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amines - SUMMARY Amines General Information Amines 1...

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Unformatted text preview: SUMMARY ' Amines General Information Amines 1 Synthesis of Amines 0 From Alkyl Halides and Azides via 8N2 Reaction Amines 2 I From Alkyl Halides and Imides via 8N2 Reaction (Gabriel Synthesis} Amines 3 0 From Alkyl Halides and Nitrogenous Compounds via 5N2 Reaction Amines 4 ' From Kctones/Aldehydehydes via Reductive Amination Amines 5 0 From Amides via Hofmann Rearrangement Amines 6 ' From Nitriles by Reduction (see Nitriles 4) Reactions of Amines 0 Preparation of Alkenes via Hofmann Elimination Amines 7 ' Preparation of Amides (see Amides 2) GENERAL INFORMATION Amines 1 Aliphatic Amines Introduction; Amines are organic compounds derived from ammonia, in which the hydrogen atoms are replaced by either alkyl or aryl groups. Depending on the number of hydrogen atoms replaced by the substituents, 1° (RNHZ), 2° (RZNH), or 3" (R3N) amines are formed. These compounds are Widely distributed and extremely impor— tant in the biological world (e.g., all amino acids are amines). Quaternary ammonium ion (R4N+) compounds can be formed by replacing all four hydrogens of an ammonium ion (NH4+) with alkyl or aryl groups. Physical Properties: . Amines have higher boiling points than alkanes of similar molecular weight. However, compared to those for alcohols of equivalent molecular weight, amine boiling points are lower. Reason: The N—H--N hydrogen bond is weaker than the O—H--0 hydrogen bond. ' All amines are more soluble in water than the hydrocarbon of equivalent molecular weight. Again, this is attributed to the ability of amines to hydrogen-bond. ' A very distinct feature of amines is their strong odor. {One whiff of the fishlike odor can certainly help one to detect an amine). 0 Chiral amines undergo rapid pyramidal inversion; thus the enantiomers cannot be separated at room temperature. Qhemical Properties: 9 The nitrogen atom of amines is SP3 hybridized. The bond angle formed by C—N—C is slightly less than 109°. . The C—N bond length is 1.47A. 0 Amines are basic. The presence of a lone pair of electrons on the nitrogen atom makes amines weakly basic, and similar to ammonia. Compared to ether, water, or alcohol, amines are more basic. When dissolved in aqueous solution, amines react slightly with water to form a new covalent N—H bond (and thus an ammonium ion) and a hydroxide ion, thus making the solution weakly basic: H H | .. | .. n—T: + H—g—H {TL—i R—elli —He:g—H H Water H Amine Alkylammonium hydroxide ' Amines are polar compounds and form hydrogen bonds. Nomenclature: - 1° Amines: Determine the longest continuous carbon chain. Replace the suffix -e of the alkane with -amine [e.g., HZNCHZCHZCH3, Propanamine (common name: Propylamine]. ' 2“ and 3° Amines: Add the names of the alkyl or aryl groups attached to the N atom of the parent 1“ amine (the one with the longest carbon chain). Prefix the name with N (for 2") or N,N (for 3°). cascnz - N - cnzcuzcua H N—Ethylpropanamjne (common name .1 ethyl propylamjne) I As a substituent, the NHZ group is called an amino group (e.g., NHZCHZCHZOH, Z-aminoethanol). SQCCIIOSQOQX: IR: N—H bond, 3300—3500 cm-l; 1° amine, 3400—3500 curl; 2° amine, 3350 cm_1_; 3° amine, no absorption. “‘ H NMR: Amine hydrogens generally appear as a broad singlet; they can be found in the range of B = 0.5— 5.0 ppm. SYNTHESIS OF AMINES Amines 2 FROM ALKYL HALIDES AND AZIDES VIA 3N2 REACTION NaN; 69 6 l) LiAlH4 , ether CH3CHQBr -—-—> CHaCHzfl = N = N —> Cflchle-lz Ethanol 2) H20 l-Bromoethane Ethyl azide Ethylamine (1° alkyl halide) (alkyl azide) (1° amine) Keys: 1. This is an excellent reaction that generates a high yield of 1° (monoalkylated) amine (RNHZ). 2. This reaction has two stages (see Mechanism). a. An SNZ reaction (see Alley! Halides 6) takes place between an alkyl halide and an azide ion to form an alkyl azide. Only primary and secondary alkyl halides can be used for the reaction. I). A reduction reaction converts the alkyl azide to an amine. LiAlH4 or hydrogenation over palladium catalyst (see Note) IS needed for this stage. 