lecslides-2

8/17/2019 LecSlides-2

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erythro dl Pair Meso


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But entropy of activation is more negative for trans, indicating a more organizedtransition state due to the anchimeric assistance.

trans acetate reacts faster in the acetolysis

reaction of 2-substituted cyclohexylbrosylates than a cis acetate.trans acetoxy group participate inthe ionization process

Both reactants are less active than a simplecyclohexyl derivative due to the electronwithdrawing acetate groups


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Solvolysis of cis- and trans-2-halocyclohexyl brosylates in acetic acid

Rel.rates ofreaction

ktrans /kcis

X = H 1

X = trans-Cl

X = cis-Cl

4.8 10 4

1.3 10 4 4

X = trans-Br

X = cis-Br

0.10

1.2 10 4 800

X = trans-I

X = cis-I

1.2 10 3

4.3 10 43 10 6

•Inductive effects of halogen atom

•Anchimeric assistance by haolgen atom

•Effectiveness of halogens as neighboringgroups I>Br>Cl


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OH group in trans- 2-hydroxycyclopentyl arenesulfonates acts as a neighboringgroup when the leaving group is tosylatebut not when it is nosylate, apparently because the nosylate group leaves so rapidlythat it does not require assistance

when 5-chloro-2-hexyl tosylate is solvolyzed in acetic acid,there is little participation by the Cl,but when the solvent is trifluoroacetic acid, which is much less nucleophilic,neighboring-group participation by the Cl becomes the major reaction pathway

a neighboring group lends assistance in proportion to the need for such assistance


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• consists essentially of two S N2 substitutions, each causing an inversion, net result isretention of configuration

• in the first step the neighboring group (Z) acts as a nucleophile, pushing out the

leaving group but still retaining attachment to the molecule• in the second step, the external nucleophile (Y) displaces the neighboringgroup by a backside attack• first-order rate law is followed in the neighboring group mechanism , Y does not take

part in the rate-determining• rate of reaction is greater than expected( > ~50 times)• A reaction between the substrate and Y involves a large decrease in entropy of

activation S‡ , since the reactants are far less free in the transition state than before.• In general reaction of Z involves a much smaller loss of S‡

• there is usually a group with an unshared pair of electrons to the leaving group (orsometimes farther away)

Neighboring-Group Participation

some of the importantneighboring groups:COO , COOR, COAr, OCOR,OR, OH, O ,NH2, NHR, NR2, NHCOR,SH, SR, S , SO2Ph,

I

, Br, and Cl


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acetolysis of both 4-methoxy-1-pentyl brosylateand 5-methoxy- 2-pentyl brosylate gives the same mixture of products

a cyclic oxonium ion is the intermediate


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Relative Solvolysis Rates of Some -Methoxyalkyl p- Bromobenzenesulfonatesin Acetic Acid

the maximum rate is usually observed for the five- and six-membered rings

• strain that develops in the closure of small rings (ring size 3,4) ( H‡ )

• decreased probability of encounter of the reaction centers (for ring sizesgreater than 7 ( S‡ )


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Sulfur Mustards (R-S-CH 2 CH2 -X) as neighboring groups

mustard gas - used in World War I as a chemical warfare agent in the form of anaerosol

Hydrolyzes much more rapidly than its analog 1,5-dichloropentaneHydrolysis proceeds by first order kinetics, very rapid, rate unaffected by addition ofother nucleophilesCyclic sulfonium ion reacts extremely rapidly, reacts with a variety of nucleophiles,including water, and also proteins and other biomoleculescause DNA damage by permanent alkylation of the guanine nucleotide in DNA strandsThese reactions create HCI, which severely burns and blisters the skin.

Find few other sulfur mustards

Bis(2,2’)-(chloroethyl)sulfide


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Nitrogen Mustards (R- NR’-CH2 CH2 -X) as neighboring groups

Cyclic ammonium ions are relatively stable compared to cyclic sulfonium or bromonium ions

May not react very rapidly with weak nucleophiles,like water

In absence of powerful nucleophiles nitrogen mustard reaction may exhibit complex kinetics.

High concentrations of good nucleophile, react rapidly with cyclic ammonium ions ,makingthe intra molecular displacement as the rate determining step.

