Honors Organic Chemistry 337
Honors Organic Chemistry 337
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Date Created: 05/16/14
Benzyne Chemistry Key Points 1 There are better ways to do this synthesis lrxLIal339 ll 2 Aryl halides can go through an eliminationaddition mechanism to produce a benzyne intermediate that can react with a nucleophile addition 3 Benzyne is a high energy intermediate P Bl p i 4 Proof When we do isotopic tracking with C13 we get a 0 p l mixture of products consistent with a benzyne miquot HA intermediate Nu displacement happens in one of two places in benzyne a We Ve also been able to trap benzyne after deprotonation step 5 Addition to form more stable carbanion Stabilization with the electron withdrawing group closer a No resonance effects because the reactive pi bond of bnezyne is perpendicular to the pi system EiImiIl39IaliMuI1 Adhillitiinn 50 f3 Fa El s 5 G Har4H2 3 f H M NH 1 m FI i rumE1hqlaniiiIne EF3 a3F3 L H quot39 quotquot quot SH IlHE li ll 2 llquotla H2 c iii Less Etahle j aam1iJarIiiuI1 Mum Eltahle aam1iJaI1iuI1 flflme neam ihne clinargre E5 aluser to H112 Ellectrunpega iwe IiI391quotI lIIamxrIrIe1 l1yil gr39 mIr Mechanism 1 Mechanism Abstract ortho proton w base elimination addition of nucleophile MIanzlhmmisln I A MECHANISM FER THE EEACTIGN The ermyne Eliminm39linn Additinm1 Elimi rj1a139ion Reactions of Benzyne NormaI AdditionElimination NaOH heat phenol NaNH2 aniline Diels Alder Misc Reaction AzaCopeMannich Reaction 1 Point of this was to synthesize previously learned concepts together Top one Mannieh cyclizatiln BEEFquot I39iIquotIE l R1 na nannznll l rearranement mz e Mechanism Addition to imine addition of CN then hydrolysis dlulnilmg the 5treiker 5quotl39I III IE5llr5 A THE P B Fu IrI11atian arfalm m Ami39nu Imitrile D lI hli EM 5 ll r H 4 V A d 5 EN Q Hquot R Flquot KjJ r1H3 H MH3 IHJIr1H2 H tmH W H l NH quot FllhlAH2 Immemmlletrllillar prmtnm llmime uPall39I1iI39I 1iFiIil iIlE Making Chirally Pure Material 1 We can make a chirally pure material by making the diastereomer from the racemic mixture by adding a chiral reagent 2 The chiral reagent prefers one enantiomer and produces that one in excess We can then separate 3 Specifically in this example we make a diasteretopic ester to resolve the enantiomers gr 3 mH 5 Asymmetrical Catalytic Hydrogenation Key Points 1 We turn the enamine into a chiral center by adding in hydrogen asymmetrically across the double bond 2 This is done by adding chiral ligands on rhodium 3 COD has double bonds coordinated by rhodium and DIPAMP forms a chiral phosphorous complex with rhodium 4 Rhodium loses coordination with one of the ligands and coordinates the alkene a Two diastereomeric transition states one from above or below b Rhodium delivers H2 across the double bond 5 One face is more favorable than the other so we generate one enantiomer Greater 99 enantiomeric excess l5ymmetri a Eyntfhesis of LDEIF 39 I Haul T A ECECIH H313 e P Ht1unm N 1R Fl ITIIH FljlEIII 0j PIGDDquotElFfI TI n1 393E yield CI OQ OQ na vIIarI39ii anr1na IquotiEr1azrvvaI I 39I 39JDlP 39IF EDD nlj hirszl ligand for medium 15G3ann ta iaunna 5ymmEfri E y39ntth e5is of 5 Hapraxeni EH2 ma Wa Ha2 H3 HIEIEIH A I Hag K S Haprmnan an aniiinfaII39n1n39n1 i rr zagnanij J i J EiT H29 nEuIHaElFquot H39I39lEI aFquot r5JIquot 5iF39 sand l 139IJI39JI aFquot are nhirezl f alas aaa fiin 251293 In this example we use the ligands as catalysts The napthyl rings are not planar either one ring is staggered up or down which makes them enantiomers There is no equilibration so we can use them as chiral ligands They are atropisomers Peptide Synthesis Main Points 1 Problem When there is an acid and amino group in the same molecule amino acid after activation of CA into acid chloride that molecule can react with itself a Example Want to make AG but we also get AA I I I I I 39 I J i39quot I r E lHaNtqT 1apcIE E HD Ha WH L ijjU 2Hr1LJ1 H u t ill iii a E J p G K L H E ml3 31J N 1 H3 L rl H39LD K iem H H i mr 2 Solution Use a protecting group on the amino group to prevent it from reacting with another acid chloride a We also want this protecting group to easily come off after making the amide linkage El 5 a quot39 EI IIfll ohlumfunma ee QFuunremgilr1iIeilh3r uquotll1fnnn1ate Exam Ies o Protectin Grou s We discussed BOC 1 BOC is an acid labile protecting group stable to all conditions of peptide synthesis and we can take it off with tri ouroaceticacid TFA IEFEE39uIF39 If ftlD 39 Eon Gmup Q Anunn J i D M G H hr1 7 gr 0 N H Ml2 l Fl 