Organic Reaction Mechanisms
Organic Reaction Mechanisms CHEM 542
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Date Created: 09/26/15
Chapter 7 Aromatic substitutions Aromaticity Aromatic compounds cyclic at structures with conjugated CC bonds According to HMO theory an aromatic molecule is one that follows Huckel s rule 4n2 nelectrons in a single ring of conjugated nbonds Aromaticity is characterized by a a delocalization resonance nbond energy that is lower than the sum ofthe energies of the component nbonds and b equalaverage bond lengths between the ring atoms rather than alternating single and double bonds a is determined from calorimetry while b is obtained from numerous spectroscopic observations and Xray diffraction NMR diatropic compounds ability to sustain a diamagnetic ring current Experimental proof of aromaticity 1 induced ring current 2 equal bond distances 3 planarity although there are spherical aromatic molecule see fullerenes 4 chemical stability 5 ability to undergo aromatic substitutions In contrast to stable aromatic molecules antiaromatic molecules 4n nelectrons in a single ring tend to be unstable and may even have diradical properties with alternating double and single ring bonds and do not display a ring current Annulenes Monocyclic completely conjugated polyenes According to the HMO the 4n2261014nelectron annulenes are aromatic while the 4n481216nelectron annulenes are antiaromatic paratropic compd a presence of paramagnetic ring current Note that according to the Huckel rule the rst pair of nelectrons goes to the norbital of the lowest energy After that the bonding orbitals are degenerate and occur in pairs of equal energy According to the Hund s rule these orbitals are filled rst with unpaired n electrons diradical structure and then paired sextet structure The degeneracy may be removed by a distortion of a molecule and the resulting loss of symmetry Annulene electronic structure I DUE Quartet Sextet arumatlc antlrarumatlc arumatlc antlraru atlc diradical diradical gt gt lt gt lt gt 4 0 B et m Lecture 23 1 Examples of annulenes Note with exception of benzene 6annulene none of the annulenes are present in the nature 76 133 K I H 1567 R u H 1346 A 1462 K 4annulene 6annulene mannulene 10annulene ZEZZE 12annulene Mlannulene 16annulene mannulene anliaromalic m 39 nonaromauc 3 isomers all non 39 aromauc NMR nonaromalic aromauc NMR dismned aromatic nonplanar quot quot39P39aquotaquot nonplanar 1 2x2 an i 1x42 4x2 anti 2x42 4X3 3 i 3x42 4x4 3an 4x42 X CH2 0 NH are planarized and are aromatic Aromaticit in char ed rin s 1 Aromatic systems with two nelectrons id be 2 Four nelectrons are generally unstable antiaromatic Q ElN cooa R R 2 ElzN OE I M e E1 Gee Egte EtOOC NElz EtOOC 8 3 Six nelectron systems aromatic and stable 9 e 9 o 1 gt o 0 4 Eight nelectron systems antiaromatic and unstable 5 Ten nelectron systems may be aromatic 10annulene nonaromatic due to its deviation from planarity NMRall hydrogens are of the alkene type Two isomers ZZZZZ ZEZZE were prepared Recent calculations suggest that the last one EZZZZ may be aromatic Examples of other aromatic systems 6 Super large systems Normal annulenes are aromatic according to the Huckel s rule 4n2 The presence of the Mobius twist and resulting phase discontinuity of the atomic orbitals would cause the reversal of the aromaticityantiaromaticity rules Lecture 23 2 Huckel orbital arra Mobius orbital array Aromatic 4n2 Aromatic 4n Antiaromatic 4n Antiaromatic 4n2 Homoaromaticity Homoaromatic systems are that contain conjugated delocalized systems that bypass one of the atoms saturated or alternatively that have a saturated atom usually carbon interrupting the nsystem H H e H H Fused rin s stems Numerous completely conjugated hydrocarbons can be derived from annulenes These fused annulenes may be represented by several resonance structures For example naphthalene 3 resonance structures may be drawn without considering Dewar forms The 12 bond has more of 00 characterthan 23 CC bond 1 1 1 Bond order