Physical Organic Chemistry
Physical Organic Chemistry CHEM 6311
University of Memphis
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Date Created: 10/23/15
Chem 6311 Warren CH16 page 1 1 Disconnection approach T50 T50 j2X 2A f gt HOZC O O HO HO 11 Analysis 111 recognize functional groups in target molecule 112 disconnect by methods corresponding to reliable reactions 113 repeat until starting materials obtained 114 disconnect at ketal 1141 ketal comes from ketone and 2 alcohols 1142 5 member ring from vicinal alcohols 12 00 bonds to build skeleton 121 disconnect at activating groups 122 enolates from carbonyl source nucleophile 123 react with alkylating reagent sink electrophile 124 ketone is commercially available 13 make diol oxidation of double bond 14 form tosylate from alcohol and reduce carboxylic acid 15 Synthesis write out plan with reagents 16 include actual reagents 17 actual synthesis created epoxide can open and react like diol with ketones o HO TsO Jk Tscl HOZC gt gt I base SnCl4 gt gt O RCO3H O 18 form CC bond before oxidation to avoid reaction with epoxide 0 o 19 Essential background knowledge for retrosynthetic analysis 191 understand reaction mechanisms Chem 6311 Warren CH16 page 2 192 knowledge of reliable reactions 193 known starting materials 194 understand stereochemistry 110 Disconnection is reverse of synthesis 1101 Benzocaine can be made by disconnection of C0 bond of ester 0 0 QB OH HOEt gt HQN HQN 111 amino and carboxylic acid groups are not easily disconnected 112 functional group interconversion 1121 carboxylic acid from alkyl group oxidation 1122 amino for reduction ofnitro group 0 0 CH3 CH3 OH OH gt gt HEN OQN 02N 1123 last step is CN disconnection o o 0 CH3 CH3 OH 0H t oer HN03 KMno4 H2 HOEtH gt gt gt gt H2804 OQN OQN Pdv C HQN HQN 113 Synthon idealized reagent 1131 disconnect acyl as nucleophile or electrophile match with other reagent 2 3 o B 0 gt E L39 l WOO 6K MeOO l s e e o o M O gt O Bk E MEDO cl MeO reagents synthons 114 FreidelCrafts reagents common CC bond formation via electrophile 1141 FreidelCrafts alkylation subject to rearrangementmultiple additions Chem 6311 Warren CH16 page 3 O 0 CI ZnHg CI lt lt lt gt HCI AlCIs AIC3 115 avoid both via acylation product is deactivated acylium does not rearrange easily 116 chloromethyl standard method single carbon addition to arene Jo ROH H Alkene H Aromatic Functional group interconversion X gt Y Chem 6311 Warren CH16 page 4 CCI3 CF3 SbF5 CN 002H HO39 H20 117 Nucleophilic reagents 1171 no RO synthon for oxygen disconnection RO39 needs arene synthon 1172 diazonium salt useful as an electrophilic arene 9 N02 NH2 N2 OH HNo H Pt 3gt L NaN02 H20 H2804 HCI R R R R R 1173 analysis below OH group is introduced via diazonium OH NH2 NH2 NO2 1 0 O O Me Br Me Br Me Me Me 1174 reduction of N02 precedes bromination to ensure on ho substitution 1175 acylation ofamine keeps electrophiles from attacking N during substitutions No2 NH2 0 HNo3 SnHC CI gt gt gt HSO Me 2 4 Me Me H o NH2 OH O f 1 BrzyHOAo NaNO2 H2SO4 gt gt Me 2 HZONaOH Me Br 2H2O Me Br 1176 other nucleophilic substitutions RO ROH CN CuCN Cl CuCl Br CuBr l KI Ar ArH H H3P02 or EtOHH 118 Orthopara product mixtures are common and must be separated l Strategy I use order of disconnection to control regiochemistry 21 Guidline 1 determined which groups direct to other substituents Chem 6311 Warren CH16 page 5 0 r8 0 OAK 211 synthesis in first step creates meta product not ortho 22 Guideline 2 Disconnect most electronegative substituents early 221 deactivation ofring problematic 23 Guidelines 34 evaluate directing effect of functional group interchange 231 R gt COzH CCI3 or CF3 op gt m 232 NH2 gt OR Cl Br I op gt op 233 N02 gt NH2 m gt op 234 adding groups while amine present easier Why 24 Guideline 5 a pair of meta op directors set up with amino group and remove amino H2N OH 241 Try preparing CO 25 Guideline 67 select starting material with dif cult substituents