Organic Reactions and Pharmaceuticals
Organic Reactions and Pharmaceuticals CHEM 14D
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This 61 page Class Notes was uploaded by Michael Reilly on Friday September 4, 2015. The Class Notes belongs to CHEM 14D at University of California - Los Angeles taught by Staff in Fall. Since its upload, it has received 56 views. For similar materials see /class/177987/chem-14d-university-of-california-los-angeles in Chemistry at University of California - Los Angeles.
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Date Created: 09/04/15
Carbonyl Chemistry Survey of Reactions Part Un Tepre 8 1r CHEM 14D UCLA What you know about carbonyl chemistry A carbonyl s functionality derives from the 5 and 5 on the C and 0 respectively There are 3 mechanistic fates of carbonyls Nucleophilic attack on the carbon Accept an electrophile at the oxygen usually H Form an enolate The rate of carbonyl reactions depends on their functionality things that affect the rate are resonance with X 0 electronegativity of X Whether X is a good leaving group steric effects X More rate practice Which reaction occurs faster in the following pairs of reactions Write the product of that reaction How can you make it even faster H2804 H2304 gt gt H20 H2 H20 H2304 st04 gt gt ca H20 NHz H20 Protonation revisited 11g Review As you may remember from 14C the pKa of an acid tells you how likely it is to dissociate H B lt gt H B High pKa means it is unlikely to dissociate conjugate base is strong low pKa means it is acidic conj base is weak Here are some representative pKas HgC H 48 MeO H 155 L 20 MeCOZ H 55 MezCO H 6 Protonation revisited OK so how can you use your knowledge of pKas to help with carbonyl mechanisms Example What would the product be of the following reactions Write NR for no reaction b H2804 1 equivalent OH 1A no reagent gt OH Back to an example from last lecture 0 H2804 o l e O MeOH OMe Map out all the protonation steps What are the pKas of all the species Catalysis Catalyst A reactant that alters a reaction mechanism making it faster and is regenerated in the reaction In carbonyl chemistry catalysts speed up the reaction by Enhancing reactivity of the carbonyl or nucleophile Shifting the equilibrium to favor the products Base Catalysis o NucH O 11R 39 Overa eactlon UX e QKNUC Base 9 e Nuc Step 1 Nuc H Bas BaseH o NUCG 60 o Step23 SAX G 6 Step4 X quot39 BaseH gt XH Base Why doesn t the equilibrium reaction go backwards The conversion of X to XH drives the reaction forwards Base Catalysis X G A Because NucH is not strong 3 enough Why is the reaction accelerated U Q Why do we need the base Nuc H Nuc X 9 Base BaseH e 9 Nuc is a better nucleophile than gt lt X NucH because of its formal 9 0 negative charge U Tetrahedral adduct is less likely 3 NUC to expel Nuc than NucH Biological Ph H H 6 Ph H S example 3 N HO Peptide N g hydrolysis H o Acid Catalysis Nuc H O 0 Overall Reaction 2 9 Step 1 i H B G 0H HO X HG HO XH OH Step 2 4 3 ngUC gIL XH TUC transfer NUC I Nuc Step5 glL G In this case sometimes the equilibrium goes backwards but we can push it to one side more on that later Acid Catalysis C9 NucH HO x 39 7 o OH Q Why do we need the a01d glL 4 V lruc A Because CO is not a good H gtX X NUCH enough electrophile C9 639 tra39rjsfer Why 1s the reactlon accelerated gt XH 9 COH is a better electrophile 4 Ho XH than CO because of its formal gUxNUC glLNUC XNUC positive charge Biological Ph H 9 example 3 N OH H3N Peptide I 3 H2O I hydrolysis H O H O Example You have already seen two examples of catalysis in the addition to pi bonds lecture What are they Draw out the mechanisms for both Enzyme Catalysis 0 Overall Reaction SAX Enzymatic catalysis is a little different Many mechanisms are unknown Usually catalysis occurs because an enzyme can 1 Orient molecules correctly orbital alignment 2 Stabilize the transition state 3 Bring 2 