Review Sheet Disconnection Approach - Physical Organic Chemistry | CHEM 6311, Study notes of Organic Chemistry

Download Review Sheet Disconnection Approach - Physical Organic Chemistry | CHEM 6311 and more Study notes Organic Chemistry in PDF only on Docsity! Chem 6311, Warren CH1-6 page 1 1. Disconnection approach O O HO HO O HO HO O TsO TsO HO2C 1.1.Analysis 1.1.1. recognize functional groups in target molecule 1.1.2. disconnect by methods corresponding to reliable reactions 1.1.3. repeat until starting materials obtained 1.1.4. disconnect at ketal 1.1.4.1. ketal comes from ketone and 2 alcohols 1.1.4.2. 5 member ring from vicinal alcohols 1.2.C-C bonds to build skeleton 1.2.1. disconnect at activating groups 1.2.2. enolates from carbonyl (source, nucleophile) 1.2.3. react with alkylating reagent (sink, electrophile) 1.2.4. ketone is commercially available 1.3.make diol – oxidation of double bond 1.4. form tosylate from alcohol and reduce carboxylic acid 1.5.Synthesis: write out plan with reagents 1.6. include actual reagents 1.7.actual synthesis created epoxide, can open and react like diol with ketones Chem 6311, Warren CH1-6 page 2 O O TsO HO2C LiAlH4 HO TsCl N O base O RCO3H O O SnCl4 1.8. form C-C bond before oxidation to avoid reaction with epoxide 1.9.Essential background knowledge for retrosynthetic analysis 1.9.1. understand reaction mechanisms 1.9.2. knowledge of reliable reactions 1.9.3. known starting materials 1.9.4. understand stereochemistry 1.10. Disconnection is reverse of synthesis 1.10.1. Benzocaine can be made by disconnection of C-O bond of ester O OEt H2N O OH H2N + HOEt 1.11. amino and carboxylic acid groups are not easily disconnected 1.12. functional group interconversion 1.12.1. carboxylic acid from alkyl group oxidation 1.12.2. amino for reduction of nitro group Chem 6311, Warren CH1-6 page 5 OH BrMe NH2 BrMe NH2 Me NO2 Me Me 1.17.4. reduction of NO2 precedes bromination to ensure ortho substitution 1.17.5. acylation of amine keeps electrophiles from attacking N during substitutions Me H2SO4 HNO3 Me NO2 Me NH2Sn, HCl Cl O Me H N O Me NH2 1) Br2, HOAc 2) H2O/NaOH Br Me OH Br 1) NaNO2/H2SO4 2) H2O 1.17.6. other “nucleophilic” substitutions: RO (ROH), CN (CuCN), Cl (CuCl), Br (CuBr), I (KI), Ar (ArH), H (H3PO2, or EtOH/H+) 1.18. Ortho-para product mixtures are common and must be separated 2. Strategy I: use order of disconnection to control regiochemistry 2.1.Guidline 1 : determined which groups direct to other substituents O O Br O Cl 2.1.1. synthesis in first step creates meta product not ortho 2.2.Guideline 2 : Disconnect most electronegative substituents early 2.2.1. deactivation of ring problematic Chem 6311, Warren CH1-6 page 6 2.3.Guidelines 3/4 : evaluate directing effect of functional group interchange 2.3.1. R  CO2H, CCl3, or CF3: o,p  m 2.3.2. NH2  OR, Cl, Br, I: o,p  o,p 2.3.3. NO2  NH2: m  o,p 2.3.4. adding groups while amine present easier. Why? 2.4.Guideline 5 : a pair of meta o,p directors: set up with amino group and remove amino 2.4.1. Try preparing OH CO2H H2N 2.5.Guideline 6/7 : select starting material with difficult substituents in place 2.6.Guideline 8 : Avoid unwanted side reactions 2.6.1. oxidation of aldehydes and chloromethyl during nitration 2.6.2. add sensitive groups later or protect CH2Cl OEt NO2 CH2Cl OEt OEt NO2 OEt Chem 6311, Warren CH1-6 page 7 2.7.Guideline 9 : use order of substitution to block unwanted o,p substituents OH n-C6H13 NO2O2N OH n-C6H13 OH n-C6H13 + OH OH NO2O2N OH 2.8.Review ortho,para versus meta directors 3. examples of one group disconnection 3.1.aromatics easy – disconnect at ring 3.2.heteroatom disconnection 3.2.1. examples: ethers and azide 3.2.2. reactions have anionic hetero atom synthon, and carbocation synthon 3.3. carboxylic acid derivatives 3.3.1. disconnect between acyl and heteroatom 3.3.2. requires more reactive derivative X O Y O 3.3.3. other derivatives made from acid chloride 3.3.4. acid chloride prepared from acid and SOCl2 or PCl5 3.4.alcohols convert to halides, tosylates, mesylates R Br R I R Cl R O S O O ROTs ROMes R O S O O CF3 3.5.RX = halides, tosylates and mesylates react with virtually all nucleophiles Reactivity of carboxylic acid derivative Cl O Most reactive O O O O O R NR'R" O Least reactive Chem 6311, Warren CH1-6 page 10 HO OH + Na toluene HO ONa NaO ONa HO OH + + 62% ? 19% ? 19% ? EtBr HO OEt 62% 4.6.Guideline 6 : Reaction of coupled identical groups can make one group unreactive O O O OH O O OH O O O + MeOH OMe O O OH 4.7.Guideline 7 : Different groups of similar reactivity are not selective (OH) OH OH 1) base 2) MeI OH OMe OMe OH + 5. Two group C-X disconnections (CH6) 5.1.disconnection of one group affects another group disconnection 5.2.1,1-difunctional groups 5.2.1. acetals and ketals O O HO HO O 5.2.2. more generally – two groups attached to same carbon 5.2.3. cyanohydrin falls in this category NH2 OH C NOH NaC N O NaC N O H+ C NOH H2, PtO2 NH2 OH 5.2.4. amino acids – Strecker Synthesis Chem 6311, Warren CH1-6 page 11 H2N CO2H R H2N CN R RCHO + NH3 + HCN 5.2.5. -chloroethers 5.2.5.1. addition of alcohol and chloride 5.2.5.2. MEM - 2- methoxyethoxymethylchloride, chloromethylbenzene? + CH2O + HCl MeO O Cl MeO OH 5.3.1,2-difunctional groups – often related to 1,2-diol, epoxides are useful Nu O Nu OHO Nu Cl OH = O 5.3.1. analysis – two 1,2- difunctional groups O N O Cl O N O OH O H N O O O H N O O OH H N O OH OH NH2 O + 5.3.2. asymmetric epoxides are very useful O O Ph OH OH Ph 5.3.3. -substituted carbonyl (how do you prepare -halocarbonyl?) Chem 6311, Warren CH1-6 page 12 O Nu O L O O O R Br O HO O R Br Br O OH O R Br HO 5.4.1,3 difunctional groups 5.4.1. Michael Addition (show first step of synthesis) O NH2 O C N OH C N 5.4.2. Acrylic acid derivatives can add HX 5.4.3. C O R R = H, OR, OH, NR2 HX C O R X X = Cl, Br 5.4.4. find 1,3 disconnection in the following and retrosynthesis to that step O O SPh NMe2 O OMe MeO OMe