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 Course Module: Organic Reaction Mechanisms
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 Module Code:  CM3222

 Aims & Objectives

 Course Outline

 Recommended Text

 Module Content: LFER, Reactive intermediates: Carbocations, Carbenes,
 Rearrangements, Nitrenes, Radicals, Mechanistic Probes
 Selected Biological Reactions (26 L + T etc)
 Prerequisites: Basic organic chemistry

 Module Aims:

 1. To teach students organic reaction mechanisms in some detail
focusing on reactive intermediates and their rearrangements.
 2. To discuss aspects of mechanistic organic chemistry and the
relationship to mechanisms found in biological chemistry.



   2-hour examination at the end of the semester (90%)
   Test and tutorials (10%)


 Learning Objectives

 After completion of study of the module you should be able to :-
 1. Understand the principles of mechanisms of reactions.
 2. Understand basic mechanistic approaches that can be applied to synthesis and chemistry in general.
 3. Understand the underlying concepts of bond-forming and
bond-breaking in organic reactions.
 4. Understand structure-reactivity relationships. LFER & Hammett plots
 5. Understand most basic organic chemical intermediates such as
carbocations, carbanions, free radicals, carbenes and nitrenes.
 6. Understand the reactions and rearrangemenst of reactive intermediates.
 7. Understand the use of reactive intermediates in targetting selected molecules or molecular groups.
 8. Relate bioorganic/biological reactions to established mechanistic types in organic chemistry.
 9. Explain many biological and medical phenomena in molecular terms.
 10. Explain the action of environmental chemicals on cellular targets
in terms of generation and reactions of reactive intermediates.
 11. Obtain an introduction to many mechanisms in biological processes.
 12. Obtain insights to the action of some drugs and their cellular targets.


 CM3222 - Organic Reaction Mechanisms "Notes for the class of sinking ship"
Tutorial 3 : Notes only

1a. + H+, -H2O, 1,2-ring expansion, 1,2-Me shift
1b. + H+, -H2O, 1,3-H shift, 1,2-expansion
1c. + H+, -H2O, 1,2-expansion, - H+ ; 1d. + H+, + H2O, - Br-, 1,2-ring contraction, - H+ ; 1e. + D+, 2-norbornyl cation, + Cl- at two positions ; - H2O, allylic resonance, N-addition cyclization, - H+
2. Hyperconjugation and +I inductive effect in stabilization of caarbocation, CH better than CD in hyperconjugative overlap (refer notes), similarly inductive effect(refer notes);secondary ion less stabilized; angle at the 7-position emanding as deviate too much from sp2 (ideal 120 deg.), destabilizing; bridgehead position is angular, not possible to flatten in a rigid system.
3a.t-BuF loses F- to t-Bu+ ; C3H8 to C3H7+, - CH3+ to CH2=CH2, then CH3CH2+, then CH3CH2CH2CH2+, 1,2-H shift, 1,2-Me shift, 1,2-H shift; this is a reversible reactions in superacid medium and not of synthetic consequence, leads finally to most stable t-Bu+ ; alternatively C3H7+ to C3H6, C3H+ plus C3H6 to C6H13+ , H-shift and fragmentation to C4H8, then C4H9+, then to t-Bu+ ; 3b. secondary ion undergoes H-shift and Me shift to product ion ; Me2EtC+ fragements to Me2C=CH2 and then leads to t-Bu+ ; alternative routes also possible, remembering in superacid minor pathways lead to final stable carbocations.
4. wax is C20 to C30 saturated hydrocarbons (sometimes partly substituted by fatty acids); CH3CH2CH2CH2CH2CH+CH2----CH3 fragments to C4H9+ plus olefin, C4H9+ undergoes rearrangements to t-Bu+ ; alternative pathways of fragmentation of the long chain carbocations will lead to smaller molecules and finally give the relatively more stable carbocation.