3m l H Ema 2l139i lr39r IruIi1rlsIireat1i1ntiLa1e KS ea f 9H g lt Ilii Hntkpmteaoiled i lliflre amiit amid 5 E JHEH nrEFI3JEZ2H in d 2 I2N Fquoti Example Reaction 1 Start with AA 2 Add to the protected and activated amine 3 Now we cannot have selfattack because the carboxyl is not activated in the first molecule 4 In the second molecule we cannot have selfattak because the NH2 is protected Only one way to attack BOC Application 1 Protect amine and use another amino acid that is also protected OMe to attack N attacks carbonyl C a OMe so we don t get selfattack with another one of the same AA c viii r A g i fa quot f L M in LI SW3 uquot E3 Makin TriPe tide Exam le 1 After making the dipeptide we need to first remove BOC with TFA so that the amine terminal is free to attack again 2 Then we add base bicarbonate to deprotonate NH3 acidic conditions and make NH2 a good NP 3 Let the NH2 attack another protected AA with a LG and we get a tripeptide 4 Whenever we re done add H30 to hydrolyze the OMe L FL Each O P Y s Y 7 H H Mlij H N O l l i E IJl E4 IS I L 5 Each l 39 jEgamp gt W FMOC Application 1 Steps Same as the BOC except we use PiP to remove the FMOC a Attack with NH2 on the protected AA PiP to remove FMOC add protected AA rinse and repeat Q lcj all v Pm pQ pQ pQ 1 Merrifield Variation 1 Problem with Methyl Ester Whenever we try to rinse purify with a methyl ester protecting group it runs the risk of washing away our product 2 Solution Use an insoluble polymer bead so we have a direct covalent bond If we wash the solution then we won t lose product This bead is a P directly connected to the O of the ester takes the place of Me 3 PIP and TFA remove the protecting group and readies for further NH2 attack Extend AA chain 4 Purpose of Washing Washing simply removes leftover reagents from the previous step It comes after washing Example Removing the Link 1 What we use for the linker dictates whether we use BOC or FMOC and whether we need to protect the side chains 8q p Q r E J l ll G IL bPLP LD pg 2 Sometimes we need to use two different PG so that only one side can attack render the other one unable to attack so we discriminate a Example Lysine would require two different PG or else we d end up releasing two NH2 groups IIquot Nl M11 Example with TWO PGs 1 We add in BOC as a PG in step 4 BOC is only acidlabile so future PiP will NOT remove the BOC PG Therefore only one amine gets free to attack a Prevents multiple possible NP 2 At the end we can add TFA which gets rid of both the BOC PG AND the linkage phenyl group 3 Driving Force a We get a benzylic linker carbocation which is stable gFH bV JFNDLJ t JLquotEL l39 m39L V quot d s W3 HP J33Wu 3 b D it g llWh b L Vi Id 39quotJ W llL k N vq q is W p u z wmJV xF4 wh D H ma K 4 DA W 1 K N We 1 L a S qm Bi as J TFA 1315 r y BOC Example Synthesis 1 We use a benzene ring as the linkage between the carboxy terminal and the bead a Can add on using SN2 reaction with benzyl chloride 2 This way when we use TFA it will not cleave the peptide off the bead because the benzyllic carbocation is relatively unstable compared to attaching EDGs on the ring 3 CBZ Side Chain Protecting Group Since we have an amine oating around in lysine we add a protecting group to prevent 0 R H H that side chain from attacking a We keep CBZ on the lysine until the Very end b We can take off CBZ with to take off both the CBZ AND the linker phenyl group strong enough to protonate and break the C0 bond EIEI Mechanism for Releasing these groups Linker Groups 1 This is created Via an SN2 reaction with the chloride 2 After we create the linker we can add our first amino acid that is protected with FMOC amine end and activated on the carboxy end will discuss later what we use 3 Add PiP to remove FMOC to free the amine for further attack NJ J Fm Zj w Hr Ila pinata L CA1 h DH 3 lquotquotJquotP it 3 A 5 IUELF quot VH 4 In the last step add TFA to remove the Wang Linker a Key Principle The Wang linker is good because we can selectively remove the wang linker and any side chain protecting groups with TFA CFSCDEH J o e l 393i H2N JNB1OH H l RE E3 removal of Wang resin Removal of Side Chains Protectors Removal of Carbocation with Scavengers 1 Notice that we get carbocations oating around as byproducts We currently have electron rich side chains that can react with the carbocations so we have scavengers in the TFA to get rid of the carbocations a Examples silicon TIS donates a hydride forms a more stable carbocation that does not react sulfur attacks as a nucleophile