length 1124 136 R 2 2 2 lt lt gt 1603 1 415R 3 3 3 4 4 4 We observe so called partial bond fixation which is typical for the reactivity of fused annulenes In the case of naphthalene we observe that 12 bond reacts more like a double bond epoxidation ozonolysis etc Note also that the major resonance contributor is the structure with a double bond at the ring fusion the rst structure Several interesting cases Acenaphthylene the additional CC has very much character of the regular CC does not contribute signi cantly to the delocalization energy Azulene the bond between two cycles has enhanced CC character Aromaticity is believed to be caused by the dipolar structure composed of the cyclopentadiene anion and the cycloheptatriene cation both aromatic In agreement is the large dipole moment of azulene 08D lBBER iii EH Similarly to azulene there are bicyclic aromates that may be stabilized by their dipolar forms Interestingly they do not have to be fused Such compounds too have large dipoles Aromaticit of heteroc cles Lecture 23 3 Conjugated heterocyclic compounds are in many cases isoelectric with the aromatic hydrocarbons Such heterocycles are aromatic stabilization by the resonance energy 1 Fivemembered ring systems containing aromatic sextet the degree of aromaticity is easily described by the resonance energy 0 o o 30043 3 o 0 Res Eng 272 454 40 E Ea E The canonical forms above also explain why pyrrole is a weak acid 2 Sixmembered systems containing aromatic sextet The nitro encontainin heteroc cles the unshared pair of electrons is not part of the aromatic sextet consequently pyridine Noxides pyridinium salts are still aromatic The same is true for pyrazine pyridazine triazine Pyranes are not aromatic break in the conjugation Pyrilium salts are aromatic and more stable than other oxonium salts Pyrazine Pyrimidine Pyridazine Pyrilium Salt Pyrans Other aromatic compounds 1 Mesoionic compounds their structure cannot be explaineddescribed by Lewis structures that do not involve a charge separation Most of them are vemembered heterocycles Example sydnones R R39 I 06 36 R e e I I RN O R N I lt gt R N N N O oo 2 The dianion of squaric acid squarate and the corresponding vemembered species 0 OH 0 0e 0 o 2H 0 OH 0 o O 0 9 e 9 Lecture 23 4 3 Homoaromatic species vide supra Another example that is reasonably stabile is the cyclobutenium cation which is explained by the formation of the homoaromatic acyclopropenium carbocation loop HOSOZF gt SbF5 SOQCIF 75 c 2 Fullerenes Bucky balls and bowels Fullenes are spherical conjugated polyenes that display aromatic properties These recently discovered forms of carbon are related to bowlshaped aromatic hydrocarbons whose parent is the bowlshaped hydrocarbon corannulene lf aromatic systems are constructed of a twodimensional array of fused sixmembered rings a planar aromatic system results that upon its ultimate extension is called graphite On the other hand if the aromatic system is constructed five and sixmembered rings where every five membered ring is isolated from other fivemembered rings by circles of sixmembered rings then a curved aromatic surface results Upon ultimate extension this pattern of construction results in carbon nanotubes and fullerenes OAc Example Corannulene compared with coronene Note that even though corannulene is not planar it can be view as being composed of concentric aromatic rings the inner ring bearing a negative charge and the outer one a positive charge l Coronene Buckyhall 91 m c 7m Fullerene Lecture 235 Electrophilic aromatic substitutions SEAr Electrophiles The reactivity ofthe eiectrophiie determines Which type ofaromatic ririg can be Substituted Eiectrophiies can be grouped into three main categories 1 Powerful electroghiles capable of substitution of activated and deactivated aroma es 0 0 2212504 HMI NOf ZHSO H30 Br or Bier Br2 MXn BIZ MKquot 13sz BrOH Ho Brim H10 C12 01 CleMXn Ci2 MX Clrmxquot ClOHZ ClOH H30 cu mZ H10 so3 P115107 H150 o 1502 R5016 Aict RSJ Ami 2 Moderately strong electroghiles capable of