3. The reaction proceeds through an alkyl azide intermediate that could be explosive, thus making this reaction dangerous. 4. Azide ion is weakly basic and very nucleophilic. 9.. ® “9 N Note: Alkyl azides can be reduced with hydrogen and a palladium catalyst. NaN 63 S H RCHzX —1> RCHzN = N =N —2> RCHaNHz a ethanol PdJ'C 1° Alkyl halide Alkyl azide 1° Amine. Mechanism: Stage I: 1. The nucleophilic azide ion (N3‘) attacks the alkyl halide, displacing a halide ion to form an alkyl azide intermediate. Stage II: 2. The alkyl azide is then reduced by LiAlH4 in ether to form :1 1° (monoalkylated) amine product. ® H H LlAlH4 , ClhEI H | I .. ') l n or} i» nme~N=fi=N§a L—y n-rlz—NH2 H 1°Alky1 halide H H Alkyl azide l“ Amine 9.. e ..e :u = N = N: (X = Br. C1, or I) SYNTHESIS OF AMINES Amines 3 FROM ALKYL HALIDES AND lMIDES VIA 5N2 REACTION ( GABRIEL SYNTHESIS) 1) lmide anion in DNIF CHSCHgflr ———-—-~——w—-e—---+ CH:CH2NH2 l-Bromoerhane 2)1)H1' H20 Ethylamine alkyl halide (1" amine) EYE 1. This is another excellent reaction that generates a high yield of 1° (monoalkylated) amines (RNHZ) (see Amines 2 for the other reaction). 2. Only 1“ alkyl halides can be used in this reaction. 3. This reaction has three stages (see Mechanism). 3. An imide (e.g., phthalimide) is converted to an imide anion. The hydrogen atom is easily abstracted by bases (e.g., KOH) because the negative charge on the nitrogen atom of the imide anion is stabilized by two carbonyl groups. 0 0 II II c\ KOH °\ 9 o CE N—H —> GE :N: K c/ c/ - II ll 0 O Phthalimide Potassium phthalimide (imide) b. An 5N2 reaction takes place between the imide anion and a 1" alkyl halide to form an alkyl imide. c. Base hydrolysis of the alkyl imide produces the amine. “- 4. This reaction is usually carried out in a polar solvent [dimethylformamide (DMFH. Note: The chemical formula for DMF is HCON( CH 3); Mechanism: 1. Base (—OH) abstracts a proton from the nitrogen of the imide to form the imide anion. 2. A 5N2 reaction follows: The imjde anion reacts with a 1" alkyl halide to form an alkyi imide. 3. Subsequent base hydrolysis forms the 1" amine product. 0 o 0 ll H H II C C 61 :.£1.. L + g 3"? N19 2, [9: 3w; (ii: L50 i I 8.. H 0 O .. o o Alkylimide Panthalimide (Base) lmide 1°Alkyl anion halide @ Base 11 drol s's (X:Br,Cl,orI) y 3” co? @[ + RCHzNflz c029 1°Amjne SYNTHESIS OF AMINES Amines 4 FROM ALKYL HALIDES AND NITROGENOUS COMPOUNDS VIA 8N2 REACTION l A ' , cu,(cnz),cuzar % cngcngscnznnz + [cngcngficnzhnu + [cmwnmcndan + [CH3(CH2)SCH2].N©Bre 1 Na H l-Brornooctane ) Octylamine (45%) Dioctylamine (43%) 3° Amine 4° Amonjum salt (1" alkyl halide) (1° amine) (2° amine) Keys: 1. This is an 5N2 reaction involving nitrogenous compounds (ammonia and 1°, 2°, and 3° amines) and 1° alkyl halides to generate various types of amines. 2. Depending on the type of nitrogen substrate, different types of amine products are formed. Nitrogen Substrate Amine Product NH3 1“ Amine 1° Amine 2° Amine 2° Amine 3° Amine 3° Amine 4° Ammonium salt 3. The reaction usually does not generate high yields of monoalkylated products. A mixture of 1°, 2°, 3°, and 4“ amine products is formed. This happens because the reaction does not stop after the first alkylation, for example, RCH2X + NH3 —> RCHzlfl'HZ + [RCH2]2NH + [RCH213N+ [RCH2]4N+ + X— 1“ Alkyl Ammonia 1° Amine 2° Amine 3° Amine 4° Ami’n‘e salt Halide Notes: 1. High yields of monoalkylated amine products can be generated by the following two reactions: a. Reaction between alkyl halides and azides (see Amines 2). b. Reaction between alkyl halides and imides (Gabriel synthesis; see Amines 3) 2. Hydroxide is not directly involved in amine alkylations. However, the alkylation reaction itself results in the formation of ammonium salts. To isolate the free amine, one must neutralize the ammonium salt with hydroxide in a separate subsequent step. Mechanism: The nation between 1° amines and 1° alkyl halides is shown below. The mechanisms involved in the reactions between 1° alkyl halides and other types of amines are very similar to that described below. 