anisole does an EAS that outcompetes the reaction that would occur within the side chains rm D Activating Carboxyl Group Add Things to CTerminus 1 Why do we not use SOCl2 a First we need to activate because CA and amine will not react by itself b We get racemization if we use SOCl2 to activate the CA Q AL 3 wuaH ELK i u E r rl1L 1ILsNpLL an Ah FL r39M391 a 2 Solution We use a mixture of DIC HOBt and new amine to prevent racemization DIC p q o 0Jr A1 Purpose of DIC Makes the oxygen on the CA a better leaving group substitute for acyl chloride HOBt Purpose of HOBt Supresses intermolecular cyclization It is a good nucleophile alpha effect that prevents formation of unwanted product Overall Reaction We create our desired attachment to the CA end 3 Normally we have the activated amine end attacking this carbonyl that is now activated ru t 5 F LI J L JI h Jr h L g rJb IN C 0 h 7 quot Eh H4 B 133 Pe Mechanism for DIC Attachment Example uses DCC but same idea Len an LED DY D H1 u ELL Ll Fl Lejan jn D nu d 54 L lb 2 39 A l H P 7 E H r J HH 5quot w IE 1 E U U ucHf w W H in14 Problem of Racemization wuc mi Cl 1 Five membered ring favorable 2 After we form this five membered ring we can get racemization because deprotonation will form the aromatic 6 e system 3 The nucleophile amine can still add in to this carbonyl though forming a racemized product 4 Using HOBT suppresses this reaction because it is a better nucleophile alpha effect It leads to our desired product after addition 530 Example Synthesis with all steps 1 Protect with FMOC on one leave CA open we will activate it with HOBT and DIC 2 Make the ester to protect the carboxylate 3 Note free AA is a zwitterion amine protonated more basic and CA deprotonated more acidic A mE Lou V irJ L E A S Elf R 3 Wr2l 3JLlH 4 lli D Ha Hjlm rffquot lof p Er Another step by step example 1 Once we have the wang linker in place add in FMOC protected amine with DIC and HOBT a This activates CA and adds the first AA in 2 Add PiP to remove the FMOC protected amine excess to drive the reaction forward 3 Then add in excess FMOC protected AA with DIC and HOBT to activate CA and add in our new AA 4 Repeat for as many AA we need to add PiP FMOCAA 5 Finally add TFA scavengers TIS anisole to take off protecting groups and wang linker a Scavengers make sure that we quench carbocations because side chains can react with carbocations ti if tE quot L1 TFrlstun qxf7I 539 E rl 54 rarIu J H Making CTerminal Amide 1 Linker Use Rink amide linker 2 FMOCprotected amine DIC HOBT activate CA and allow growing Rink amid chain amine to attack 3 Why we make amide instead of CA 4 After each step use PiP to remove FMOC 5 Ecleavage for last step to get our peptide Note that when we cleave we end with an amide instead of a carboxy Ribosomes and Peptide Synthesis T I rzv mrg paphzle chain 1I1IjIfl ilzgg NEE Lii39I vv H2uu i3939 ii39 I H2i39iquotIiIquotl39I39 quot39I39391Zl f an in39npl5 ERMA quotsLJ LquotVLxquotLIquot Lfquot1f iflJquotTL39 L39Ll39L Z Measa igar a i e39iieEgmtesi5 1 Amino Acid tRNA s nthetase enz me facilitates addition of ATP which activates the AA serves as our DICHOBT combination 2 AA tRNA Synthetase Enzyme then this enzyme adds on the activated ester onto the tRNA H1 Eryn quot 4 5 H J dag an 9 WE i N U 5 a Reaction is downhill because we go from activated ester to ester and the EWGs on the ring stabilize 3 tRNA and mRNA each tRNA attaches to an mRNA the mRNA tells what tRNA to come by and bring what AA 4 Mechanism of attachment quotC39 V i 3 quot 0 D E 4 Mechanism of detachment Stop codon releases the final amino acid to make the C terminus carboxylate Load unnatural amino acid 1 Amber suppression stop codon artificial TRNA that uses this stop codon so the peptide keeps on growing past the stop codo Enzyme needed to put this AA onto this artifcla TRNA 62 Unnatural AA Chemistry ESL 1 jullgg p 1 We use a codon attached to the tRNA that does not recognize natural K 0 B amino acids We can use stop codons because they naturally do not recognize tRNA allows peptide to leave L E39 quotM 53 fl 2 Amber Suppression Codon Every time we pass the amber 1 suppression codon on the mRNA a tRNA with the unnatural AA r V 339 adds 1n U 3 Attaching Large Peptides Together BALE 1 We can make 80 AA chains with solid phase FMOC chemistry 3 3 2 Idea 1 We can use linkers that release in mild conditions acetic acid so that we do not cleave PGs PGs require stronger acid TFA to cleave a Driving Force After cleaving the linker we are left with an aromatic carbocation