Addition of good nucleophiles and more likely the first order kinetics followed!!!!!! Aninteresting paradox


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Rates of formation of cyclic ammonium salts in water at 25° C

Rate of formation of cyclic sulfonium salts in 20% auqeous dioxane at 100 o C

3-membered rings have less unfavorable entropies of activationEnthalpies of formation of relatively strain free 5- and 6-memberd ringssignificantly lower than that for 3-membered rings

Normal bond angles of divalent sulfur is much smaller (~ 100) than trivalent nitrogen (~109)Less bond distortion and strain in formation 3-membered sulfonium ions


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participation of aromatic electron

solvolysis of 3-phenyl-2-butyl tosylates

Phenonium ions are derivatives spirooctadienyl cationThey are related to the Wheland complexes of electrophilic aromatic substitutionReactions resulting in three membered cyclic phenonium ions can be compared toIntramolecular Friedel Crafts reactions

a spirooctadienyl cation


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Phenethyl tosylate solvolyzes in CF 3CO2H orders of magnitude faster than ethyl tosylateThe intermediacy of a phenonium ion in the solvolysis of phenethyl tosylate was provenby isotope labeling


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Solvolysis rate studies in 2-arylethyl systemsfor primary and secondary systems, two pathways can exist

For tertiary systems,the mechanism is S N1 and open carbocations ArCH 2CR2+ areintermediates

Solvent and the nature of the aryl groupaffect the

EtOH


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Approximate k /ks Ratios for Acetolysis of p-ZC 6H4CH2CH2OTs at 90 o C

k changes substantially as Z is changed from activating to deactivatingks is fairly constant , remote field effect of Z

Percentage of k

Relative importance of aryl participation is a function of the substituents onthe ring

Relative extent of participation of the -phenyl groups is highly dependent on the solvent

In solvents of good nucleophilicity (e.g., ethanol), the normal solvent displacementmechanism makes a larger contribution.

As solvent nucleophilicity decreases, the relative extent of aryl participation increases.


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The electrons of carbon-carbon double bonds can also become involved innucleophilic substitution reactions. This participation can facilitate the ionization step

if it leads to a carbocation having special stability

7-norbornenyl tosylates

In a cetolysis anti-tosylate is is 10 11 more reactive than the saturated 7-norbornylanalog

The syn isomer reacts 10 7 times slower than the anti isomer.

The rate data is strong evidence that the group assists in the departure ofthe OTs

Anti 7-norbornenyl tosylates Syn7-norbornenyl tosylates

Participation of electrons of carbon-carbon double bonds


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reaction product in thise case of syn isomer is derived from a rearranged carbocationion that is stabilized by virtue of being allylic

intermediate nonclassical “bishomocyclopropenyl ” cation involved


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very strong interaction between C7, which carries the formal cationic center, and the C2-C3 double bondthese three carbons linked together by two electrons: three center-two electron bondingsituation

electrons may be cyclically delocalised making the cation a bishomo analogue of thearomatic cyclopropenyl cation (bishomoaromatic ring system)the C2-C3 double bond is longer than a typical double bond, because electron density has been removed from the C2-C3 bonding region and delivered to C7

Non classical nature of 7-norbornenyl cation

Non classical nature of 7-norbornenyl cation was contested by H C BrownRefer bernard miller

homoallylic carbocation - homoallylic refers to theposition on a carbon skeleton next to an allylic position


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Homoaromaticity refers to a special case of aromaticity in which conjugationis interrupted by a single sp 3 hybridized carbon atom

3-bicyclo[3.1.0]hexyl cation---tris-homocyclopropenyl cation

As in an aromatic cyclopropenyl cation, positivecharge is delocalised over three equivalentcarbons containing two π electrons.Only that this conjugation is interrupted bythree -CH 2 – groupsIt is tris-homo counterpart to the cyclopropenylcation


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Neighboring group participates only when there is sufficient demand for itParticipation by a potential neighboring group can be reduced or eliminatedif an outside nucleophile is present that is more effective than the neighboring group inattacking the central carbon, or

if a sufficiently good leaving group is present,orif the stability of the potential carbocation is increased

stabilization by the p-anisyl group is so great that further stabilization that would comefrom participation by the C=C bond is not needed

Both the norbornadienyl derivatives givethe same mixture of solvolysis products,i.e., stereoselectivity is not present

Presence of a p-anisyl group at the 7 position exerts a powerful leveling effect on therate difference

High solvolysis ratesolvolysis in acetone – water at 85 oCof norbornadienyl derivativewas only 2.5 times faster thanthat of the saturated analogue


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How about the solvolysis rate of 7-chloronorbornadiene compared toanti-7-chloronorbornene??