molecules together You are not responsible for the following mechamsm Biological Ph H 39139 example 3 Peptide hydrolysis NucH 0 3A Enzyme Nuc H 3 T O H2NE O H 0 Ph Chymotrypsin N 3 N H Mechanism of Peptide Cleavage by Chemotrypsin Asp 10 G N K lllllll 0 H H N Gly 193 0 R LEG H H ydrophob ic 5 Pocket H00 H N o e R W N H Chemotrypsin like most enzymes is a large polypeptide than can encompass molecules like this amide in it s reactive center lSt step is the encapsulation 211d step is the formation of a hydrogen bond stabilized tetrahedral intermediate Mechanism of Peptide Cleavage by Chemotrypsin WW E If w W 5 K H sHN 5amp9 WHW IIIIIII O O Hngw o e R W n L119 I 3rd step the am1de bond 1s O H egg cleaved to leave an ester and HO the amine RNHz leaves m 4th step H20 comes along and reforms a different tetrahedral intermediate Mechanism of Peptide Cleavage by Chemctrypsin WW N igmmHCEVMH hw lO 5th step the tetrahedral EWW intermediate collapses to leave le PIgB 39 N a carboxylic acid OIIIIIII N 0 V H R HO 6th step the acid leaves the enzyme 3 Two Fates of Carbonyl Reactions x LG 0 lt 0 GO NUC NUC Hltx EXX x 5 LG HO Nuc Nuc EXX 1 Nucleophile 2 Tetrahedral 3 Either LG is kicked out or attacks 5 side intermediate 0 accepts a proton H of CO depending on the nature of X X LG X at LG Carboxylic acid OH Aldehyde H Acyl Halide Cl Br I Ketone R Ester OR Anhydride OCOZR Amide NH2NR2 Acetals and Ketals H2804 EH Ti jJ OA jig 34 HEB ii Hemiacetal O OH H2804 EtOH if e O HO O ED 0 i E a I o O O Acetal L1kew1sehem1ketals and O ROH HO OR ROH R0 OR ketals are formed in the A Moat X Moat X same acidcatalyzed manner from ketones Q is this addition or substitution What else can we do with acetals and ketals CHZOH CHZOH CHZOH HO 0 H20 HO OH H20 HO 0 HO HO Ho OH HO HO OH 0 HO This sugar acetal dDglucopyranose is converted to another stereoisomer BDglucopyranose Via the same mechanism Acid or base can catalyze this reaction 0 0 0H s OH r p TsOHcat o 0 II 2 H20 0 n R ptoluenesulfonic acid pTsOH OH In chemical synthesis ketones are often masked as ketals to avoid reactions at the ketone This is called protection Example Aeetal and ketal synthesis is reversible Write the mechanism for this reaction 01x5 aq H2804 i Example The following reaction occurs in two steps one equivalent is added followed by another Draw the intermediate in the box Which step occurs faster HOCHZCH2OH H3PO4 cat HOCHZCH2OH H3PO4 cat A Side Note Equilibrium All of these reactions are completely reversible 0 R0 HO OR R0 R0 OR u H cat 4 H cat 4 hemiketal ketal How can we push the reaction to go to products LeChatelier s Principle Add excess amount of reactants and your equilibrium reaction will be pushed towards products In the above example if we want to go from ketone to ketal we add large amounts of alchohol ROH If we want to go backwards we add water The Grignard Reaction 0 OH 1 RMgBr Overall React1on I RMgBr is an organometallz c compound It behaves like an inorganic salt except that the anion kind of is carbon Makmg Gr1gnard reagents CH3Br CH3MgBr Methyl bromide Magnesium metal Methyl Grignard Mechanism Imines RN H2 R o N Overall Reaction gt H Hquot Mechanism R H R RNH 2 HEN oe H H N OH H3 HX transfer HX lee R 9 H R N H N FF H N H2 4 3x l HX H H Uses reductive amination one of the most proli c reactions R R o RNH2 N NaBH4 NH A Side Note Proton Transfer H R O 39 r R What does th1s mean HN OH H N O6 H flax transfer Hx H transfer is an abbreviation used to simplify mechanisms It refers to deprotonation and protonation usually by the solvent In the above example that translates to R i HR NHoe H N OH 1 19 P a H FLY sol HX transfer HX R QUEEN 39 G H solvent utdtjl l O J lllll SH X K H Another Side Note Reduction and Oxidation These two terms refer to the oxidation state of the carbon remember your 14A Easiest way to think about it Reduction occurs when a double bond becomes a single bond or a triple