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Aliphatic Ethers Pharmacy Student • Ethers have two alkyl groups bonded to an oxygen atom. ´ CnH2n+2O ´ CnH2n+2O Nomenclature of Ethers • Simple ethers are usually assigned common names. To do so: Name both alkyl groups bonded to the oxygen, arrange these names alphabetically, and add the word ether. For symmetrical ethers, name the alkyl group and add the prefix “di-”. • More complex ethers are named using the IUPAC system. One alkyl group is named as a hydrocarbon chain, and the other is named as part of a substituent bonded to that chain: Name the simpler alkyl group as an alkoxy substituent by changing the –yl ending of the alkyl group to –oxy. Name the remaining alkyl group as an alkane, with the alkoxy group as a substituent bonded to this chain. • The oxygen atom in alcohols, ethers and epoxides is sp3 hybridized. Alcohols and ethers have a bent shape like that in H2O. • The bond angle around the O atom in an alcohol or ether is similar to the tetrahedral bond angle of 109.5°. • Because the O atom is much more electronegative than carbon or hydrogen, the C—O and O—H bonds are all polar Hydrogen bonding make ROH more soluble and have higher b.p. than ROR or RH . Preparation of Alcohols, Ethers • Alcohols and ethers are both common products of nucleophilic substitution. • The preparation of ethers by the method shown in the last two equations is called the Williamson ether synthesis. 8 Methods of Preparetion: 1- Willianson’s continuous etherification Primary alcohols can dehydrate to ethers This reaction occurs at lower temperature than the competing dehydration to an alkene. Step 1 CH3CH2-OH H+ CH3CH2-OH2 -H2O CH3CH2 Step2 CH3CH2 + HO-CH2CH3 Step 3 CH3CH2-O-CH2CH3 H CH3CH2-O-CH2CH3 H - H+ CH3CH2-O-CH2CH3 HSO4diethyl ether Williamson continuous etherification 1) The Williamson Ether Synthesis : Reaction of an alkoxide with an alkyl halide or tosylate to give an ether. Alkoxides are prepared by the reaction of an alcohol with a strong base such as sodium hydride (NaH) The Williamson ether synthesis is an SN2 reaction. Synthesis of Ethers O H Alcohol (Lewis Base, Nucleophile) • H O H Protonated Alcohol SN2 Reaction O H Protonated Ether + H2O Utility of this Reaction is Limited in its Scope: Mixture of Ether/Alkenes with 2° Alkyl Groups Exclusively Alkenes with 3° Alkyl Groups Only Useful for Synthesis of Symmetric Ethers ROH + R’OH ROR + R’OR + R’OR’ Williamson’s Synthesis 1- Reaction with alkali metal (Na- K) R OH RONa + + Na R’X C2H5ONa + CH3Cl R ONa + ½ H2 ROR’ + NaX C2H5 O CH3 Williamson Synthesis of Ethers Unsymmetrical Ethers From RONa + Halide, Sulfonate, etc. O Na LG O Asymmetric Ether • Utility of this Reaction is Much Greater Than Condensation: Works with 1° and 2° Halides, Sulfonates, etc. Still Exclusively Alkenes with 3° Alkyl Groups Lower Temperatures Favor Substitution over Elimination SN2 Conditions Apply Prefer Unhindered Substrate Chemical Properties Ether linkage is quite stable towards bases, oxidizing and reeducing agents. Cleavage takes place under quite vigorous conditions as conc. Acids. Reaction of Ethers with Strong Acid • In order for ethers to undergo substitution or elimination reactions, their poor leaving group must first be converted into a good leaving group by reaction with strong acids such as HBr and HI. • HBr and HI are strong acids that are also sources of good nucleophiles (Br¯ and I¯ respectively). • When ethers react with HBr or HI, both C—O bonds are cleaved and two alkyl halides are formed as products. • The mechanism of ether cleavage is SN1 or SN2, depending on the identity of R. • When 2° or 3° alkyl groups are bonded to the ether oxygen, the C—O bond is cleaved by an SN1 mechanism involving a carbocation. With methyl or 1° R groups, the C—O bond is cleaved by an SN2 mechanism. • The mechanism of ether cleavage is SN1 or SN2, depending on the identity of R. • When 2° or 3° alkyl groups are bonded to the ether oxygen, the C—O bond is cleaved by an SN1 mechanism involving a carbocation. With methyl or 1° R groups, the C—O bond is cleaved by an SN2 mechanism. 