1. The nucleophilic N atom of the 1° amine (RNHZ) attacks the alkyl halide (R’X) via an 5N2 mechanism and displaces the halide ion. 2. Base (e.g., an amine) abstracts a proton to form the 2“ amine product. 3. Some of the 2° amine product again reacts with the alkyl halide via an 5N2 mechanism to displace a halide ion. 4. Repetition of step 2 leads to the formation of a 3" amine product. 5. Repetition of the 5N2 reaction with the 3° amine leads to the formation of 4° ammonium products. H H H H .. | I | | ENC—Cl %> Hip —c—I=I' L FIHN— ——n- + nNI-lfxe . . I _ 9 I I I Amine H x H H H 1°Alkyl L‘- To 2 Amme halide “NH: tr—e—x H (3) e , x n' I. (ltHzFl' from H 2" H " R'CHX — ‘ n—G’N—CHgn'xe 4—2 R—N—CHQR' «L I H l . @ R—N—C—R CH2“ 3°Amine Ill: lll 4°Ammoniumsalt t Hill-I2 (X = BR, C1. or I) SYNTHESIS OF AMINES FROM KETONES/ALDEHYDES VIA REDUCTIVE AMINATION REACTION NH; —>©N"3 -4..- ® Hleickel 1° Amine 0 Id NHH / \ @11an ‘lm ——~—m+ _ _ H [N' kel ZDA ' Aldehydes ® 1 ‘c "W Dr ketones \ G) RzNH TRZ ® HWickel 3D Amine Keys: 1. This is a reductive amination reaction that converts a carbonyl compound, specifically a ketone or aldehyde, to an amine. 2. The overall reaction can be broken down into two stages (see Mechanism for details): Amines 5 a. The reaction between nitrogenous compounds {NI-I3, 1° and 2° amines) and ketones or aldehydes to form a carbon-nitrogen double bond (an imine or iminium ion) (see Aldehydes/Ketones 5). b. The imine compound is reduced with hydrogen and a catalyst {e.g., Ni, Pd). Sodium cyanoborohydride (NaBH3CN) can also be used as the reducing agent. 3. Depending on the type of nitrogenous substrate, different types of amine products are formed. Nitrogen Source Amine Product NH3 1° Amine 1° Amine 2° Amine 2° Amine 3" Amine Note: Tertiary amines cannot undergo this reaction. Mechanism: The mechanism for 1° amine synthesis is described below; the mechanisms for 2“ and 3° airline syntheses are very similar to that of 1° amine synthesis. Overall, the reaction can be divided into two stages: 1. Conversion of a ketone/aldehyde to an imine (for a detailed mechanism see Aldehydes/Ketones 5) Nucleophilic attack by ammonia on the carbonyl carbon atom. . Proton transfer from the nitrogen to the oxygen atom. Loss of a hydroxide ion forms an iminium ion intermediate. . (i) When NH3 and 1° amines are the nitrogen substrate, a proton is lost from the iminium ion intermediate to form the imine and water. (ii) When 2° amines are the nitrogen substrate, there is no proton loss from the iminium ion intermediate. The intermediate can be reduced directly to form an amine product. 2. Reduction of the imine with H2 and the catalyst to form the amine. eLp erg» 0 die/ill Con Cll l CI Proton transfer I _._:-. KB .. R'—C—Fl ‘-.—'— R'ic—N—H FI'—C—N—H L/fi. l | | | NH: R H R H Ketone ® 7 ”fine; ® :9 R'—C—NH +—-— R'—C=NH R'—C=N—H 2 HglNickel | 7 | I5 a Q n H e" lo Amine lmine imam‘lggfl intermediate SYNTHESIS OF AMINES Amines 6 FROM AMIDES VIA HOFMANN REARRANGEMENT REACTION 0 II B , N OH (R) — C5H5CHCHZCNH2 A» (a, — cfinseneuznm2 | H20 | CH3 CH3 (R)-3-Phenylbutanan1.ide (R)-2-Phenylpropananune Keys: 1. This reaction converts 1° amides to 1° amines. 2. It is important that the final amine products have one less carbon atom than the starting amides. The product has lost the carbonyl group of the starting amide. As a result, this reaction is valuable in producing 1° amines with a shorter carbon chain length. 3. The reaction can be divided into four stages: a. Conversion of a 1" amide to an N—bromoamide. b. Formation of an alkyl isocyanate from the N—bromoamide involving a rearrangement step. c. Conversion of an alkyl isocyanate to an unstable alkyl carbamic acid. d. Formation of the final 1° amine product. 