bond becomes a double bond or single bond OR a heteroatom N 0 etc is removed Oxidation occurs when a single bond becomes a double or triple bond OR a heteroatom is added So looking at reductive 0 RN Iquot392 N NaBH4 NH amination again U A C2 C2 C The charge on the carbon is reduced from 2 to 1 In class examples Ester Carboxylate Acetal Another Side Note Reduction and Oxidation Some carbonyl examples OH 0 NaBH 1 LAIH OH Reductlon J lt 4 39 4 J R R 2 H30 R LiAlH4 is a stronger reagent than NaBH4 so it will also reduce carboxylic acids and esters to alcohols NaBH4 will not react with those functionalities H O 1 DIBALH O k A J AI R OR39 2 H30 R Diisobutylaluminum hydride DIBALH OH PCC O 0 0 OX1dat1on k gt N cK HsC CH3 H3C CH3 H69 0 CI Pyridinium chlorochromate Note You do not need to know these mechanisms PCC Nucleophilic Substitution Reactions Occur when a leaving group is present 0 e H OH2 0 6O CH 0 HC OJ 3 H3O OH A 94 3 9k 3x Ph t OCHg ph CH3 Ph New Ph CH3 Ph CH3 H3c MgBr H3C MgBr d d d d Example Back to the Grignard reaction In this particular example substitution of OCH3 with CH2CH3 is followed by addition of CHZCH3 4153 0 gtmIU gtgtmgtmm The Nucleophile The overarching thing that makes a nucleophile good or bad is the ability of that molecule to donate electrons to an electrophile aka nucleophilicity Many factors affect nucleophilicity including Resonance Atomic size Electronegativity Inductive effects Solvent The same factors affect basicity In fact good bases make good nucleophiles and vice versa Basicity while similar to nucleophilicity is de ned at least in this context as the ability of a molecule to donate electrons to hydrogen A small catalogue of LGs Good Sulfonates OSOzR like OTs 0r OMS I N2 Methylsulfonate 5So OK MS O Br C1 COzR H20 ROH Bad OH OR F Never H R Solvent and 8N2 Nonpolar solvents Polar solvents Name Proticity Dichloromethane Structure methylene chloride Vater Hg prone Tetrahydrofuran THF Acetic acid HOAc V I Ethyl ether Methanol MeOH CH34 IEH protic Ethanol EtOH Hexane chn2 iiH prctic General things to learn about solvents How polarity relates to solvation energy How protic solvents affects ionic salts How a solvent can affect a reaction Why polar aprotic solvents are best for SNZ reactions Hzc ziiclxlcrwr3 CH3ltCH1gt4CH1 aprotic aprotic prctic aprotic aprotic A New Mechanism G 8N2 NQ zq Ffo gt Nuc R LGe zNUC 8N1 R KITG gt R Lee gt Nuc R Since the rst step involves the creation of two formal charges that step is very slow compared with the second step Hence the rate depends solely on how fast the leaving group can dissociate from the electrophile The carbocation meaning a positive charge on carbon intermediate is very important to the reaction SNl vs 8N2 How do you decide if a reaction will go through an 8N2 mechanism or an SNl Because the transition state for SNZ is less energetically costly making breaking a bond gt just breaking a bond SNZ is usually favored if it is possible For SNZ to occur you need A moderate or better nucleophile A moderate or better leaving group NOT a tertiary carbon For SNl to occur you need A moderate or better leaving group A stable carbocation intermediate 10 with resonance or better E1 vs E2 Alkyl Halide E1 E2 Methyl 1 RCHZX 2 RZCHX 3 R3CX Impossible Only if conjugated Weak bases H20 ROH andor allylic or benzylic substrates Weak bases Impossible Favored Strong bases R0 HO Strong bases Example 001 M NaOEt 80 EtOH 20 H2O O CI k 10 M NaOEt gt EtOH Maj or E2 others E1 Hofmann Elimination The use of a bulky base can change the selectivity Example x VA Vt NH3 product major minor I gtNa0tBu wk VK Hofmcmn tBuOH product minor major tBu 8N2 vs SNl vs El vs E2 Weakly Basic Unhindered Hindered Nuc l RS Strongly Basic Strongly Basic RCOO Nuc RO Nuc tBuO Methyl No Reaction 8N2 8N2 8N2 1 8N1 E1 conj 8N2 8N2 E2 2 8N1 E1 8N2 E2 E2 3 SN1E1 SN1E1 E2 E2 Poor Nuc H2O ROH Exception alert If there are