326: Organic Chem - Study Guide
326: Organic Chem - Study Guide 326
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This 14 page Study Guide was uploaded by Andrew Ghobrial on Wednesday October 15, 2014. The Study Guide belongs to 326 at Stony Brook University taught by Fowler in Fall. Since its upload, it has received 103 views. For similar materials see Organic Chem in Chemistry at Stony Brook University.
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Date Created: 10/15/14
CHE 326 Studv Guide Diels Alder Reaction The Diels Alder reaction is a 2n 41 cycloaddition reaction In this reaction a conjugated diene the 4n component reacts with an alkene the 2 component The alkene is usually called the dienophile The reaction was discovered by German chemists Otto Diels and Kurt Alder They received the Nobel Prize for this achievement in 1950 O 0 i An example of a Diels Alder reaction Molecular Orbital Analysis The reaction occurs because there is a perfect symmetry match between the HOMO of the diene of the LUMO of the alkene and between the HOMO of the alkene and the LUMO of the diene This perfect symmetry match allows two pairs of electrons to flow to form the two new bonds between the two molecules Here is a diagram showing these two most important MO interactions LUMO LUMO lgt I HOMO I ae e I S The full interaction diagram is shown on the left The two individual important HOMO LUMO interactions are shown on the right c or 64 Q A curved arrow mechanism can be drawn as well O It does not matter which way the arrows are drawn The simplest DielsAlder reaction is the one shown here 13butadiene plus ethene Note that the diene has to be in a scis conformation Subsitutents 200 C R closed vessel The simplest Diels Alder reaction between butadiene and ethane is not very favorable It has a very large energy of activation How can we make it more favorable We can add substituents that enhance the flow of electrons The highest energy electrons in the reaction are in the diene HOMO If we add one or more Electron Donating Groups EDG to the diene we can make in more electron rich and an even better electron donor We can also speed up the reaction by making ethene a better electron acceptor by adding Electron Withdrawing Groups EWG Here are some examples of dienes that have been made more reactive by the addition of one or more Electron Donating Groups CH3 O W L Olto ogtO NCH3 Q3 CH 3 A B C D E F The addition of simple alkyl groups will activate the diene as in compound A Substituents with oxygen or nitrogen atoms that have lone pairs are even better Cyclopentadiene E and furan F are especially good dienes because they have a forced s cis conformation Here are some examples of dieneophiles that have been made more reactive by the addition of one or more Electron Withdrawing Groups 51 o 3 N h 3 G H I J The most common electron acceptor groups are carbonyls Most any carbonyl substituent will work aldehydes ketones esters amides or acids A cyano group as shown in I is also a very good EWG Compound J is maleic anhydride It has two carbonyls pulling electrons out of the double bond making is a very powerful dienophile Note that an ester group attached via its 0 atom is a EDG as in compound C but an ester group attached via the carbonyl C atom as in H is an EWG Don t get these two confused Stereochemistry The stereochemistry of the Diels Alder reaction is complicated but the reaction is very powerful because the stereo chemistry is well understood and predictable Stereochemistry of the Dienophile The stereochemistry at the two carbons of the dienophile is conserved in the Diels Alder reaction If two groups are trans in the alkene then they will still be trans in the cyclohexene ring If two groups are cis in the alkene then they will still be cis in the cyclohexene ring This is an absolute rule and never violated Stereochemistry must match at these two carbons Stereochemistry of the Diene The stereo chemistry of the diene is confusing because in its more stable form a diene will exist in the strans form To react the diene has to rotate into the scis form One has to be very careful to keep track of the positions of the substituents m C m m t WHKt t t c m c c strans scis The six substitution sites have been labeled as follows The tsubstituents are on the 1 and 4 carbon atoms and are trans to the other double bond The c substituents