生物化学Chapter+22+AminesPPT课件.ppt

Chapter 22 Amines,Amines are organic derivatives of ammonia in the same way that alcohols and ethers are organic derivatives of water.,The important organic reactions of amines (nucleophiles) are with the common electrophiles : alkyl halides via nucleophilic substitution, aldehydes or ketones via nucleophilic addition carboxylic acid derivatives, especially acid chlorides or anhydrides via nucleophilic acyl substitution.,22.1 Nomenclature,Functional group suffix = -amine Functional group prefix = amino The suffix -amine is added to the name of the alkyl substituent. Alternatively, the suffix amine can be used in place of the final e in the name of the parent compound.,Chenli,Chenli,Primary amines are named in the IUPAC system in several ways depending on their structure. For simple amines, the suffix -amine is added to the name of the alkyl substituent. Alternatively, the suffix amine can be used in place of the final e in the name of the parent compound.,In secondary and tertiary amines, the alkyl groups may be the same or different.,Compounds with four groups attached to nitrogen are also known, but the nitrogen atom must carry a positive charge. Such compounds are called quaternary ammonium salts.,An -NH2 group, when not the principal group, is named by the prefix amino-.,Symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group.,Unsymmetrically substituted secondary and tertiary amines are named as N-substituted primary amines. The largest alkyl group is chosen as the parent name, and the other alkyl group are considered N-substituents on the parent (N since theyre attached to nitrogen).,22.2 Structure and Bonding,The amine functional group consists of an N atom bonded either to C or H atoms via s bonds. Both the C-N and the N-H bonds are polar due to the electronegativity of the N atom. The trigonal (三角形的) pyramidal(金字塔形的, 锥体的) arrangement of bonds around nitrogen is shallower in aryl amines vs alkyl amines.,Chenli,Structure and Bonding in Amine,The bonding in amines is similar to the bonding in ammonia. The nitrogen atom is sp3 hybridized, with the three substituents occupying three corners of a tetrahedron and the nitrogen nonbonding lone pair of electrons occupying the forth corner.,Chenli,Chenli,CH3NH2 The more red an area is, the higher the electron density and the more blue an area is, the lower the electron density,Amines can react as either bases or nucleophiles at the nitrogen. There is low electron density (blue) on H atom of the -NH group. Removal of the proton generates the amide ion (care : not to be confused with the carboxylic acid derivative RCONH2) The -NH group is a very poor leaving group and needs to be converted to a better leaving group before substitution can occur.,Chenli,Chenli,陈立,CH3NH3+ The more red an area is, the higher the electron density and the more blue an area is, the lower the electron density,The ammonium N atom is a region of low electron density (blue) due to the positive charge. Ammonium ions are not nucleophilic. There is low electron density (blue) on H atom of the -NH3 group. Removal of the proton regenerates the amine. The -NH3 group is a potential leaving group,This is a result of resonance delocalisation of the lone pair into the aromatic p system (such delocalisation is also responsible for the decreased basicity of aryl vs alkyl amines).,Chenli,Chenli,alkyl ammonium pKa 10, aryl ammonium pKa 5,22.3 Physical properties of Amines,The polar nature of the N-H bond (due to the electronegativity difference of the two atoms) results in the formation of hydrogen bonds with other amine molecules, see below, or other H-bonding systems (e.g. water). The implications of this are:,high melting and boiling points compared to analogous alkanes high solubility in aqueous media,intermolecular H-bonding in amines,Amines are highly polar and therefore have higher boiling points than alkanes of equivalent molecular weight have. Like alcohols, amines with C5 are generally water-soluble. Primary and secondary amines form strong hydrogen bonds and are highly associated in the liquid state.,22.4 Basicity of Amines,Because of the nitrogen lone pair of electrons, amines are both basic and