  Tutorial 2 : Reminder - notes only

1a. carbocation stabilized by aromaticity and cyclopropyl groups ; 1b. resonance stabilized tertiary, although a flattened propeller, there is sufficient pi-to-carbocation overlap. 1c. bridgehead (rigid) angular cation, pi orbitals orthogonal, no resonance stabilization.
2a. secondary stabilized by 2 aryl groups, p-MeO-phenyl is strongly stabilizing. 2b. secondary, pMeOphenyl resonance stabilization, 2c. tertiary, 2d. secondary, 2e. primary bromide, 2f. primary chloride.
3a. 1-adamantyl system can be flexible, structure refer notes, various reasons CH and C-C hypercojugation, only slight deviation from flatness, back-lobe stabilization. 3b. {2.2.2] system better than [2.2.1] system in ability to achieve some degree of flatness at the bridgehead position, [2.2.1] is to rigid to be able to provide a flat carbocation.
4a. note conformations, any axial interactions can be relieved by ionisation of Br; alternatively the axial-axial interactions can be viewed as raising the energy of the reactants (or ground state); not t-Bu (equatorial) can be assumed to anchor the 6-ring. 4b. note angle change sp3 (109-60 degree) to sp2 (120-60 deg.) is more severe in the cyclopropane, cyclobutan if assumed to be 90 deg. will suffer less angle change (109-90 deg) to (120-90 deg) to form carbocation, actually cyclobutane is puckered and there is possible sigma-participation of C-bond.
5a. CH4 + D+ gives CH4D+ which can lose H+ ; CH3+ can react with CH4 ; CH3CH2+ can react with CH4, etc. 1,2-rearrangements to give most stable carbocation.
6a. use 1,2-H and C- shifts and also 1,3-H shifts.

  Take-Home Set: Brief Notes only

0. Note the problems can take time to solve, some not expected to be done in a short time. As a general rule, one may get "stuck" with a problem for hours (beware when you have limited time) but at other times the problem may seem to "click" or one can visualize the few steps to the product. Obviously for the present set there are opportunities to refer and cross-check. There is considerable orginability in the answers which is good.
1. The products are optically pure, i.e. there is stereospecificity in the mechanism. The conditions of reaction are typically for carbocation and with migration, one common type of intermediate is the bridged phenomium ion from NGP. Since there are two different products which cannot be from the same bridged ion, another bridged phenomium ion intermediate has to be drawn. If you examine the conformation in Newman projection or sawhorse structures, you can draw two of the usual bridged intermediates using the two possible migrating phenyl groups. Next it can be observed that one intermediate has eclipsing Ph-Me (less favourable) and another eclipsing Ph-H. The the less favourable intermediate and the TS leading to this will be less favourable and provides the minor product. As to why only one position of the bridged ion was attacked, it could mean that the migration is quite advanced (meaning the intermediate bridged ion is not totally symmetrical), favouring attack at the phenyl-substituted carbon which of course can accomodate more charge due to the substituent effect. (almost all answers correct)
2. Note that at high temperatures, difficult (energywise) pathways can compete with low-energy pathways, given the extra amount of thermal energy. If the problem as given is restricted to carbene-mechanism, one has to think of carbene-insertion, carbene-rearrangement, carbene-carbene rearrangements and all the reverse reactions.
First to describe the molecule, I should label the six membered rings from left to right as A, B, C and D(down,right), the five-membered ring as E. One simple mechanism will be to consider ring E as an insertion product ring A C-H + :C=CH- carbene, if this is reversed we have no more ring-E but a carbene on ring B-CH=C: , if this is allowed to insert into the C-H bond of ring D, then we have the product.
Another innovative scheme rearranges the five-membered ring E into a cyclobutyl methylene (the reversal of this will be the 1,2-shift to give the five memebered ring E), the carbene inserts into the ring-D C-H to give a strained 6-ring (6,6,6,6,6,4-membered-rings) hydrocarbon, the 4-ring derived from ring-E now does a reversal of carbene insertion to ring A C-H, the carbene formed on the new ring then undergoes 1,2-H shift to the product.
Another innovation uses carbene-carbene rearrangements. Ring E can do the reverse H-shift to give a carbene (a carbene at the ring-E carbon can normally give a 1,2-H shift to the starting material), allow a backward carbene addition to ring-B double bond to cyclopropene intermediate, ring open to a 7-membered carbene on ring-B, carbene addition backwards to ring C to give a cyclopropene intermediate, ring open to a carbene (7-membered ring D), rearrange to a ring-D-CH: carbene which can insert in the cyclobutane C-H (from ring-E). A reversion of carbene insertion to ring-A C-H will give a carbene at the new 6-membered ring, 1,2-hydride shift gives the product. Other similar schemes uses these carbene-carbene rearrangements to good effect.
3. a give-away, refer notes.
4. Will need to label the bonds. bond-a will be potential benzene-C to front C=O, bond-b will be potential benzene-C to top bicyclo[2.2.1]-2-carbon, bond-c will be the back potential benzene-C to the back C=O bond.
One common pathway employed by many uses the "exceptional?" 1,3-rearrangement (breaking bond-c)in the rearrangement of the Baeyer-Villiger intermediate electron deficient O-atom. This if followed by 1,2-shifts (break bond-c) and a final break of bond-a will give the product.
Using the principles in carbocation reactions, the 1,2-rearrangement in the Bayer-Villiger intermediate will need to break bond to rearrange to an ester product or to give a carbocation at the potential benzene-C after breaking bond-a. Alternative this carbocation can reform (by ionisation) from the ester of rearrangement. With a carbocation, all bond-c to break so that a 1,2-rearrangement occurs with the migration of the back carbonyl. The new carbocation on the six-membered ring can collapse to aromatise if bond-b breaks generating the "norbornyl-type" carbocation which can recombine with the COOH or COO- fragment to give the product.
5. A variety of reactions - some from books and some from journals. generally OK