are on the 1 and 4 carbon atoms are cis to the other double bond The m substituents are on the middle carbons 2 and 3 t C When the reaction occurs the m substituents end up on the double of the cyclohexene The tsites will be cis to each other on one side of the ring while the c sites will be cis to each other on the other side of the ring In many cases the c sites will simply be hydrogen atoms This is because of the fact that you can not form the scis conformation if the c substituents are large The reaction will work with one small c group like a methyl But with two methyl groups it will be very slow m m Major steric problems can occur here t t 9 The reaction also works very well if you bridge the two c positions to form ring t t t t t O t Good dienes locked into the scis position m m m m m m Putting the Two Parts Together Consider the reaction given as our first example at the beginning of this Study Guide It is a typical example The dienophile is electron poor because of the carbonyl group Electron Withdrawing Group It reacts with a simple diene with one Electron Donating Group the methyl it T on 0 plus enantiomer The product of the reaction is correct as shown We get a pair of enantiomers But how would we be able to predict that this product In reality there are eight possible products as shown in the chart below How do we know which enantiomeric pair to predict f endo a Different Stereochemistry lt lt Enantiomers opposite chirality r Stereoisomers C Q0 7 exo K Different Regiochemistry lt Structural isomers f endo 9 0 9 0 o o i 0 Different Klt Stereochemistry lt Stereoisomers II K h 0 9X0 k Compounds a and e are enantiomers from achiral reactants they will be produced in equal amounts Compounds a and b are stereoisomers The products with cis substituents are called endo those with trans substituents are called exo Compounds a and c are structural isomers differing by the regiochemistry of the reaction So how do we distinguish between the four enantiomeric pairs We have to make two decisions one for the regiochemistry and one for the stereochemistry At the end of this study guide we will see how we can target a single enantiomer We will start by a look at the regiochemistry of the reaction Regiochemistry of the Diels Alder Reaction The regiochemistry of the Diels Alder reaction is determined by the patterns of electron density on the diene and the dienophile For the diene the important thing is the partial charges found on the end C1 and C4 carbons The most reactive dienes have Electron Donating Groups An Electron Donating Group will dump electron density into the diene system Where it shows up will depend upon where the EDG is located If a EDG is on Carbon 1 then O O 8 lt7 u Carbon 4 gets a G 5 partial negative charge If a EDG is on J O O lt Carbon 2 then Carbon 1 gets a partial negative charge If the EDG is on carbon 1 then a partial negative charge will show up across the diene on carbon 4 If the EDG is on carbon 2 then a partial negative charge will show up on the neighboring carbon 1 Reactive dieneophiles have Electron Withdrawing Groups EWG An EWG on carbon 1 will deplete the electron density on carbon 2 39O39 9quot If a EWG is on aw O 5 O J Carbon 1 then l J J Carbon 2 gets a 9 5 T partial positive charge The regiochemistry of the Diels Alder reaction can then easily be determined by simply matching up the charges First consider a diene with a EDG at the carbon 1 position The dienophile will approach with the EWG group next to the EDG group This is a 12 or ortho arrangement of substituents o O 539 Substituents are next to each other This is called 8 Ej IIIO g a 12 relationship or quotorthoquot 8 If the EDG group is at the two position the dienophile will flip over and we will get a 14 or para arrangement of the substituents Substituents are across the ring from each other This is called a 14 relationship or quotparaquot Substituents in the 13 or 8 l quotmetaquot position are never seen because the charges don39t line 5 l P O 5 O 86 8 O r K also was 8 Stereochemistry of the Diels Alder Reaction The stereochemistry of the Diels Alder reaction determines the position of an Electron Withdrawing Group on the dienophile relative to the substituents on the diene There are two possibilities The EWG can be cis or trans to the t positions of the diene If it is cis the geometry is called endo if it is trans the