substitution of activated aromates but not deactivated RaC R3CXMX R1c MXM T mam W Rlc Hm chcm H Rz ClRL RCHZX Mxn RCHlx Mx chzxen ax ii RCEO RCXMXquot RCEO39 mxmi 0 li U H cheMxn ch MXquot cheivtxn o A RCOH ch MXquot H39 8 RE OH MXMJ ux H quot X R1CO Hquot RIC m R2CO MXn Ricz Mx n 3 Weak electrophiles capable ofsubstitution ofunly aromates HCENH HCEN HX HcE H x Nam HM H s Nzo H20 ArNN AxNxxZ Hm2 3 MEN 2 1120 Lecture 23 6 Leading theory arenium ion mechanism R 0H6 R n complex a acomplex Wheland complex R E H R H O H 9 E E n complex Steps Step 1 Complexation of the electrophile with nelectrons of the aromatic system 3 complex This reaction is reversible There is no selectivity associated with the formation ofthe ncomplex Stpe 2 Collapse ofthe ncomplex to a ccom lex Wheland com lex intermediate in which the electrophile is bound to the carbon at the site of substitution together with hydrogen originally associated with that site The formation of the ccomplex may be reversible The ccomplex formation is usually the rate limiting step ccomplex structure a nonaromatic cyclohexadienyl cation an arenium ion and is partially stabilized through resonance structures H egedw Step 3 Regeneration ofthe aromatic sextet by removalloss ofthe original substituent This step is generally very fast fthe departing electrophile is H assistence of a base may be required This entire process may be reversible depending upon whether a proton can become attached to the ipso carbon and the substituent lost as an electrophile see sulfonation However this reverse process is rather uncommon R Q E HKJIBO Lecture 23 7 Proof of the areniumion mechanism Isotope effect isolation ofthe arenium intermediates spectral evidence The S 1 mechanism unimolecular electro hilic substitution This mechanism is rare found in the cases where a carbon is the leaving atom or in the presence of a very strong base It consists of two steps with a carbanion intermediate O O39qu OE This mechanism is typical for decarboxylation of aromatic carboxylates 0 o 5 Ea A H w 0 O The evidence for this mechanism is the rst order kinetics and the fact that the presence of electronwithdrawing groups that stabilize the carbanion intermediate facilitate the reaction Electro hilic aromatic substitutions structureactivit relationshi s Orientation and reactivity in monosubstituted benzene rings Substituents have a significant effect on the reaction rate and regioselectivity and these effects are interconnected 1 All activating groups are on ho and paradirecting But all on ho and paradirecting groups are not necessarily activating groups there are on ho and paradirecting groups that are deactivating eg halogens 2 All metadirecting groups are deactivating they remove electron density form the ortho and parapositions leaving the metapositions relatively unaffected The regioselectivity directing effects are explained by resonance and field effects and how these effects stabilizedestabilize the intermediate arenium ion Wheland complex Note that majority of SEAr products are kinetic products not thermodynamic the reactions usually are not reversible since the reverse reaction is usually very unfavorable vide supra That means that the structure of the product is determined by free energy of activation but not by the stability of the product The transition state is closer to the arenium ion intermediate than to the starting material or products According to the Hammond postulate we assume that the transition state resembles the arenium ion intermediate This means that we can assume that the factors that increase the stability of the intermediate will most likely also lower the activation energy required to reach the Lecture 23 8 intermediate And because the intermediate is rapidly converted to products we can use the estimated stability of the arenium ions to predict which product will be predominantly formed Note if the substitution is reversible we will obtain a distribution of products that corresponds to the stability of products not to the activation