in place 26 Guideline 8 Avoid unwanted side reactions 261 oxidation of aldehydes and chloromethyl during nitration 262 add sensitive groups later or protect oer CHQCI oer oer CHQCI oer N s Chem 6311 Warren CH16 A page 6 27 Guideline 9 use order of substitution to block unwanted op substituents quot39C6H13 OH OH OH Z quot39C6H13 7 quot39C6H13 OH OH OH 02N megCE 2 02N No2 28 Review orthopara versus meta directors examples of one group disconnection 31 aromatics easy disconnect at ring 32 heteroatom disconnection 321 examples ethers and azide 322 reactions have anionic hetero atom synthon and carbocation synthon 33 carboxylic acid derivatives 331 disconnect between acyl and heteroatom 332 requires more reactive derivative 0 0 2 2 333 other derivatives made from acid chloride 334 acid chloride prepared from acid and SOCI2 or PCI5 34 alcohols convert to halides tosylates mesylates RCl I I RBr RO Q Ro CFa O O Rquot ROTs ROMes 35 RX halides tosylates and mesylates react with virtually all nucleophiles ROR39 RSH RSR39 R X 392 ROH gtgtO RNH2 E RCN ROH RN02 RNHNHCONH2 RN3 Chem 6311 Warren CH16 page 7 36 analyze and synthesize the following compound single disconnection W 37 avoid competing elimination reactions analyze the following compound FhO 4 Strategy ll use differences in reactivity CH5 single disconnection 41 Guideline 1 more reactive group prevails O OH O OH I o 0 HO O H 42 Guideline 2 first product must be less reactive than starting material 0 o F hOUCI PhOH CI1CI 43 Guideline 3 use protecting group when least reactive group must react 431 amino group more reactive than carboxylate 432 protection and deprotection ofamino group allows selective interconversion of carboxylate example of protectiondeprotection o R pyridine O R up gt 2K PhO CI HZN COZH PhO u HZOOH COZH 433 Sodium thiolate formed from sodium sulfide and alkyl bromide just as reactive as sodium sul de 434 dialkyl sulfide forms as well Chem 6311 Warren CH16 page 8 NaSH RBr RBr NaSH gtRSH NaBr gt RSNa HZS gt RSR NaBr 435 thiourea adds once hydrolysis yields monosubstitution alkyl thiol 8x 5 SR 0 k RBr gt 6 9 E X RSH NH H20 2 H2N NH2 H2N H2N NH2 436 Analyze sulfide synthesis Ph SCH20H2NMe2 Bus 44 Guideline 4 second identical functional group may have different reactivity 441 NaSH is weak reducing agent after electron rich amino group remaining N02 less reactive harder to reduce no longer identical compare 13dinitropropane N02 NH2 NaSH MeOH N02 N02 45 Guideline 5 limiting reagent can limit reaction of identical groups 451 yields are not usually good tomene HOMOH Na gt Ho 0N3 NaO ONa HO OH 62 19 19 EtBr gt HO CE 62 46 Guideline 6 Reaction of coupled identical groups can make one group unreactive o o O OH O O MeOH OMe A l gt O gt OH OH O o O O 47 Guideline 7 Different groups of similar reactivity are not selective OH Chem 6311 Warren CH16 page 9 OH OH 1 base OH OMe OMe OH M M M 2 Mel 5 Two group CX disconnections CH6 51 disconnection ofone group affects another group disconnection 52 11 difunctional groups 521 acetals and ketals O H0 533 w y H In my ma al39l39a L a 6am avk 1 J 1 V 523 cyanohydrin falls in this category OH OH 0N 0 NH N GA 2 Z d 2 j Nac OH N OH O N H 0 H2 Pto2 NH Nac gt 2 524 amino acids Strecker Synthesis R R k k RCHO NH3 HCN HZN COZH HZN CN 525 occhloroethers 5251 addition of alcohol and chloride 5252 MEM 2methoxyethoxymethylchloride chloromethylbenzene OH MaoVOVC39 2 Mac CH20 HCI 53 12difunctional groups often related to 12diol epoxides are useful 0 Nu n e 0 OH OH Do 2 Nu V CI NU 531 analysis two 12 difunctional groups Chem 6311 Warren CH16 page 10 OH F H gt2 we co to on 11on a to 532 asymmetric epoxides are very useful OH OH PO lo Ph 2 W Ph 533 ocsubstituted carbonyl how do you prepare ochalocarbonyl N T Z LCI o o f 81 16 54 13 difunctional groups 541 Michael Addition show rst step of synthesis ltgt oNH2 2 O OVC N Z O OH CN 542 Acrylic acid derivatives can add HX R R HX I O Xc o 543 R H OR OH NR2 X 0 Br