no hydrogens 3 to the leaving group E2 cannot occur If possible ie not tertiary then 8N2 will happen otherwise SNl Addition to Pi Bonds Reaction Summary 53 ltj 5x1 9 a C2H20 0 aO gt quota as I Iai w x39 Ezso 0H H20 Addinon stereochemisny Mixed Addition regioselecnvity Mmkomkov Same for HX additions CHA CH3 1 Eh z xminzoz Addinon stereochemisny Syn Addition re Eioselectivity AmiMmkomdmv ozonolysls quotH Marknvnikov Addinon siercochemxsny Syn Adamo regioselecnvity None Note stereochemistry not important for Notes on Pi Bond Reactions All additions of X2 go through a cyclic halogen cation mechanism Although you are not required to draw that in the mechanism carbocation will do the rami cations are anti stereochemistry in the product no possibility of rearrangement HX and H3O additions can rearrange Watch for resonance contributors if the pi bond is conjugated Triple bonds react in much the same way but make sure you remember about tautomerization EAS Reaction Summary Reac uu Name Reactimi Example and mi 3 Elem39 ph f Brominatian 3 1 4 H E v 3 fryquot in E231 E Origin of elecrmpiiile B BIquot 23E EI B FaEr z BI FaBr quot i5lti FEEL 05 P arr 39c39n39or Chlorination 33 i 1 7 m1 CH CH 39 Origin of elecrrnp39u e i t39rre i cans km Reaction Name EAS Reaction Summary Reaction sample and origin 9 Elecn39aph Br N1trat10n Br Br A NOV aq mo3 A 1 H350 NO Origin of electi ophile 30 KHDQSH M07 11N 0H Q QVDOFL O 0 Sulfonatiou O Easily reversible 0 so H3504 aq H50 0 so Sulfanic and OH Origin of electroph e EAS Reaction Summary Reaction Name Reaclian sample and origin 0 Elem 39l lili FriedelCra s Alkylatiou xu Alcl Origin of electrophile S R CIAAIU 4 RDclgAucls Friedel ra s OCH3 OCH3 o 0 OCH3 Acylatiou A A103 4 O Oligm of electrophile o O k a 5 e a H3 cx mclg CH5 jclgmh EAS Reaction Summary Reaction Name Reaction Sample and oring 0 3quot ka Diazo Coupling OH Nayoj 3 9 r NH 8 KEN 1 a A aq HCI OH Nm 9 rnnzrlimt Directing Effects Electron donating group EDG orthopara director Includes Alkyl group benzene ring OH OR NH N39HR NR3 F C 1 Br I etc Provzrle CIrbocr on smbiim an I Icn39ve or resell Ice e eczs Electron Withdrawing group EWG meta director Includes N03 CN NR 0 CFg SOsH etc Unless there are signi cant steric factors BOTH ortho and para will be products of the reaction Otherwise it will just be para EAS Activators Deactivators Most op directors are activating groups with lone pairs OH NHZ etc are all strongly activating CH3 Ph are weakly activating halogens are the exception they are slightly deactivating m directors are deactivating When determining priority of directing effects activating groups will take precedence over deactivating groups Addition to a pi bond HBr and peroxide HOOH react to give antiMarkovnikov addition to a pi bond B Markovnikov gt HBr gt4 gt Br Ant1 MarkovnIkovz HBr gt H202 This reaction is selective to HBr other halogens like HCl won t work Resonance With Radicals Resonance with a pi bond can still happen but it looks a little different E Resonance with a neighboring atom with a lone pair CANNOT happen Why 2K The three radical mechanistic fates atom transfer happens during propagation f r Br Br Br gt gt gtL Bro radical combination happens during termination r 3 Br Br2 addition to a pi bond only with HBr H202 gt Br gtBr Radical Addition to a pi bond HBr and peroxide HOOH react to give antiMarkovnikov addition to a pi bond B Markovnikov gt HBr gt4 gt Br Ant1 Markovmkov HBr gt H202 This reaction is selective to HBr other halogens like HCl won t work What is a Carbonyl A carbonyl is a carbon double bonded to an oxygen 0 This is acetone a very common solvent and a major ingredient in things like nail polish remover It is a ketone a carbonyl with two carbons coming from the carbon 0 o o i H OH uo T Cl Aldehyde Carboxylic Ester Amide Acid Chloride Acid Methyl Ester C ioi 09 is Anhydride Carboxylate Thioester Carbonyl reactivity A