Reacts about 750 times faster than anti-7-chloronorbornene in aceticacid solutionDo the double bonds participate as shown below?

Studies show that the orbital at C7 interacts with only one double bond at a time.Activation energy of around 19.5 kcal/mol is required to ‘flip’ the C7 bridge frominteraction with one double bond to interact with the other.Then why the higher rate??


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Aromatic rings fused to anti-7-norbornenyl rings participating in the displacement ofgroups at C7

Cycloheptatrienyl cations also acts as neighboring groups in the 7-norbornyl system

But degree of participation ismuch smaller than that by adouble bond


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-(syn-7-norbornenyl)ethyl brosylate at 25 o Cundergoes acetolysis 140,000 times faster than the

saturated analog

Participation of carbon-carbon double bonds in solvolysis reactions is revealedin some cases by isolation of products with new carbon-carbon bond

formation of the bicyclo[2.2.1]heptane ring

norbornyl cation

solvolysis of 2-cyclopent-3-enylethyl tosylate


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Carbon –Carbon Single Bond as a Neighboring Group

2-Norbornyl System

exo-2-norbornyl brosylate

solvolysis in acetic acid of optically active exo-2-norbornyl brosylate gave a racemicmixture of the two exo acetates; no endo products formed

endo-2-norbornyl brosylate solvolyzed 350 times slower than the exo isomer


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1,6 bond assists in the departure of the leaving groupa nonclassical intermediate is involved

nonclassicalIntermediate

solvolysis of the endo Isomer is not assisted by the 1,6 bond because it is not in afavorable position for backside attack

1 and 2 positions are equivalentattacked by the nucleophile with equal facility


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Acetolysis of the endo isomer also leads exclusively to the exo acetates!

A Classical ion first formedand then converted to the more stableNonclassical intermediate

Support??product is not racemic but contains somewhat more B than A (correspondingto 3 –13% inversion,depending on the solvent), suggesting that some of the classical ion ,

gives B before it can collapse to the nonclassical intermediate

B


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concepts of participation and the nonclassical intermediate challenged? (H.C. Brown)The experimental observations could alternatively be explained by invokingtwo classical carbocations rapidly equilibrating as shown below for endo-brosylate,that would give the same racemic products

Present only as aTS, not as intermediate?

stereochemical outcome due to an exclusive exo attack to be expected from any 2-norbornyl system not only for the cation but even for reactions not involving cations,because of steric hindrance to attack from the endo side?the high exo/endo rate ratios because the exo rate that is normal and the endo rateabnormally low, because of steric hindrance to removal of the leaving

group in that direction


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hydride shjfts of the norbornyl cation

hydride shifts alone cannot explain the products found from the solvolysis of2-norbornyl systemspredicted carbon label positions are not in the same positions as experimentallyobserved


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the conventional Wagner-Meerwein carbon shift as proposed by Brown

would give racemic products with the label in the correct positions

If the hydride shifts and carbon shift are all facile, all the carbons and all the hydrogensof 2-norbornyl cation will become equivalent.Infact, both the 1H and 13C NMR spectra show only one line at room temperature instable ion media.


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Donation of filled orbitals to empty orbitals is always stabilizing, and when the filled

orbitals are aligned with the empty p orbital of a carbocation, this donation can andwill occur.

gas phase hydride ion affinity (HIA)

kcal/ mol kcal/ mol

typical HIA 2° I 3° energy difference is 17 kcal I mol.The substantially smaller value in this case indicates a special stabilization of this 2° ion

X ray studies :Geometry of methylnorbornyl cationsubstantial lengthening of the C1-C6 bond andshortening of C1-C2 bond

Studies that support the bridged non-classical structure

lower temperatures solution NMR of 2-norbornyl ion in stable ion media(temperaturesbelow -150 oC in SbF5 - SO2 and FSO 3HSbF5 - SO2) where hydride shifts are absentshows equivalence of C1 and C2 ---- stable structure is the symmetricalbridged ion, or the barrier to the reaction so smallsolid state NMR spectrum of 2-norbornyl cation taken at 5 K----- the system still appearsto be a single, symmetrical ion.