20 1-Action of HI R-O-R HI/ Low temp ROH + RI HI / High temp 2RI + H2O CH3-O-CH3 CH3OH + CH3I 2 CH3I + H2O This reaction can proceed by : 1- SN1 or SN2. + .. R-O-R’ .. H H R-O-R’ + I - SN2 SN1 RI + R’-OH (R is 10 or 2o ) R+ + ROH I RI ( R 3o) Action of PCl5: R-O-R + PCl5 C2H5-O-C2H5 + PCl5 2R-Cl + POCl3 2CH3CH2Cl + POCl3 Thio Alcohols (Mercptants) R-SH Thiols (R–S–H) is sulfur analogs of alcohols and ethers, respectively Sulfur replaces oxygen Thiols Thiols (RSH), also known as mercaptans, are sulfur analogs of alcohols They are named with the suffix –thiol SH group is called “mercapto group” (“capturer of mercury”) Methods of preparations : Thiols are prepared from alkyl halides by SN2 with NaSH displacement with a sulfur nucleophile such as SH – The alkylthiol product can undergo further reaction with – the alkyl halide to give a symmetrical sulfide, giving a – poorer yield of the thiol 2- Heating of Alcohols with P2S5 R-OH + P2S5 CH3-OH + P2S5 R-SH + P2O5 CH3-SH + P2O5 3- Heating of Alcohols H2S at high temperature pressure, and catalyst: R-OH + H2S R-SH + H2O Chemical Properties: 1- With alkali metals: 2R-SH + 2 Na 2 R-SNa + H2 2 C2H5 – SH + 2 Na 2 C2H5 –SNa + H2 sod. Ethyl mercaptide 2- with Aldehyde : CH3CHO + 2C2H5SH S-C2H5 HCl CH3CH + H2O mercaptal S-C2H5 N: 1s22s22px12py12pz1 Amines Structures of amines C N N: 1s22s22px12py12pz1 sp3-hybrid C-N: sp3-sp3 hybridized orbitals overlap N-H: sp3hybridized -1s orbitals overlap Pyramid Tertiary amines with 3 different groups: R' R'' N R''' Interconversion of amine enantiomers H R' N R'' R''' Structure and Classification of Amines Amines are derivatives of ammonia NH3. Contain N attached to one or more alkyl (Aliphatic amine) or aromatic groups (Aromatic amine). • The shape around the nitrogen is pyrimidal and there is a lone pair of electrons on the nitrogen -NH2 amino group+ CH3-NH2 NH CH2 CH 2 3 CH3-NH-CH3 Ethylbenzene Structure and Classification of Amines Amines can be classified as 1º, 2º or 3º, just like carbons, based on how many alkyl groups are attached to the nitrogen H N H H Ammonia NH2 Primary Amine H N N Secondary Amine Tertiary Amine Amines Amines are classified into three groups: depending on the number of carbon groups bonded to nitrogen. CH3—NH2 CH3 CH3—NH Primary 1° Secondary 2° CH3 CH3—N—CH3 Tertiary 3° Naming Amines IUPAC name – 1° amines The same method as we did for alcohols. -Drop the final “-e” of the parent alkane and replace it by -amine”. - Use a number to locate the amino group (-NH2) on the parent chain. NH2 NH2 NH2 NH2 CH3-CH-CH-CH3 CH3-CH-CH3 CH3 CHCH3 3 2 1 3 Cl 4 2 1 2-Propanamine Cyclohexanamine 2-propanamine 3-chloro-2-butanamine H2 N 5 4 32 1 NH2 6 1,6-Hexan ediamine 1,6-hexanediamine Naming Amines IUPAC name – 2° and 3° amines – Take the largest group bonded to nitrogen as the parent amine. – Name the smaller group(s) bonded to nitrogen, and show their locations on nitrogen by using the prefix “N”. CH3 NHCH3 N-Methylanilin e N CH3 N,N-Dimethyl-aniline cyclopentan amine CH3 CH3-N-CH2-CH3 N,N-Dimethylethanamine Methods of Preparations 1-Alkylation of ammonia The reaction of ammonia with an alkyl halide leads to the formation of a primary amine . •The primary amine that is formed can also react with the alkyl halide, which leads to a disubstituted amine that can further react to form a trisubstituted amine. Therefore, the alkylation of ammonia leads to a mixture of products 