in one case In the other case we have stabilizing EDG to stabilize the carbocation Adding acetic acid yields the following products 4353 lLHJ gt mi a 3 We now have two protected AAs that we can attach together NH2 and COOH a Problem Usually we have possibility for oxazalone formation after adding HOBT and DIC which causes racemization of the product However this process is usually slow because we have a carbamate with an oxygen inductively pulling away electrons so that the reaction of O attacking is SLOW i In our current situation we have a carbon next door instead of an oxygen therefore we get higher rates of racemization because more oxazalone formation occurs iiquot ET VS NITROGEN coordinatesTIES UP the carbonyl so that the 0 can t efficiently share resonance in Solution Native Chemistr Li ation 1 Use FMOC peptide synthesis to make our 80 AA chain 2 Thioester Exchange We use a Cterminal thioester and attack with a Nterminal cysteine a We no longer get racemization because we do not get oxazalone formation The thioester is not a reactive electrophile b In contrast the cysteine attack is much faster one sulfur exchange for another i Reason Two sulfurs are polarizable and can easily align themselves such that the reaction goes faster than the oxazalone formation outcompetes it Make this neater 64 Analyze proteins with SDSPAGE how big are they 1 Protein SDS HJEquot quot 2 Detergent polar and nonpolar ends We make polar groups face water and lipid chains are inside 3 Denatures protein unfolds the protein a Lipid chains coat the protein from the SDS detergent b One SDS per amino acid c So if we have 300 amino acids we need 300 SDS molecules s 1 PAGE Run current through gel 2 Load protein in well i Coat with negative charge so the charge is pulled to the side and repelled from negative end ii Rate of migration 1 size inversely prop to size 3 Use molecular weight ladder to show how big the AA is 4 Visualize Dyes a Highly conjugated aromatic ring b Stain gel with dye the dye sticks to the protein blue protein band Polyacrylimide 1 00 persulfate Radical initiator 2 Ends up on the alhpha position stabilized by the carbonyl CO 9 1139 r I l I H E H H L 3 a D 4quot quotNquotquotl Vljr 2 II D i U D 1 FJHIE 5 l D quotg 39 ll 5 1 Links chains together it rmp To make more sturdy we add cross linkers Bisacrylmide C3 K 9 L F L 39 0 W H Deducing Sequence of AA 1 Example 300 AA sequence a Edman Degradation 2 Nh2 attack of carbon 4 15 FL WJLM Mr 1 Cyclic product like oxazalone 1 We re going to cleave the peptide bond E39 3939 39j Ll K 9 Hqizb 2 W mmag FA H H A Cleave off the last amino acid Now we form something more stable from the right ring Iquot H A W at Protein use N terminus and act with the thiocyanate make urea add TFA for intramolecular S attack CO five membered ring to cleave off last AA HClH20 to rearrange Then run on HPLC chromatography 1 There are standards and we can see that we had alanine retention times Peak corresponds to Ala 2 300 amino acid peptide we know what the Nterminus is We still have the 298 AA so we can add the phenyl thiocyanate again release another AA Limit only can do for 100 AA Lysine Problem Mass Spectrometry 1 Soft Ionization Methods a Allows use to analyze proteins coax into gas phase without breaking the molecule apart b Put large molecules in gas phase without fragmentation i Fenn electrospray TanakaMALDI 1 Vaporize to remove water repulse force without water causes ionization into the gas phase a Lower pH so everything is protonated or neutral b Strip away the counterion by removing water leave with a blob of charge that ies off c Change environment so the molecules absorb low energy 2 MALDI a Dissolve protein in matrix deposit solution protein on a surface that dries b Add laser and it sublimates the mixture c Sublimating 9 lose counterions 9 left with protein in gas phase Protein in gas phase mild conditions Now we can run a charge through a vacuum and take the proteins and pull to the other end 1 Inversely proportional to mass 2 Smaller moves faster through tube We can deduce exact mass by seeing when it moves to the end of the tube Determining Sequence 1 Take protein and add protease enzyme that cleaves proteins into small peptides 2 Take peptides and get exact mass using MALDI or electrospray 3 Sequence 2D MS 1st dimension ion of the AA then take the ion and put energy to fragment the peptide Backbone fragmentation is most common 4 Take all the pieces and move backwards
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