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Functional Group Interconversion by Nucleophilic Substitution.

Outline. Alcohols to Alkylating AgentsSulfonate EstersHalidesIntro. Of Functional Groups at Saturated CarbonSolvent effects (Nudity)NitrilesAzidesOxygen NucleophilesNitrogen NucleophilesSulfurPhosphorus. Outline Continued. Cleavage of C-O bonds in ethers and estersInterconversion of CO-X

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Functional Group Interconversion by Nucleophilic Substitution.

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    1. Functional Group Interconversion by Nucleophilic Substitution. Chapter 3

    2. Outline Alcohols to Alkylating Agents Sulfonate Esters Halides Intro. Of Functional Groups at Saturated Carbon Solvent effects (Nudity) Nitriles Azides Oxygen Nucleophiles Nitrogen Nucleophiles Sulfur Phosphorus

    3. Outline Continued Cleavage of C-O bonds in ethers and esters Interconversion of CO-X Derivatives Prep. For Acylation CO-halide Prep for Esters Prep for Amides Problems: 1, 4, & 5

    4. Conversion of Alcohols to Alkylating Agents Sulfonate Esters Toluenesulfonate (tosylate) Me-Ph-SO2- From Tosyl-Cl, needs base to buffer Methanesulfonate (mesylate) Me-SO2- From Mes-Cl Often trifluoroderivative, better leaving group. CF3-SO2-Cl All react with alcohols Need base to buffer and aprotic solvents

    5. Thionyl Chloride (SOCl2) Through chlorosulfite RO-SO-Cl Inversion of configuration SN2 Xanthate ROH + Base (NaH) + CS2 + Me-I RO-CS-CMe then SO2Cl2 to R-Cl Retention of config., two SN2 Xanthates big in cellulose chemistry. Conversion of Alcohols to Alkylating Agents - Halides

    6. Conversion of Alcohols to Alkylating Agents Halides II From Phosphate esters Some rearrangement Must be an acid stabile compound Ph3P + CCl4 to give Ph3P+CCl3 Cl- Forms Phosphite esters and Cl- attacks

    7. Examples

    9. Substitution General Solvent effects Leaving group reactivity RSO3- > I- > Br- > Cl- Hydrocarbons, halogenated Hydrocarbons, and ethers unsuitable Acetone and MeCN fair DMSO, DMF, HMPA and alcohols better suited Phase Transfer Quaternary ammonium salts; 2 liquid phases Crown for nudity, look over reference 32 in book

    10. Cleavage of C-O bond in Ethers and Esters HX, X= I, Br, Cl, F blunt force where milder conditions needed Usually activation to a C-X bond then substitution Examples 1-3 in Scheme 3.2 for CN substitutions Examples 4-7 for Azides (NaN3) Examples 8 & 9 Amine Example 10, Oxygen alkylation from Enamine Williamson ether synthesis for 13-16 Diazoalkanes for fun, #17. Carboxylates as the nucleophile 18-20

    11. Scheme 3.2 #s 1-3

    14. Hydrolysis

    15. Ethers by Base Cata. Alkylation

    16. Esterfication

    17. Phosphorus and Sulfur

    18. Kaboom!!!

    19. Carboxylic Acid Derivatives SOCl2 with RCO-OH to RCO-Cl RCO-Cl Reacts with all Nucleophiles to give Derivatives RNH2, RRNH, RCO-O-OCR, ROH, RSH, RSeH, etc. Cleavages: Ethers to alcohols BBr3, BF3, BF3Et2O, Me3SiI, and rest in Scheme 3.3 Esters to other esters Me3SiCl/NaI + RCO-OR to silyl ester

    21. To Acylation Compounds Formation of RCO-Cl (Br) Highly reactive to form all RCO-Z compounds Acyl-pyridinum highly reactive Enhances rate As well as 4-N,N-dimethylaminopyridine Increases nucleophilicity and bacisity Enhances rate 104 3 and hindered alcohols accomplished Anhydrides + MgBr2 + hindered amine Diisopropylethylamine 1,2,2,6,6-pentamethylpiperdine Lanthanide triflates (M(OSO2CF3)3 mild for 3 Sc, Lu, Yb

    22. More Acylation Cata. Me3Si-OSO2CF3 good for 3 Inert solvent Active agent; O-Si of the anhydride Tributyl phosphine + Anhydride via acyl phosphonium ion Bu3P+-COR Ph3P + NBS give RCO-Br Ph3P + RCO-OH gives RCO-OPPh3 Carbonyldiimiazole gives Amide + CO2 DCC(dicyclohexylcarbodiimide) used in polypeptide synthesis.

    23. Examples

    24. Esters RCO-Cl (Br also) + Alcohol choice RCO-OH + Alcohol and H+ cata. Fischer Rx. Needs drying force, Azeotrope Getter solids Anhydrides third choice

    25. Amides CO-Halide or Anhydride plus amine in water Schotten-Bauman DCC, for in situ generation CO-OH + Amine NO2-C6H4- and 2,4,5-trichloro-C6H2- for peptide activation N-hydrosuccinimides activator (also esters) BOP-Cl (picture) Aluminum Amides Al2O3 final product

    26. Problems Chapter 3 # 1, 4 & 5

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