carbonyl is a carbon double bonded to an oxygen 0 5 tautornerize H q 6 The carbon is less electronegative than the oxygen hence the carbon is susceptible to nucleophilic attack and the oxygen can act as a nucleophile Things that add to this effect ie electron Withdrawing groups will increase carbonyl reactivity and Vice versa Tautomerization also plays a role it allows the alpha carbon to participate in nucleophilic attack The three mechanistic fates of carbonyls 1 Nucleophilic attack on the carbon addition and substitution 30 JJJquot 9 Tetrahedral adduct k X Always produced by nucleophilic 211 71 attack at CO 5 a3 nuc j sp2 C becomes an sp3 carbon nuc 2 Accept an electrophile often a proton at the oxygen 1 Protonate on lone pair H B Rife 15kg 2 Protonate on pi bond H B quot OH Ojgt 695 H or wk 1 meg The three mechanistic fates of carbonyls Form an enolate assisted by resonance stabilization of the conjugate base 0 03 56 a A agg a gt Lek ht 6 539 Resonance hybrid Shows the at reactivity of a carbonyl at both the E oxygen and the occarbon General Mechanisms Most CO reactions involve nucleophilic attack at the carbon Often this will occur after the CO is protonated second fate to become COH when best LG X U 9 X Nucleophilic carbonyl substitution 0 5 X nucleophilic acyl substitution 511 v reversabe when nuc nuc can be a LG U0 nuc Tetrahedral HO X adduct X no LG present 921 accept proton U0 Addition OH and OR as 21 leaving group OH and OR can only leave when in a tetrahedral adduct with O39 or the product is conjugated G 0 CH 0 Electron Repulsion 9gtlt H Ph OCH3 ph Telraheaml adaud 4 out CH2 CH3 0 CH1 Comuganou H lt 4 4 OH chorgy OH H5C CH4 p quot H Ho Telraheaml adaud Comugauon acqwea Rates of carbonyl reactions When comparing addition or substitution carbonyl reactions it is useful to take some things into account 1 Resonance any possible resonance with the CO group will slow down a reaction Why Electronegatiyity an electronegatiye atom connected with a CO will speed up a reaction and Vice versa Why Leaving group a good leaving group will speed up a reaction Steric effects bulky carbonyls react slower Acetals and Ketals GigTIESJ OH quotH H2804 2 2 A09 iOA HK39 9 ii Hemiacetal O OH H2804 EtOH if e O HO O G i E 1 w S2 o O O Acetal d H2804 L1kew1sehem1ketals and O ROH HO OR ROH R0 OR ketals are formed in the A Moat X Moat X same acidcatalyzed hemiketal ketal manner from ketones Q is this addition or substitution Carbonyl Reactions Summary Imine formation reversible o RNH2 Rm gt H Hcat H Reduction and oxidation 0 1 DIBALH j R OR39 2 H30 R OH J NaBH4 j 1 LiAH4 OH lt gt J R R 2 H30 LlAl4 can also reduce esters and amides OH PCC 0 You are NOT A gt u responsible for these HsC CH3 H3C CH3 mechanisms Grignard reaction 0 OH 1 RMgBr also does subst1tut10n A Ogt a H 2 H3 R on carbonyls W LGs Carbonyl Reactions Summary Substitution reactions H o HNMe iOH 2 Cl 2 MeOH Vice low Mk Reversible substitution NMe2 O O ROH gt 3971UOH Hcat 71 OR Enols enamines and enolates are nucleophilic Cinder 0f Decreasing Nucleczpb ic reactivity ENDLATE 3 ENAMINE 22gt ENDL u I MCI u Li M x Emulate is nucleaphilic clue Ennmiue is me damelf Elml is madea ate tn nucleup h iu due m nucleuphij e due to ET Oxygenquot sma l atcmic radius El N EH3 is fl I21 Add i nual El Fm m negative charge ale trauegatire than electron density anger EN 33 fmm axygeu c39f39 DE H E tDi 5 m uucleoph icity hydmxyi gmup I Oxygen is mere E Eecta39anegatire than N 41 Sr Examples 0 O 1LDA CH3 2 CH3I 0 09 H3c kjl A th Prh K Meehamsm H3C 1 thaprh 9quot CH3 Also acceptable O l The Aldol Reaction 0 0 90H PhCHO M 6H O gt Note the LBunsaturated carbonyl this is your cue that an Aldol reaction followed by elimination has occurred Sometimes you get stuck with the alcohol form not the dehydrated product What if you want to then dehydrate U H30 h gt gt H EtOH H H
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