energy Electron releasin substituents that do not have an unshared air of electrons on the atom connected to the aromatic ring stabilization of all three possible arenium ions omp an increased rate 2 Z stabilization 2 H H H Ortho Elt gt Q E lt gt E Para Q E Z Z Z Meta H H E E E stabilization z Examples alkyl substituents Note the effect of hyperconjugation r quot9 C H H C H E E H 2H Electron withdrawin substituents that do not have an unshared air of electrons on the atom connected to the aromatic ring destabilization of all three possible arenium ions but mainly the on ho and parasubstituted arenium ion where the positive charge is in direct communication with the substituent The destabilization of on ho paraarenium ion results in metadirecting effect Generally exhibits a decreased substitution rate et39 kegiz N of Zita161 esoglcgpj 353 I I 39H sites of J69 w Lecture 23 9 Examples in order of decreasing deactivation NR3 N02 CF3 CN SO3H CHO COR COOH COOR CONH2 CCI3 NH3 except meta directs also para PR3 SR5 F F Fdestabilizatiun F Fdestubilizaa39un F F F F F F F F F F F F 5 5 5 5 5 H H H E E lt9 E 0 H Q H H PW Q H H G Nu destabilized rmnmmcz structure F F F F F F F F F 5 6 5 Q 3 H G H E E E Substituents that contain an unshared air of electrons on the atom connected to the aromatic ring the arenium ions may be stabilized by the participation of the unshared pair of electrons thus providing additional avenue for the delocalization but mainly the on ho and parasubstituted arenium ion where the positive charge is in direct communication with the substituent Note the resonance is more important than the field effect Examples in order of decreasing activation 039 NR2 NHR NH2 OH OR NHCOR OCOR SR and the four halogens X e o 39o39 39o 39O o r a t 39 39 leiectromc u w Z3 Z9 Z9 Z9 B N A at OH H Omb x K Halogens inductively electronwithdrawing decrease in the rate electrondonating via resonance which makes these substituents orthoparadirecting Lecture 23 10 Orth 0 additional additional 393 stabilization 39239 H 39239 H 23H H 2 39239 gm mmquot 39z39 awe H Poro EH EH Meto Z Z Z N0 additional I stabilization H E Multiple substituents directing effects of each substituent is added stronger wins Reactivity of polycyclic compounds Polycyclic aromates react faster than simple benzene derivatives since they are usually more electron rich and can delocalize charge more effectively than a single aromatic ring 11 11 H CO Reactivity of heteroaromatic compounds nExcessive a heteroatom donates a pair of nelectrons to the nsystem pyrrole thiophene furan more favorable charge more favorable charge separated form separated form n 6 3 9 919 9 93 H 0 H a e 63 6 H H H as 3 3 preference 2 gt 3 Lecture 23 11 nDef cient heterocycles heteroatom accepts an unshared pair of nelectrons An example is pyridine and other heterocycles with the NCH unit N is more electronegative than C therefore a better acceptor ofthe electron pair lt lt siteswith decreased 9 l I 4 I 4 I I electronic density 7 no 9 o N N N quot on y The reactivity of aromatics in eectrophiic aromatic substitution depends on the hardness ofthe reacting aromatic and the reaction site on it Electrophilic aromatic sutstitution of pyridineNoxide Sites of E9 3 increased I I w electron 4 4 density I I Or 391 To W 9 N a If VQ 6 3 0 g 0 6 Electrophilic aromatic substitution of lndole lndole itself is a nucleophilic heterocycle and reacts very easily with eectrophiles The preferred site of attack is on 03 rather than on 02 This is in stark contrast with the reactivity of pyrrolel The reason for this reactivity is the higher electron density of the 11 HOMO orbital on 03 in indole and the fact that eectrophiic attack on the C2 position would require a loss of the aromatic stabilization of the fused benzene ring One can envision using the resonance structures shown below Considering this resonance pathway we see that the resulting cation formed by attack on 03 produces a cation that can bene t from stabilization of the ring nitrogen without disrupting the aromaticity