  Tutorial#8: Brief Notes only

1. Select C-Br not C-Cl to react with Sn ., intramolecular cyclization (5-ring of course), resulting radical undergoes another cyclization, H-atom transfer from Sn-H completes the chain. 1b. C-I bond reacts with Sn. , radical cyclizes to new radical. Allow to cyclize on O=C to give 5-ring, bond cleavage expels Me. Cyclization involving bond-forming better than SH2-type expulsion of Me. in the last step. 1c. Generate radical from Sn. , allow for the reversal of cyclopropyl ring opening to obain cyclopropyl ring opening. Fast reopening (use other bond of cyclopropane) of ring gives the product radical. 1d. Sn. adds to S and cleaves the O-C bond, allow for fragmentation to open cyclobutane-ring and give olefin, which leads to primary radical exocycli to 5-ring. Proximity of C=O allows addition to C-O. which reversibly opens to six-membered ring radical, H-atom transfer completes the reaction.
2. A normal 1,2-shift would cause the triphenylmethyl group to move to the electron-deficient carbene center and provide a ketene which will react with benzyl alcohol to give the "normal Wolff rearrangement product" benzyl ester. The unusual product requires reaction to the ortho position of the phenyl group. If a truly singlet carbene reacts to give zwitterionic intermediate which reorganizes the electrons to ketene and ring opening. Protonic addition and elimination gives the aromatic system while the ketene group reacts with benzyl alcohol to form the ester. If not stated, a diradical or triplet state can add and fragment and reorganise to form the ketene. Aromtisation can be by protonic addition and elimation. If you assume the carbene reacts with benzyl alcohol to give a cation which then reacts at the ortho-phenyl position, similar protonic addition/elimination and reaction of ketene with benzyl alcohol give the product.
3. At a glance one can do a singlet 1,3-addition although this will be one of the rarest example, a triplet 2-step addition will provide the same product. Another possibility is a normal carbene 1,2-addition to give a zwittenionic intermediate which being in resonance cyclize to a 1,4-addition product.
4. As drawn aa a triplet a rapid radical-type cyclopropyl ring opening is possible (nano- to pico-second chemistry; not yet Nobel prize-winning femto-second speed) which gives vinyl radical and allylic radical, the cross-coupling of which will provide the product. A preliminary 5-ring cyclization (at milli to micro-second rate) may not compete with the nano- to pico-second cyclopropyl ring opening.
5. Cycloaromatize all three, note that the middle-ring diradical is close enough to cross couple with the other diradicals. If radical couplings occur a large aromatic hydrocarbon forms with two radical centres which pick up two D-atoms from the substrate provided.
6. Halogen-Li exchange, carbene (or carbenoid formation) formation, carbene rearrangement to allene which is strained and reactive. Reaction with olefin gives cyclobutane product.

