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Aliphatic Ethers

Aliphatic Ethers. Pharmacy Student. Ethers have two alkyl groups bonded to an oxygen atom. Ethers R-O-R or R-O-R ´ C n H 2n+2 O. Ethers R-O-R or R-O-R ´ C n H 2n+2 O. Nomenclature of Ethers. Simple ethers are usually assigned common names. To do so:

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Aliphatic Ethers

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  1. Aliphatic Ethers Pharmacy Student

  2. Ethers have two alkyl groups bonded to an oxygen atom. Ethers R-O-R or R-O-R´ CnH2n+2O

  3. Ethers R-O-R or R-O-R´ CnH2n+2O

  4. 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-”.

  5. 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.

  6. 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

  7. Hydrogen bonding make ROH more soluble and have higher b.p. than ROR or RH .

  8. 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.

  9. 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.

  10. Step 1 CH3CH2-OH H+CH3CH2-OH2 -H2O CH3CH2 Step2 CH3CH2 + HO-CH2CH3 CH3CH2-O-CH2CH3 H Step 3 CH3CH2-O-CH2CH3 H+ CH3CH2-O-CH2CH3 H HSO4- diethyl ether - Williamson continuous etherification

  11. 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.

  12. Synthesis of Ethers We’ve Already Seen Ether Synthesis by Alcohol Dehydration: • 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’

  13. Williamson’s Synthesis • 1- Reaction with alkali metal (Na- K) • R OH + Na R ONa + ½ H2 • RONa + R’X ROR’ + NaX C2H5ONa + CH3Cl C2H5 O CH3

  14. Williamson Synthesis of Ethers Unsymmetrical Ethers From RONa + Halide, Sulfonate, etc. • 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

  15. Chemical Properties • Ether linkage is quite stable towards bases, oxidizing and reeducing agents. • Cleavage takes place under quite vigorous conditions as conc. Acids.

  16. 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. • HBrand 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.

  17. 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.

  18. 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.

  19. 1-Action of HI HI/ Low temp • R-O-R ROH + RI HI / High temp 2RI + H2O CH3-O-CH3 CH3OH + CH3I 2 CH3I + H2O

  20. This reaction can proceed by : • 1- SN1 or SN2. • .. H + H • R-O-R’ R-O-R’ • .. + I- • SN2 RI + R’-OH • (R is 10 or 2o ) • SN1 R+ + ROH I- RI ( R 3o)

  21. Action of PCl5: • R-O-R + PCl5 2R-Cl + POCl3 • C2H5-O-C2H5 + PCl5 2CH3CH2Cl + POCl3

  22. Thio Alcohols (Mercptants) R-SH • Thiols (R–S–H) is sulfur analogs of alcohols and • ethers, respectively Sulfur replaces oxygen

  23. Thiols • Thiols (RSH), also known as mercaptans, are sulfur analogs of alcohols • They are named with the suffix –thiol • SHgroup is called “mercapto group” (“capturer of mercury”)

  24. Methods of preparations : • Thiolsare 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

  25. 2- Heating of Alcohols with P2S5 • R-OH + P2S5 R-SH +P2O5 • CH3-OH + P2S5 CH3-SH + P2O5 • 3-Heating of Alcohols H2S at high temperature pressure, and catalyst: • R-OH + H2S R-SH +H2O

  26. 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 : • S-C2H5 • CH3CHO + 2C2H5SH HCl CH3CH + H2O • mercaptal S-C2H5

  27. N: 1s22s22px12py12pz1 Amines

  28. C－N： sp3-sp3 hybridized orbitals overlap N－H： sp3hybridized -1s orbitals overlap Structures of amines N: 1s22s22px12py12pz1 sp3-hybrid Pyramid Tertiary amines with 3 different groups: Interconversion of amine enantiomers

  29. 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 • CH3-NH2CH3-NH-CH3 NH2 -NH2aminogroup+

  30. 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

  31. Amines Amines are classified into three groups: depending on the number of carbon groups bonded to nitrogen. CH3 CH3   CH3—NH2 CH3—NH CH3—N—CH3 Primary 1° Secondary 2° Tertiary 3°

  32. NH2 NH2 CH3-CH-CH3 CH3-CH-CH-CH3 Cl 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. 1 5 3 2 4 3 6 2 1 4 3 1 2 2-propanamine 3-chloro-2-butanamine 1,6-hexanediamine

  33. CH3 CH3-N-CH2-CH3 aniline 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”. N,N-Dimethylethanamine

  34. 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 ofproducts                                                                               

  35. 2) Catalytic reduction of Alkyl cyanides ( nitriles) CH3CN H2/Ni CH3CH2NH2 (ethyl amine) 3) Hoffmann degradation reaction Of Amide

  36. 4-The Gabriel synthesis of primary amines Primary alkyl halide, SN2 Potassium salt of Phthalimide Reagent: Imide

  37. NaOH/H2O HCl /H2O CO2Na CO2H CO2H CO2Na + R-NH3Cl- + R-NH2

  38. 5- Reductive amination: Imine 1o Amine 3 2

  39. Physical properties of Amines • They have unpleasant odors (rotting fish like ammonia). • Amines solutions are basic (ammonia or died fish odor) • 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).

  40. 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).

  41. Chemical Reactions of Amines Basicityof 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

  42. 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.

  43. Common substituent groups: -NH2, -NHR, -NR2 -OH -OR -NHCOCH3 electron donating -C6H5 groups -R -H -X -CHO, -COR -SO3H electron withdrawing -COOH, -COOR groups -CN -NR3+ -NO2

  44. 1-Basicity: • CH3CH2NH2 + HCl CH3CH2NH3+Cl- • ethyl amine ethylamine hydrochloride • 2- Alkylation: H R R • R-NH2 RX R-N-R RX R-N-R R-N+-R- • R 3- Acylation: With acid chloride O O RNH2 + R’CCl RNHCR’ + HCl CH3NH2 + CH3COCl CH3NHCOCH3

  45. 4- Reaction with Nitrous Acid (To differentiation1,2,3 Amine

  46. 4- Reaction with Nitrous Acid (To differentiation1,2,3 Amine • A-Primary Amines: • RNH2 + HNO2 ROH + N2 g + H2O • C2H5NH2 + HNO2 (NaNO2/HCl)C2H5OH + N2 g. + H2O • B-Secondary Amin N= O R-NH-R’ + HNO2 (NaNO2/HCl) R-N-R’ + H2O N= O CH3-NH-CH3 + HNO2 (NaNO2/HCl) CH3-N-CH3 + H2O N-nitrosodimethyl amine C- Tertiary Amines doesn’t react with nitrous acid

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