4. The rearrangement step is unique in this reaction: The R group attached to the carbonyl carbon moves over and bonds to the neighboring nitrogen atom (see Mechanism following step 4b). Furthermore, the rearrangement does not change the stereoconfiguration of the alkyl group, for example, (S) 1° amide —> (S) 1” amine Note: Curtius rearrangement reaction ‘ ii Q o The reaction mechanism is similar to that of the n—c—g—fiau M, “N“: + CO: ., N2 Hofmann‘ rearrangement reaction. D . Acy] azide 1a Amine ° The reactlon converts acyl andes to 1 amines. The amine product has one less carbon atom. ° ° . . . . II NaN3 || 9 a; 0 The acyl ande 15 formed from an ac1d halide. FI—O—X —> FI—C —E—NEN Acid halide Acyl azide Mechanism: Stage 1: Formation of an N—bromoamide from a 1" amide 1. Base (—OI—I) abstracts a proton from the nitrogen atom of the amide to form an amide anion. 2. Nucleophilic addition of the anion to bromine to form an N—bromoamide. Stage 2: Formation of alkyl isocyanate 3. Base abstracts the last proton from the nitrogen atom of the bromoamide to form an N—bromoamide anion. 4. Rearrangement step a. The nitrogen atom of the anion donates a pair of electrons to form a double bond between the carbon and nitrogen atoms. b. The R group attached to the carbonyl carbon moves over and bonds to the nitrogen atom. c. The bromide ion is forced to leave, thus forming an alkyl isocyanate. Note that the rearrangement takes place in one step. Stage 3: Formation of the alkyl 0 resin H20 0 Far—Far are 0 fat?" carbamic acid n—li—i?’ _% n—li—ii __H JA R_‘":_f$/ 5. Nucleophilic addition of OH 1°Amide \H Amide é N_ Bmmom (16‘s, to the carbon atom of the iso- anion cyanate and protonation of @ the nitrogen atom by water _ forms the unstable N—alkyl 90.. HQ?" 3.9 0 ® carbamic acrd. O=C—N—R @l 5-: :(fi—n @i H—éifi—Br : 9 Stage 4: Formation of the final J3" IL Hoe CID amine product N~A11tylcarbm1ic acid " Alky] isocyanate MBmmomide 6. Spontaneous loss of C02 © '43 man from the carbamic acid forms . o . the final 1 amine product. HZNR + co; 1°Amine REACTIONS OF AMJNES Amines 7 PREPARATION OF ALKENE VIA HOFMANN ELINUNAHON AgZO. H20 Excess CH I I? e cl'lacHzCHchle'lz —>’ cflscflchchz N (canal “mm—M CHQCHzCH = CH2 Butylamine Butyltrimethy] ammonium 1'3““:“5 (1° Amine) iodide Keys: 1. This reaction converts amines to the less substituted alkene as the predominant product. 2. The reaction can be divided into two stages: a. Conversion of the amine to a quaternary ammonium iodide. b. Formation of an alkene via an E2 mechanism. 3. Surprisingly, the regioselectivity of this E2 reaction yields the less highly substituted alkene as the predomi- nant product (Hofmann’s rule} instead of the more highly substituted alkene (Zaitsev’s rule). Reason: The transition state of the E2 reaction of an alkyl halide involves simultaneous breaking of both a CH and a CX bond. If the X atom is highly electronegative (e.g., F or W), it makes adiacent CH bonds more acidic. The mechanism thus shifts toward one in which there is more CH bond breaking than CX bond breaking in the transition state. This favors the less substituted alkene. Also, a large leaving group creates enhanced steric effects, which also favors less substituted alkenes. Zaitsev 5 rule: X E RXN GHacHQCchHCH; 2—) CHacH2CH = CHCHs + CHscchchH = CH2 a Major product Minor product Hofmarm's rule: “. Hofmann's CH30H2CH20HCH: CH1CHgCH20H g CH2 + CH;CH2€H = CHCH; Elimination NH: Major product Minor product Mechanism: Stage I 1. Excess CH3I reacts with the alkyl amine to generate a quaternary ammonium iodide salt. In this case, the alkyl amine is the nucleophile. Stage II 2. The quaternary ammonium iodide reacts with aqueous silver oxide, thereby replacing the iodide ion with hydmxide ion and forming the quaternary ammonium hydroxide. 3. The quaternary ammonium hydroxide is subsequently heated, and an E2 reaction takes place to generate the alkene product. fill. H—C—I .. EB HCHgCHzflflz r|l U A» HCH2CH2 "(creme 1° Alkylamine ests Quatemaxy ammonium iodide AgIO ® H10, CHJOH Agl H997 H H H H \ / @132 \ ,“uH memos + H20 + c=c\ 4W “we—Q . V H Tnmethylarrune R H H CngCHsL Alkcne Quaternary ammonium hydroxide ...
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