  #9 Revision: Brief Notes only

1. Conventionally the double-headed arrow is for resonance;note that compounds given can be isomers (not the same molecule) otherwise they can be the same, just drawn rotated. 2. The two are both aliphatic acids and should have similar electronic effects. Differences in ionisation will be from the sizes of the groups, ie. steric effects. Ionisation in a solvent, e.g. water gives anions and protium ion. Whether one is stronger than the other will be in the extent of ionisation or solvent stabilization of the anion. Steric factor inhibits solvation. 3. Note: ideas of aromaticity and anti-aromaticity. Use of resonance may not adequately describe the real situation. In the case of cyclobutadiene the square structure when drawn as resonance will show that all 4 positions arer equivalent or all diene positions are equivalent to Diels-Alder cycloadditioin. Since the results do not show this, it means that the rectangular representation is correct. Further there is a rate for the rectangular isomerisation. If this is too fast then it may not be possible to show the difference. 4. Draw the structures and note possibilities for inductive and resonance effects. Note p- may be further than m-positions. sigma plus or minus refer to resonance-dominant cases in positively charged or negatively charged TS respectively. 5. When there is NGP or no NGP, stereochemical requirements are there. In cases where there is weak NGP there can be competing pathways. Note possible pathways and their stereochemical consequences. One can in most cases rationalize the data as competing pathways. 6. 1,2-Rearrangements are "carbocationic-like" or migrations to electron-deficient center. There are many examples from Pinacol, Beckmann..Curtius. The pinacol rearrangement forms a kinetic product from the most readily formed carbocation. 7. Carbocation forms early in the TS and reactant-like, ie. as in the conformation of the diazonium ions. Conformation favours the least interactions. A minor product indicates that the carbocation has a lifetime long enough for a slight bond rotation which places the other phenyl for migration. 8. As there is no bond-breakage, there is no primary kinetic deuterium isotope effect. Usually small >1.0 secondary deuterium isotope effects, this depends on the nature of the reaction. In the present case it is not a case of stabilization by hypeconjugation or some inductive effect, the twisting motion brings into play the size of the methyl groups. Inverse secondary kinetic isotope effect can be steric in nature.

  Quiz#4: Brief Notes only

1A: no C-D bond is broken, b-position to leaving group; sec. deuterium isotope effect, beta-effect, note a better hyperconjugative overlap in 1A while C-D is orthogonal in 1B.
Note electron-donor effects is possible, note the resonance effect is only possible with proper allignment of the aromatic ring with respect to the leaving group. Ortho groups distort the olefin so there is likely not planarity in the olefin but this will be useful for the ionisation step which allows resonance stabilization.
3a: NIH shift gives an intermediate after which a C-D/C-H bond is broken, a primary kinetic deuterium isotope effect will be present normally of value greater than 2 and can be up to 7 at room temperature.
3b: If there is no NIH shift, the first step can have a secondary kinetic deuterium isotope effect while the second step there is no NIH, so no discrimination in the loss of H or D. the net result will be a small value (sp3 to sp2) of secondary kinetic deuterium isotope effect.
4. Deaminations are exothermic, you can view as reactant-like TS, ie. the diazonium ion as reactant or the conformation of this. Conformation depends on the large groups non-eclipsing. So the major migrating group is determined by the most favourable conformation of the reactant and less on the migratory aptitude.
5a. If you rationalize that the TS will be better bridged ion, a better influence of substituents will provide larger negative slope; if you take the view that eclipsing Me will require more assistance then more effect of the substituents will be required by the eclipsing Me in the TS while with no eclipsing Me-groups less of substituent effects will be necessary, then a less negative slope should be observed.
5b. Change from secondary to primary means more assistance (NGP) by substituents will be required which means (especially for donor substituents) a large negative value or rho+ will be expected.
5c.A tertiary carbocation needs no assistance or bridging NGP as stated. So the cation center is far from the phenyl group, ie. small rho expected; rho is used rather than rho+ because there is no NGP-type of pi-resonance contribution, only through sigma-bond electronic effects.
6. Note NGP by bromine, cis or trans products, note flipping is possible, note stereochemistry.