geometry is called exo t O t c O m C m m x K t C K or t C 39 m m 39 5 c m t t C strans scis endo exo To understand these phenomena we need to examine the molecular orbitals of the dienophile The dienophile in our example is actually a diene where one carbon atom has become an oxygen atom The MO structure is thus a close analogue of butadiene HOMO gtquot E l V 3 o z LUMO L lt lt HOMO A H 39 HOMO i O L Butadiene plus ethene 88 LUMO ltlt from page 1 exo The above drawing is pretty complicated but let us walk through it On the left we see the dienophile With the carbonyl added to the double bond the dienophile is itself actually a diene The four MOs of the dienophile are shown with the red orbital representing the oxygen contribution 1 gt0 But 3 en 2 one o fltgt Elt ltgt o 6 The center of the diagram shows the electron flow from the butadiene HOMO into the LUMO of ethane This is taken from the complete diagram shown on page 1 On the right side we see the HOMO of butadiene donating electrons into the LUMO or the dienophile There are two possible orientations In the top right we have the endo geometry with the EWG group of the dienophile turned inward under the diene Looking at the diagram we can see that all four atomic orbitals of the dienophile can overlap with the four atomic orbitals of the dienophile In the bottom right we have the exo geometry with the EWG group of the dienophile turned outward away from the diene This is called the exo geometry In this orientation there is no interaction with the atomic orbitals of the CO group Over all there is less possible orbital overlap This approach is less favorable than that of the endo geometry Endo wins t m t O m m m t H O O t I gt I V 39 t O H m 0 Time for some examples We now know how to determine both the regiochemistry and the stereochemistry of the Diels Alder reaction So et s look at some examples A In this reaction the diene is cyclopentadiene and the dienophile is maleic anhydride Both compounds are symmetrical so there is no regiochemistry issue The addition will be endo so the sterically least favored product is formed B In this reaction the diene is cyclopentadiene and the dienophile is an aldehyde The diene is symmetrical so there is no regiochemistry issue The addition will favor endo not exo o S3 T I I H H H O endo 9amp0 major product minor prOdUCt C In these reactions we explore the stereochemistry of the dienophile The key thing is that the stereochemistry of the dienophile is conserved A cis alkene gives a cis substituted cyclohexene A trans alkene gives a trans substituted cyclohexene O cis gives cis B l J p 0 quotCH3 K O O N H3C trans gives trans CH3 D In this reaction the diene has a EDG an ethyl group on carbon 1 The dienophile has an EWG an ester group The regiochemistry will be 12 or ortho The stereochemistry will be endo meaning the ethyl group and the ester will be cis The methyl will be trans to the ester since it was trans in the reactant Remember 12 is favored over 13 E In this reaction the diene is a cyclohexadiene with an added methyl group The dieneophile will add endo with the ketone located across the ring 14 from the methyl group Remember 14 is favored over 13 F In this reaction the diene has electron donating alkyl groups on both carbons 1 and 4 The maleic anhydride dienophile is symmetric so there is no regiochemistry issue The addition will be endo 0 0 Q lt O 0 Z I j WW IIltO Pe H o G In this reaction the diene has a EDG a methoxy at carbon 1 The dienophile has a EWG carbonyl attached to one carbon and a methyl attached to the other end with a trans geometry The product will form with the carbonyl next to the methoxy group 12 They will be mutually cis because the carbonyl directs the product endo The methyl will be trans to the carbonyl because it was trans in the original reactant 3methylcyclopent 2 enone H Here is an intramolecular example When the reaction is intramolecular it is not always possible to follow the normal rules for regiochemistry and stereochemistry The reaction shown below is a good example The reaction gives the exo product instead of the normally expected endo isomer These two ring carbons are trans so this is an exo reaction You can verify the exo geometry by looking at our example from before The carbonyl below is cis to the t groups in the endo isomer trans to the t group in the exo isomer t O m c m 6 m t t ap c