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The Cyclopropylmethyl (cyclopropylcarbinyl )System

cyclopropylmethyl substrates solvolyze with abnormally high ratesproducts often a mixture of unrearranged cyclopropylmethyl, cyclobutyl andhomoallylic compounds

Cyclobutyl and certain homoallyl substrates also solvolyze abnormally rapidly and givesimilar products. (all undergo solvolysis faster than analogous structures)Reactions carried out with labeled substrates showed considerable scrambling into all

of the carbons of all three products.

solvolysis of cyclopropylcarbinyl tosylate is approximately 10 6 times faster than that ofisobutyl tosylate

an intermediate where many ofthe carbons become equivalent?


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key carbocationic intermediates that could be involved in these solvolysis reactions

Conventional carbonium ions as

the less conventional bicyclobutonium ion??

But a common intermediate present in these cases?

This common intermediate couldthen be obtained by three routes


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Special stability of cyclopropylmethyl cations (more stable than the benzyl cations)explaines as due to conjugation between the bent orbitals of the cyclopropyl rings

and the vacant p orbital of the cationic carbon that lies parallel to the C-2,C-3bond of the cyclopropane ring and not perpendicular to it

Substantial p character in the bonding orbitalsof the ring.The C -C bonding MOs do not lie along the lineconnecting carbons of the ring, instead bulge

out and away from the ring.The electrons in these cyclopropane C-C bondsare higher in energy than in standard alkanes(the ring is strained).These orbitals interact with an empty p orbital

parallel


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Cyclopropyl as a Neighboring Group

endo-anti-tricyclooctan-8-yl p-nitrobenzoate

solvolyzed ~10 14 times faster than

solvolyzed only about five timesfaster than

Need for a suitably placed cyclopropyl ring

solvolyzed three times slower than


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Methyl as a Neighboring Group

Can a C-C bond lend anchimeric assistance even in a simple open-chain compound?On solvolysis, neopentyl systems undergo almost exclusive rearrangement

Is the departure of the leaving group concerted with the formation of the CH 3 –C bond?Does the methyl participate?

Support from isotope effect studies, that indicates that the methyl group in theneopentyl system does indeed participate although it may not greatly enhance the rate

Is an intermediate or only a transition state?small amounts of cyclopropanes (10 –15%) can be isolated


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Hydrogen as a Neighboring Group

Does the hydrogen participate in the departure of the leaving group?

Is an intermediate or only a transition state?

solvolysis of deuterated sec-butyl tosylate in trifluoroacetic acidProduct an equimolar mixture of 1 & 2, but no 3 & 4 formed

If reaction did not involveneighboring hydrogen atall (pure S N2 or S N1), theproduct would be only 1

if hydrogen does migrate, but only open cations are involved all four products possible


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Effect of Substrate Structure on S N reactions

Average Relative S N2 Rates for Some Alkyl Substrates

transition state is more crowded whenlarger groups are close to the central carbon

Branching at the and Carbons

Effect on S N2 ----- crowded transition state…decreased rate


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Effect on S N1---increases the rate for S N1stability order of alkyl cations (tertiary>secondary>primary)

Branching at the Carbons

B strain (back strain) relieved by ionization to the carbocation

the rate smoothly rises with the increasing number of ethylgroups,but increase in rate is relatively small, and caused

by normal field and resonance (hyperconjugation) effects.Substitution with the second isopropyl group the crowdingis great enough to cause B strain, and the rate is increased10-fold.Except where B strain is involved, branching has littleeffect on the S N1 mechanism, except that carbocationswith branching undergo rearrangements readily.

branching


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2-adamantyl system is a secondary system that reacts by the S N1 mechanismbecause backside attack is hindered for steric reasons

a methyl group at the 2- position increases solvolysis rates by a factor of ~ 10 8

•SN1 mechanism is important under all conditions only for tertiary substrates.Wherever a hydrogen is present, elimination becomes a dominant reaction with tertiarysubstrates.

•Secondary substrates generally react by the S N2 mechanism, but S N1 mechanism maybecome important at high solvent polarities

•Simple primary substrates react by the S N2 mechanism even when solvolyzed in solventsof very low nucleophilicity ( CF 3 COOH, CF3 CCH2OH) even with very good leaving groups(e.g., OSO 2F)


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Very unreactive toward nucleophilic substitutions

Electronegativity of carbons follow the order sp > sp 2 > sp 3

Simple S N2 mechanism has never been convincingly demonstrated for vinylic substrates

Vinylic substrates can be made to undergo S N1 reactions (even then rates are generally low

compared to saturated compounds)a) when substituents that stabilize the cation are present as in -aryl vinylic halidesor RCBr=CR’2 ,where R = cyclopropyl, vinylic, alkynylor R2C= C =CR’X b) even without a stabilization, by the use of a very good leaving group, OSO 2CF3 triflate)