of the benzene ring Lecture 23 12 Site with increased electron density 11 3 0 lt13 9amp9 N N N H 6 H H H E H 1363 E9 9 lt gt 69 N E N N H H H Mechanistically very interesting are substitutions of 3substituted indoles which can lead to 23 disubstituted indoles The substitution product depends on the substituent on C3 and the electrophile For example formylation of 3methylindole leads to NformyI3 methylindole However sulfonation diazocoupling and acetylation yield C2 substitution Hard bases display high electronegativity and low Qolarizability The formation of the ncomplex in particular requires a formation of a cyclohexanedienyl cation Hard bases reaction sites are not prone to undergoing electrophilic substitution Scheme 103 Activation Hardness for Aromatic and Heteroaromatic Compounds Hydmcarbons Heleroaromzitics 036 new 04 ll 039 10 M79 050 DJ 18 a no Q 0255 0l39 0 MM 0203 0 M7 N 0 gt increasing reactivity increasing reactivity Activated benzene Deactivated benzenes F OH NHZ COZH CH 0 0462 j M21 Ii mgr 0322 0269 13492 0435 0434 n 222 0 I39 was 0353 0307 0325 0276 A home study assignment Electrophilic substitutions specific cases Lecture 23 13 1 Nitration 9 H2804 HN03 9 N02 2HSO439 H30 the rate limiting step is the formation ofthe ccomplex 9 nitration in the inert media 2HN03 9 N02 N0339 H20 is the ratedetermining step 9 acylnitrates 2 Halogenation 9 l2ltBr2ltCI2 activated aromatics othenNise Lewis acids are required Protic acids help 9 hypohalous acids XOH and XOH H 3 Sulfonation and halosulfonation in many cases reversible particularly at high temp 9 H2804 H3O 9 H3804 9 halosulfonation Ar ClSOon 9 ArSOzCl tosylchloride 4 FriedelCrafts alkylation 9 catalysis Lewis acids see 6 for strength of LA gt catalysts 9 haloalkanes or alcohols in the case ofalcohol protic acids act as a catalyst too9R CC H 9 CHC carbocation also possible Markovnikov s rule is observed 5 FriedelCrafts acylation O O 0 H e e e II H e G R c X MXH MXM R Co 4 R CEO R C X MXn R C X MXn complexed acylium ion RCOH protonated acylium ion Aromatic acylium ions are charge delocalized and especially stable acylium ions 0 e G CEO lt gt co Mechanism the same as in all SEAr H OLewis acid H O H OH 4 C C Q R R 6 R Lecture 23 14 6 Diazocoupling Diazonium salts are stable weak electrophiles baseassisted deprotonation is the rate limiting step The mechanism of diazo coupleing is the same as in all aromatic substitutions 6 639 n NN lt gt N N Attacking electrophile Substitution of groups other than hydrogen ipso substitution Reactions of this type usually require baseassisted removal of the original substituent Z Mechanism 3 E K 26939 Examples ofthis type of reaction are the resubstitution reactions involving SO3H TMS SnR3 groups K Me Me Si Me I2 AgBFA OI39 ICI AcOAg T R Sn R 9 X Because some groups TMS SnR3 direct the SEAr to themselves they are called ipso directing groups Electrophilic aromatic substitutions of metallated aromatics Metallated aromatics ArM are much better nucleophiles than simple aromatics ArH and therefore react with numerous electrophiles even the weak ones very quickly Lecture 23 15 1 Electrophilic substitutions involving hydrogenlithium exchange Certain aromatics react directly with secBuLi in the on hoposition to the metallation directing group MDG The presence of the MDG enforces regioselectivity in aromatic ring metallation Mechanism the complexed Li in the transition state make the associated secBu group much more basic to the extent that it can remove H from the aromatic ring NOTE the removal of the H does proceed via the formation of the benzene carbanion polarized but electroneutral bridged TS 5 u Bu H HPIIJ 539HmEx 2 Li E CE cm 6 Co r31 secBuH Li R MDG R MDG R MDG R MDG R MDG Typical MDGs CO of the amides carbamates or O of ethers and acetals MDG MDG 0 5 O wick a Wick H Li Examples this metallation strategy is particularly effective in electronrich heterocycles where the monosubstituted products are difficult to obtain Lecture 23 16
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