  Tutorial 5 : Brief notes only

1a - 1f. H+ with ROH forms carbocation with NGP from neighbouring bromine group. Draw the bromine bridged cation intermediate and allow chloride ion to attack at the two positions "backside" to the bridged intermediate and ring open. Note the two positions of attack and the products can be examined for stereochemical purity or whether they are the same, or mirror images or meso, etc other stereochemical relationship. Note the 3-bromo-2-butanols can give products with stereochemical relationships which can be specified by their configurations
2a - 2d. Note participation can occur when the leaving group is transoid to the neighbouring group. If cisoid usual SN1 occurs and the stereochemistry of the products will be determined on attack on both sides of the carbocation, with slight modification by the ion pair formed or by the neighbouring group.
A tertiary carbocation with aryl stabilization need not have NGP for ionisation.
NGP for acetate extends 1,2-only unless there are special circumstances.
3A - 3F. When the conformation is fixed by an anchor group, only transoid arangement can lead to NGP. The products will have to be drawn out and the stereochemistry examined. Cisoid groups will ionise in usual SN1 mechanism especially in non-nucleophilic solvents.
4a. Note conformation. Draw Fisher projections. Consider NH2 (or N2+ derived from it) to be the large group relative to H. Note: as there is no special conformation to favour P-MeO or p-Me or p-H , all are equally likely to migrate. This is a case that the carbocation is like the reactant (R-N2+ reactant) from Hammond postulate. Substituent effects are not called into play to assist ionisation and migration.
4b. Carbocation formation is reversible, bridging is also important as carbocation stability is important. Donor groups will stabilize the TS of the bridged intermediate.

  Tutorial 6 : Brief notes only

1a. rho+ is negative as expected of “carbocationic-like” TS, rho+ indicates involvement of resonance of the substituent groups but the small value is indicative of a low sensitivity to substituent effects. Bridging is not well developed for meta e-withdrawing substituents, but if a large rho+ occurs with strong donor groups a change to a large rho+ value will signal a mechanism change to a bridging aryl (assisted by donor group resonance). 1c. A small negative rho value similar to the data above may be the result of non-Ar-bridging TS; rho will change to a large value with donor-substituents which supports bridging in the TS (inclusive of a change of mechanism). 1b. Note: a tert-carbocation, small rho and not rho+, transmission of polar effects inductively through sigma-bonds, and the distance of the carbocationic centre results in low negative value. 1d. There is an –O+ generated. Note for X, there is no resonance involvement with substitutents, sp2 carbonyl carbon migrates (pi-face not involved directely with +charge), rho value depends on TS, extent of migration and positive charge development. For Y, note that rho+ indicates that the resonance (pi-face) is involved as expected due to direct bond formation to aryl group in the TS. Small value however is indicative that there is little bridging, a likely situation of very early bond-formation in the TS.
2. Add H+ N3- (HNNN) to the double bond. Loss of N2 gives cationic intermediate (or TS to this), allow Ph or Ar to migrate, react the cationic intermediate with H2O, note the products can be hydrolysed to amines or ketones.
3. Add H+ to C=O, 1,2-Me shift, then 1,2- t-Bu shift provides product with the original label. If t-Bu+ is lost, which is the reverse of t-Bu+ addition to the double bond, then the minor product will form, the label will be as from the mechanism.
4a. Hoffman degradation, note retention of configuration. Lactam formation. 4b. Nitrous acid causes deamination to positive-charged intermediate, anti- or transoid- migration with retention of configuration, react with H2O to give product. 4c. Allow N2 to leave, there can be cationic intermediate, but beware a nitrene (not yet covered) could arise. Beware also that bond shifts can be tricky, best to draw in the hydrogens as well; allow nucleophilic attack by NH2, and easy prototropic shifts.
5 a. Since there is no unusual factors, Ph (better) migration will be favoured as the major pathway. 5 b. refer Curtius rearrangement 5 c. refer Baeyer-Villiger rearrangement. 5 d. refer pinacol-rearrangement, better donor group migrates as the major pathway. 5 e. same as 5d but note the usual problem of ortho groups, steric factor will not favour bridging; so ortho-C6H4 becomes a poor migratory group despite donor effects. 5 f. the deamination by HNO2 first gives N2+ which loses N2 exothermically; conformation of the reactants determines the order of migration, with the Ph group stabilizing the carbocation a slightly longer lifetime will allow for some rotation and a fraction of the better migrating group can also migrate.