nucleophilic. Amines are much more basic than alcohols, ethers, or water. (R-NH3+ pKa 10, R-OH2+ pKa -3) Some amines are stronger and some are weaker in base strength. N is less electronegative than O and therefore N is a better electron donor. alkyl and non-aromatic heterocyclic amines are slightly stronger bases than ammonia aryl amines are much weaker bases than ammonia, a result of the delocalisation of the lone pair into the p system of the ring,Chenli,Basicity of Some Amines,22.5 Preparation of Amines,Chenli,Chenli,Reduction reactions Rearrangements Nucleophilic substitution reactions,Amines via Reduction,Reduction of nitro compounds Reduction of nitriles Reduction of amides Reduction of imines/enamines Reductive amination of aldehydes/ketones,Amines via Reduction: A Summary,Amines via Rearrangement,Hofmann rearrangement (degradation) Curtius rearrangement,22.5.1 Alkylation of Ammonia or Amines,Reaction type: Nucleophilic Substitution,Mechanism of Ammonia Alkylation,Chenli,Step 1: The N in ammonia functions as the nucleophile and attacks the electrophilic C of the alkyl halide displacing the bromide and creating the new C-N bond.,Step 2: An acid/base reaction. The base (excess ammonia) deprotonates the positive N (ammonium) center creating the alkylation product, the primary amine.,Ammonia reacts as a nucleophile with alkyl halides to give primary amines in a substitution reaction. Yields are often poor as the product , a primary amine, RNH2 , is itself a nucleophile and can react with more alkyl halide. The result are mixtures containing primary amines, secondary amines, tertiary amines and quaternary ammonium salts. This can be avoided if a large excess of ammonia is used.,Chenli,Summary,This is a scheme for converting alkyl halides to their corresponding primary amines. It has the advantage that it does not create more than one alkylation but the disadvantage that it cannot be used for formation of acyl amines,22.5.2 Gabriel Synthesis (Alkylation of Phthalimide苯邻二甲酰亚胺),Chenli,Chenli,Mechanism of the Gabriel Synthesis,Step 1: An acid/base reaction. Deprotonation of the imide N-H proton by the base, hydroxide. This proton is more acidic than a simple amine due to the resonance stabilisation by the two adjacent C=O groups. This generates a strong nucleophile, the -ve N.,Step 2: The N nucleophile attacks the electrophilic C of the alkyl halide displacing the bromide and creating the new C-N bond. This product can be compared to an N-alkyl amide.,Step 3: The imide can be cleaved via a mechanism analogous to that of amides. Hydrolysis creates the dicarboxylic acid and the required amine.,Summary,The advantage of this method is that over alkylation is avoided. Reaction of phthalimide with KOH removes the N-H proton giving an imide ion, a good nucleophile. Nucleophilic substitution by the imide ion on the alkyl halide generates an intermediate, N-alkyl phthalimide(苯邻二甲酰亚胺). Hydrolysis or hydrazinolysis(肼解)liberates a primary alkyl amine. Aryl amines cannot be prepared via this method since aryl halides do not undergo simple nucleophilic substitution.,Chenli,Chenli,22.5.3 Preparing Amines from Alcohols,22.5.4 Reduction of Nitriles , Amides and Oximes(肟),22.5.5 Reduction of Nitriles,Reaction type : Oxidation - Reduction or Nucleophilic Addition,Chenli,Chenli,Amino Alcohols via Reduction of Cyanohydrins,The nitrile, RCN, is reduced to the 1o amine by conversion of the C N to R-CH2-NH2 Reagents : either lithium aluminum hydride (LiAlH4) / ether solvent or catalytic hydrogenation (e.g. H2/Pd). Alkyl nitriles are prepared by nucleophilic substitution (SN2) by cyanide ion, CN-, of primary or secondary alkyl halides. Aryl nitriles can also be reduced to aryl amines.,Summary,22.5.6 Reduction of Nitro Compounds,Reaction type : Oxidation - Reduction,Nitroarenes can be reduced to primary aryl amines: Typical reducing agents include, Fe / H+, Sn / H+ or catalytic hydrogenation (e.g. H2 / Pd) Nitroarenes are prepared by the nitration of aromatics. This is probably the most important method for the synthesis of anilines (Ar-NH2) and, therefore, accessing the chemistry of diazonium compounds.,Reduction of Nitroarenes - Example,Nitroarenes can be reduced to primary aryl amines. Typical reducing agents include, Fe / H+, Sn / H+ or catalytic hydrogenation (e.g. H2 / Pd) Nitroarenes are prepared by the nitration of aromatics. This is probably the most important method for the synthesis of anilines (Ar-NH2) and, therefore, accessing the chemistry of diazonium compounds.,Summary,22.5.7 Reduction of Amides,Reactions usually in Et2O or THF followed by H3O+ work-ups,Reaction type: Nucleophilic Acyl Substitution then Nucleophilic Addition,R, R or R“ may be either alkyl or aryl substituents,Reaction Of LiAlH4 With An Amide,Step 1: The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of the ester. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.,Step 2: The tetrahedral intermediate collapses and displaces the O as part of a metal alkoxide leaving group, this produces a highly reactive iminium ion an intermediate.,Step 3: Rapid reduction by the nucleophilic H from the hydride reagent as it adds to the electrophilic C in the iminium system. p electrons from the C=N move to the cationic N neutralising the charge creating the amine product.,Synthesis of Amines from Amides,22.5.8 Reductive Amination of Ketones and Aldehydes,Reaction type : Nucleophilic Addition then Oxidation - Reduction,Key to Successful Reductive Amination?,Reductive Amination - A Versatile Strategy,Reductive Amination - Primary to Secondary Amines,Stepwise Reductive Amination is Possible,Reductive Amination - Secondary to Tertiary Amines,Iminium Ions and Enamines: Possible Intermediates in Reductive Amination,Summary,Aldehydes and ketones react with ammonia to give 1o amines, 1o amines to give substituted imines and 2o amines to give enamines(烯胺). These N species can then be reduced to amines. The method provides access to 1o, 2o, or 3o amines. Typical reagents : most commonly catalytic hydrogenation (e.g. H2/Pd) R, R and R“ may be either hydrogen, alkyl, or aryl.,Chenli,Leukart Reaction,This is a useful reaction to convert a ketone or aldehyde into an amine,References 1. R. Leuckart, Ber. 18, 2341 (1885) 2. Moore, ML, Organic Reactions vol. V, p301, 1949,The Leuckart reaction is a key step in the synthesis of amphetamines(苯丙胺).,Recent examples of the Leuckart Reaction include the following:,Reference: Loupy A, Monteux D, Petit A, Merienne C, Aizpurua JM, Palomo C, Journal of Chemical Research-S (4) 187-187A.,Comments: The rate of this reaction can be increased using Microwaves! It also produces several stereoisomers.,Eschweiler-Clarke Reaction,The reactions are usually carried out in an acidic buffer to activate the C=O and facilitate dehydration but without inhibiting the nucleophile.,The Mechanism,22.5.9 Preparation of Amines from Carboxylic Acids and Their Derivatives,Hofmann Rearrangement Curtius Rearrangement Schmidt Rearrangement,Hofmann Rearrangement,An unsubstitued amide is treated with sodium hypobromate (i.e. sodium hydroxide and bromine)to give a primary amine that has one carbon fewer than the starting amide.,Chenli,Chenli,Recent Examples Zhang, L-h.;* Kauffman, G.S.; Pesti, J.A.; Yin, J. J. Org. Chem., 1997, 62, 6918-6920,Curtius Reaction & Rearrangement,The stepwise conversion of a carboxylic acid to an amine having one fewer carbon unit, via the azide and isocyanate, is referred to as the Curtius reaction. It involves the Curtius rearrangement, which is the formation of isocyanates by thermal decomposition of acyl azides. This is a very general reaction and can be applied to almost any carboxylic acid: aliphatic, aromatic, alicyclic, heterocyclic, unsaturated, and containing many functional groups.,Reference: Journal; Radwan, Shaban M.; Bakhite, Etify A.; MOCMB7; Monatsh.Chem.; EN; 130; 9; 1999; 1117 - 1128.,22.6 Reactions of Amines,Chenli,Chenli,Amines are Brnstead Bases and Nucleophiles,Reactions Involving Amines,Several reactions involving amines are already been presented Basicity Reaction with aldehydes and ketones Reaction with acyl chlorides ,anhydrides , and esters,The important organic reactions of amines (nucleophiles) are with the common electrophiles : alkyl halides via nucleophilic substitution aldehydes or ketones via nucleophilic addition carboxylic acid derivatives, especially acid chlorides or anhydrides, via nucleophilic acyl