Unsaturation at the Carbon HRC CHX RC CXX

vinylic cations are linear

empty p orbital lies in the plane of the double bonda cis or a trans substrate often gives a 1:1 mixture of cis and trans products,reactivity in cycloalkenyl systems decreases with decreasing ring sizethe relative size of R 1 and R 2 can influence the entry of nucleophile giving

preference of one product over the other


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The SN1 rates are increased when there is a double bond in the position

allylic and benzylic substrates react rapidlyRelative Rates for the S N1 Reaction between ROTs and Ethanol at 25 oC

have about the same effect of rate enhancement as double bonds

SN1 rates at an allylic substrate are increased byany substituent in the 1 or 3 position that canfurther stabilize the carbocation by resonance orhyperconjugation, like alkyl, aryl, and halo groups.

Unsaturation at the Carbon.

double bond in the position

triple bonds in the position (in propargyl systems)


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Compounds of the formula ZCH 2X, where Z has unshared pair of electrons (as in Z = RO,RS, orR2N) undergo SN1 reactions very rapidly because of the increased resonance in the

carbocation. resonance effect dominate field effects for these groups

In solvolysis of these moleculesC=O group exhibits aretardation effect of 10 7.3

Resonance stabilization may offsetthe inductive destabilizationmaking the rate retarding effect negligiblein cases

Substituents

When Z in ZCH 2X is RCO, HCO, ROCO, NH2CO, NC, or F3C, SN1 rates aredecreased compared to CH 3X due to the electron-withdrawing fieldeffects of these groupsthe partial positive charge on the adjacent carbon destabilizes the

carbocation

When Z is SOR or SO2R SN1 is retarded by the electron-withdrawing effect of the SORor SO 2R group,and the S N2 mechanism is retarded presumably by the steric effect.


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SN1 rates are generally lower for compounds of the type ZCH 2CH2X, than forunsubstituted systems, because the resonance effects are absent, but the field effectsare still there, although smaller, unless they behave as neighboring groups and enhancethe rate

Substitution do not have much effect on S N2 rates unless they behave as neighboring

groups and enhance the rate or unless their size causes the rates to decrease forsteric reasons.

Substituents


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The S Ni Mechanism (substitution nucleophilic internal )

nucleophilic substitution proceeds with retention of configuration

then dissociate into an intimate ion pair

part of the leaving group attacks, from the front as it is unable to get to the rear

DN + ANDe

alkyl chlorosulfites forms in a second order reaction

Evidence for the mechanism:the addition of pyridine to the mixture of alcohol and thionyl chloride results in theformation of alkyl halide with inverted configuration.pyridine reacts with ROSOCl to give ROSONC 5H5. The Cl freed attacks from the rear

decomposition of ROCOCl (alkyl chloroformates) into RCl and CO 2 also follows S Nimechanism


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Nucleophilic Substitution at an Allylic Carbon: Allylic Rearrangements

under SN1 conditions ( Mechanism) 1/D

N+3/A

N

Free carbocation ?? Or Ion pair?Exhibits product spread in the direction of starting compound .

product spread decreases with increasing polarity of solvent, stabilising the free carbocation


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Why the product spread?Formation of an unsymmetrical intimate ion pair in the first step (different fordifferent starting compound)a considerable amount of internal return of this ion pairthe counterion remains close to the carbon from which it departed.The field of the anion polarizes the allylic cation, making the nearby carbon atom

more electrophilic,it has a greater chance of attracting the nucleophile

on acetolysis gave not only both the acetates, but also

the isomerization was faster than the acetate formationthe rate of formation of the rearranged chloride was unaffected

by the addition of external Cl -


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allylic rearrangements can also take place under S N2 conditions,the nucleophile attacks at the carbon rather than the usual position

Occurrs where S N2 conditions hold but where sterically retarded by the normal S N2mechanism

Increasing the size of the nucleophile increases the extent of the S N2' reaction atthe expense of the S N2

leaving group can also have an affect on whether the rearrangement occurs

3/1/A NDN


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nucleophile to attack at the position instead of the position

2-buten-1-ol and 3-buten-2-ol, both gave 100% allylic rearrangement when treatedwith thionyl chloride in ether

Ordinary allylic rearrangements (S N1') or S N2' mechanisms could not be expected togive 100% rearrangement

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