  Tutorial4 : Reminder - notes only

1. SN1 TS# dependent on the stability of the carbocation to be formed. Note that cyclopentane has inherent 1,2-H-H interactions when they are not perfectly staggered conformation (although eclipsing situations can be avoided in a puckered conformation). There is relief from interactions in forming an sp2 center. Angles are not so serious. A rigid system such as bicyclo[2.2.1] system has more serious 1,2-H-H eclipsing interactions due to the angular constraints. A more pronounced effect can be observed by relief e.g. by ionisation or generating an sp2 system.
Since the driving force comes from the above, less dependence on substituent effects are evident for the compounds reacting with faster rates; alternatively you could reason that the TS# has become relatively more reactant-like and less carbocation-like (less flat if you may like it to be so) and therefore less sensitive to resonance stabilization of substituents.
2. primary-OBs; although SN1 assumed there must be SN2 but will be pseudo SN1; notice slight assistance, most stable ion will be Ph stabilized which is shown by the results; product and rate criteria indicate participation. The triple bond is not as good as the double bond as a carbocation on a sp2 carbon is difficult. Products and rate shows inadequate evidence of significant participation.
3a. R-H with superacid H+ gives R+, followed by a 1,2-Me shift
3b. H+ addition to double bond to give cation stabilized by OMe, rearrange to cyclopylcacrbinyl, 1,2-rearrangement to cyclobutyl, fragmentation to protonated (phenyl) alpha-methoxy stryrene, deprotonation and reprotonation to final alpha-methoxy-alpha-methyl-benzyl carbocation
3c. protonate C=O, NGP of triple bond and pick up bromide.
3d. The hydride is positioned (although 1,5) across to leaving group. Very minor product from 1,2-H shift, 1,2-H shift and a H-loss, something rare (refer to the extremely low yield) like loss of H+ from protonated cyclopropane to give cyclopropane.
4a. polar solvent stabilizes a polar transition state; stabilization by solvent makes the TS to ionisation less sensitive to substituent effects.
4b. Sensitivity to substituent effects less for more remote reaction (ionisation) center.
4c. Double bond (pi bond) allows transmission of polar effects; double bond is also shorter than single bond. Resonance effect (although not directly) to carbon closer to the reaction centre. 4d,e. Note TS# has a dispersal of positive charge to HOH, loss of charge means positive rho. Note the very exothermic nature of the reaction and the TS# resembles the reactants (i.e. the carbocations) and not the neutral alcohol products. Sensitivity to substituent effects will be for the less stable secondary carbocation (also flat). A propeller shape triphenylmethyl cation is considerably more stable (and not totally flat) and less sensitive to substituent effects. Alternatively the tert. cation causes the TS# to be relatively less reactant-like and less dependent of reactant stabilization by substituents.
5a. Considered large, primary kinetic isotope effect.
5b. secondary, about 10-12% per deuterium, beta-effect. 5c. A value of 2.3 is large and considered primary kinetic isotope effect, there is bond-breaking of D. In terms of primary kinetic isotope effect, relative low values of 2 supports the non linear TS.
5d. Small; secondary kinetic deuterium isotope effect (alpha-effect)