2) Catalytic reduction of Alkyl cyanides ( nitriles) 1)LiAl H4 / ether 2)H3O+ R-C=N CH3CN H2/Ni R-CH2-NH2 CH3CH2NH2 (ethyl amine) 3) Hoffmann degradation reaction Of Amide O Br2/ NaOH RCH2-C-NH2 or NaOBr O CH3C-NH2 acetamide Br2 / NaOH or KOH / Br2 R-CH2NH2 CH3-NH2 +NaCO3+NaBr+ H2O (methyl amine) 4-The Gabriel synthesis of primary amines Primary alkyl halide, SN2 R X O R NH2 C Reagent: C N K Potassium salt of Phthalimide O O O C C C O N H KOH C O O NK R X C DMF C Imide O N R O O C C C N H KOH C O NK O O R X C DMF C N R O NaOH/H2O HCl /H2O CO2H CO2H + R-NH3Cl- CO2Na CO2N a + R-NH2 5- Reductive amination: R (R')H C O + NH3(or R''NH2) -H2O R (R')H C NH(R'') Imine R H2, Ni CH NH2(R'') 1o Amine (R')H H C O + NH3 H2, Ni 90 atm 40 ~ 70¡æ (CH3)2C O + H2NCH2CH2OH 3 H2, Ni, EtOH 95£¥ CH2NH2 (89%) (CH3)2CNHCH2CH2OH 2 Physical properties of Amines 1. They have unpleasant odors (rotting fish like ammonia). 2. Amines solutions are basic (ammonia or died fish odor) 3. They are polar compounds; Difference in electronegativity between N - H (3.0 – 2.1 = 0.9) 4- 1° and 2° amines have hydrogen bonds (N-H). Weaker than alcohols (O-H). 3° amines do not form hydrogen bonds (no H atom). Physical properties: 5- 1 , 2 amine can form H bond So their MP > alkane of similar M.Wt (B.P Amine > Alkane) 6-Boiling points: Hydrocarbons< Amines < Alcohols 7- Almost soluble in water (hydrogen bonding). Chemical Reactions of Amines Basicity of amines: 1-Amines basic because N has non bonded pair of electrons which can be donated to an acid to form ammonium salt. 2- base strength depend on the degree of substitution on N. - More basic CH3-NH-CH3 > NH2-CH3 > NH3 3-Activating groups. Increase basic properties.-- RNH2 > ArNH2 aliphatic more basic than aromatic - Amine > RCONH2 (Amide) less basic from amine Why are aliphatic amines more basic than ammonia? NH3 + H2O NH4+ + OH- R-NH2 + H2O R-NH3+ + OH- The alkyl group, -R, is an electron donating group. The donation of electrons helps to stabilize the ammonium ion by decreasing the positive charge, lowering the ΔH, shifting the ionization farther to the right and increasing the basicity. Common substituent groups: -NH2, -NHR, -NR2 -OH -OR -NHCOCH3 -C6H5 -R -H -X -CHO, -COR -SO3H -COOH, -COOR -CN -NR3+ -NO2 electron donating groups electron withdrawing groups 1-Basicity: CH3CH2NH3+Cl- CH3CH2NH2 + HCl ethyl amine 2- Alkylation: R-NH2 RX H R-N-R ethylamine hydrochloride RX R R-N-R 3- Acylation: With acid chloride O O RNH2 + R’CCl RNHCR’ + HCl CH3NH2 + CH3COCl CH3NHCOCH3 R + R-N -R R 4- Reaction with Nitrous Acid (To differentiation1,2,3 Amine 1°-Amines + HONO (cold acidic solution) Nitrogen Gas Evolution from a Clear Solution 2°-Amines + HONO (cold acidic solution) An Insoluble Oil (N-Nitrosamine) 3°-Amines + HONO (cold acidic solution) A Clear Solution (Ammonium Salt Formation) 4- Reaction with Nitrous Acid (To differentiation1,2,3 Amine A-Primary Amines: RNH2 + HNO2 ROH + N2 g + H2O (NaNO2/HCl) C2H5NH2 + HNO2 C2H5OH + N2 g. + H2O B-Secondary Amin N= O (NaNO2/HCl) R-NH-R’ + HNO2 R-N-R’ + H2O N= O (NaNO2/HCl) CH3-NH-CH3 + HNO2 CH3-N-CH3 + H2O N-nitrosodimethyl amine C- Tertiary Amines doesn’t react with nitrous acid Hinsberg Test: unknown amine + benzenesulfonyl chloride, KOH (aq) Reacts to produce a clear solution and then: a- gives a ppt upon acidification primary amine. b-Reacts to produce a ppt secondary amine. c- Doesn’t react tertiary amine. HINSBERG’STEST :(Action of benzene sulphonyl chloride) • 1 amine: N-alkylbenzene sulphonamide is formed, which is soluble in alkali RNH2 + KOH SO2Cl → SO2-NK-R soluble salt. SO2 NHR + HCl -2 amine: N,N-dialkyl benzene sulphonamide is formed, which is insoluble in alkali R2NH + SO2Cl SO2NR2 KOH insoluble salt 3 Amine doesn’t react with benzenesuphonyl chloride S