quotJ T m m m strans scis endo exo I Here is another example This time endo wins CO2Me The EWG is cis to the quottquot C so this is endo isomer IlH quot39co2Me exo minor J Here is one more example from the recent chemical literature This time the reaction give equal amounts of the exo and endo isomers IMDA stands for lntraMoecuar Diels Alder The two transition states are drawn These are impossible to predict unless you are an expert Don t worry no one is going to ask you to predict one as complicated as this Electron withdrawing group activates dieneophile Electron donating group activates diene Lewis Acid Catalysis We discussed earlier the fact that an Electron Withdrawing Group on the dienophile will enhance the compounds reactivity 39 39 9quot s If a EWG is on O g O 5 O J Carbon 1 then J JW Carbon 2 gets a 9 5 C partial positive charge This effect can be made even stronger if a Lewis acid catalyst is added to the reaction Common catalysts are derivatives of boron like BF3 or Al like AICI3 Lewis Acid accepts negative F F 8ll F charge BF3 F e F B o o F e0 F 0 F 1 2H L Carbon2getsa 6 5 partial positive charge The following reaction occurs without a catalyst but the presence of the catalyst will speed up the reaction and makes the endo selectivity even more favored 39 BF3 gt m s T H Enantiomeric Selection One important feature of Lewis acid catalyzed Diels Alder reaction is the fact that it gives us a route to a single enantiomer The previous reaction actually gives two products a pair of enantiomers BF3 gt Q 5050 ratio H o H H O enantiomers If a chiral boron catalyst is used instead of BF3 then one of the enantiomers may be favored This is very similar to the action of an enzyme in a living system Chiral Catalyst gt Q7J Ratio does have to be 5050 H o H O H enantiomers 10 Here is a real example from Professor EJ Corey at Harvard University Ph 39239 Ph 6 Corey 6 0 gt owl Catawst Ratio is not 5o5o cI3sc H9 B 7J 39 EtO O EtO Corey EtO O quot tquot quotquot t 1 99 CH3 To explain the selectivity one has to look at the transition state of the reaction The following picture can be drawn The catalyst has formed a Lewis acid Lewis base complex with the dienophile Only one face to the dienophile is open so there is one favored reaction to give the predominant enantiomer Web References Follow the following links to read more about the Diels Alder reaction For Corey s Paper httppubsacsorqcqi binarticlecqiiacsat2002124i34pdfia027468hpdf This link will only work from a Stony Brook IP address 1 Y IC Q i am CllE F39l so4 mo 22 39quot E39 L Elllilw1la39lJ ulE3939i lquot39I alE r39llI3lquotJ39lli39 1J 39lJ3939fI39I31 Pli39r3 quotlt BroadSpactrum Er1antos alectlve llels iderCa1algrsls by Ehllral Eatlonln U EElEQbrEITDlldll39IEE III1 Hj39Iiru l jeu Thomas W Lee and E J Corey 139 caiitiiquota39 1quotn39aquotImiI539 ma a rI3939i39 amp a39 i ir39atr 155rs ri i39s iin539iir39i395 39J i239lie39 39r i 39 3939 R39l i39139r 33 iII39 fquoti39 7393939i 339 The Wikipedia has a nice general article easy to understand httpenwikipediaorqwikiDiels Alder reaction The Virtual Textbook of Organic Chemistry site at Michigan State University has a nice general article on the Diels Alder reaction with sample problems httpwvvwcemmsuedureuschVirtualTextaddene2htmdien3 11 Problems 1 Predict the product of each of the following Diels Alder reactions T p jO 8 w 12 2 The following compounds can be made using the Diels Alder reaction Identify the reactants b H 3C 9 O JJ c IIIICH3 CH3 LQE d COZMG CN DAfoowed by H2Pd 9 o f O CO2Me 13 3 The following compound was an intermediate compound in an attempted synthesis of the terpene 8Himachalene It was the major product of an intramolecular Diels Alder reaction Identify the reactant lntramolecular T Diels Alder Bonus problem Propose a total synthesis of the compound shown above from starting materials of five carbons or less 4 The following intramolecular Diels Alder reaction is part of the synthesis of the natural product Macquarimicin A a compound isolated from a bacterium that shows antiinflammatory activity a Four possible products are shown Choose the one with the correct stereochemistry I IIquot I u I IIquot I IIquot b The dienophile in this reaction is not directly attached to a electron withdrawing group yet it can still be considered to be activated Explain 14
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