides are explosive! Do not isolate. Chapter 2 Dr. EEY 71 71 5/6/2020 Reduction of Nitriles Nitrile (CN) is a good SN2 nucleophile. Reduction with H2 or LiAlH4 converts the nitrile into a primary amine. Chapter 2 Dr. EEY 72 72 5/6/2020 Reduction of Nitro Compounds The nitro group can be reduced to the amine by catalytic hydrogenation or by an active metal and H+. Commonly used to synthesize anilines. Chapter 2 Dr. EEY 73 73 5/6/2020 The Hofmann Rearrangement of Amides In the presence of a strong base, primary amides react with chlorine or bromine to form shortened amines, with the loss of the carbonyl carbon atom. This reaction, called the Hofmann rearrangement, is used to synthesize primary and aryl amines. Chapter 2 Dr. EEY 74 74 5/6/2020 Mechanism of the Hofmann Rearrangement: Steps 1 and 2 Chapter 2 Dr. EEY 75 75 5/6/2020 Mechanism of the Hofmann Rearrangement: Steps 3 and 4 Chapter 2 Dr. EEY 76 76