substitution.,Chenli,22.6.1 Acylation,Chenli,Chenli,Primary and secondary (but not tertiary) amines can be acylated by reaction with acid chlorides or acid anhydrides to yield amides.,Reaction type: Nucleophilic Acyl Substitution,Primary amines, R-NH2 and secondary amines, R2-NH undergo nucleophilic acyl substitution with carboxylic acid derivatives to give amides. The most common examples are the reactions of acid chlorides and anhydrides, though esters do react with amines.,Summary,22.6.2 Hinsberg Reaction,If a sulfonyl chloride, RSO2Cl, is used as the acylating agent, a sulfonamide is produced.,Hinsberg Test,22.6.3 Quaternary Ammonium Compounds,Quaternary ammonium salt,Quaternary ammonium hydroxide,Phase-Transfer Catalysis,A substance that transfers ions from an aqueous phase to an organic phase An effective phase-transfer catalyst must have sufficient hydrophilic character to dissolve in water and form an ion pair with the ion to be transported hydrophobic character to dissolve in the organic phase and transport the ion into it The following salt is an effective phase-transfer catalysts for the transport of anions,Phase-Transfer Catalysis,Phase-transfer catalyst,22.6.4 Hofmann Elimination,Reaction type: Elimination,Primary References Hofmann, A.W. Ann., 1851, 78, 253. Hofmann, A.W. Ann., 1851, 79, 2203. Hofmann, A.W. Ber., 1881, 14, 659. Cope, A.C.; Trumbull, E.R. Org. React., 1960, 11, 317. DePuy, C.H.; King, R.W. Chem. Rev., 1960, 60, 431.,1. Quaternary ammonium salts undergo an E2 elimination when heated with silver oxide, Ag2O, in water. 2. Amines can readily be converted into quaternary ammonium iodides by treating them with excess methyl iodide. 3. AgO / H2O reacts giving the quaternary ammonium hydroxide, silver iodide precipitates.,When heated the hydroxide induces a base promoted 1,2- or b-elimination giving an amine and alkene. The regioselectivity is opposite to that predicted by Zaitsevs rule in that it leads to the less highly substituted alkene. The less highly substituted alkene may be referred to as the Hofmann product.,The outcome is dictated by steric effects of the large leaving group and the alkyl chain. NH2- and NR2- are very poor leaving groups (both anionic), but NR3 is much better (neutral) Compare this with with -OH and H2O in the dehydration of alcohols.,22.6.5 Selectivity of the Hofmann Elimination,In general E2 reactions occur most rapidly when the H-C bond and C-LG bonds at 180o with respect to each other. This is described as an antiperiplanar (periplanar全平面的) conformation. This conformation positions the s bonds that are being broken in the correct alignment to become the p bond.,Chenli,Chenli,The staggered(错列的), antiperiplanar alignment is preferred because it aligns the two s bonds that become the p bond.,Hofmann Elimination,While quaternary ammonium halides are relatively stable salts, the corresponding hydroxides undergo E2 elimination when heated.,Hydroxide ion is a base, bromide is not,Hofmann Elimination,Quaternary ammonium hydroxides are relatively unstable and when pyrolyzed, undergo elimination to form a tertiary amine and an alkene. This process is called the Hofmann elimination.,Preparation of Quaternary Ammonium Hydroxides?,are prepared from trialkylammonium halides through ion exchange with silver(I) oxide.,Preparation of Quaternary Ammonium Hydroxides,Hofmann Elimination,Hofmann Elimination - Mechanism,Hofmanns rule: elimination occurs in the direction that gives the less-substituted double bond,Hofmann Elimination - Regioselectivity,Steric factors seem to control the regioselectivity. The transition state that leads to 1-butene is less crowded than the one leading to cis or trans-2-butene.,Hofmann Elimination - Regioselectivity,Conformational Analysis of sec-Butyltrimethylammonium Hydroxide,E,Lowest energy conformer,Highest energy conformer,Hofmann Elimination - Regioselectivity,In this transition state, the large trimethylammonium group is gauche to two C-H bonds,Hofmann Elimination - Regioselectivity,This transition state is higher in energy because the trimethylammonium group is gauche to a C-CH3 bond,Hofmann Elimination - Regioselectivity,This transition state is higher in energy because the trimethylammoni