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The cyclohexanone enamine attacks the beta carbon of the cyclopentenone. Its nitrogen lone pair forms an iminium C=N bond as the enamine pi bond forms the new C–C bond; simultaneously the enone pi system shifts onto its oxygen. proton transfer converts the resulting cyclopentanone enolate back to the ketone.

A final iminium deprotonation regenerates an enamine, but the position of its double bond matters. Label the nitrogen-bearing cyclohexane carbon $h_1$, its initially nucleophilic neighbour $h_2$, and the other neighbour $h_6$. After addition, $h_2$ bears the cyclopentanone substituent. deprotonation at $h_6$ gives $h_1=h_6$, the less substituted, less hindered enamine drawn in A. Merely restoring the original $h_1=h_2$ bond would give a different regioisomer. Interconversion through the iminium ion permits this enamine regioisomerization under the reaction conditions. The methyl and mesylate substituents are spectators during this first Michael addition.

The phenolic O–H is most acidic; the benzylic CH2 adjacent to the amide carbonyl is second. Phenolic deprotonation gives a phenoxide stabilized by resonance in chemistry. Removing an alpha-amide C–H gives an enolate/carbanion stabilized by the carbonyl and the adjoining aryl group, but requires substantially stronger basicity for a comparable equilibrium concentration. The morpholine nitrogen is an acylated tertiary amide nitrogen and has no N–H proton. The other morpholine and aromatic C–H positions do not have the same direct carbonyl stabilization.

E, with the axial anomeric acetate, hydrolyses faster. The tert-butyl substituent strongly favours the chair in which it is equatorial, so the two substrates cannot freely interchange axial and equatorial acetate simply by an inexpensive ring inversion. protonation activates the anomeric acetoxy leaving group. As its C–O bond cleaves to release acetic acid, a lone pair on the endocyclic oxygen donates into the developing anomeric orbital, producing an oxocarbenium ion. water attacks that carbon, and deprotonation gives the cyclic hemiacetal. Attack from either face accounts for the unspecified anomeric configuration of OH in the product.

The axial C–OAc bond in E can adopt antiperiplanar geometry relative to an endocyclic oxygen lone pair. This favourable $n_O\to {\sigma }_{C-O}^{\ast }$ interaction assists departure in the ionization transition state. The corresponding bond in F is poorly aligned in its preferred chair; achieving comparable overlap requires an unfavourable chair change, placing tert-butyl axial, or substantial ring distortion. The distinction is stereoelectronic control of acetal hydrolysis, rather than merely counting steric crowding in the products.

An axial acetal can itself receive ground-state stabilization from the anomeric effect, so “axial means unstable” is not an adequate rate argument. What matters is the relative Gibbs energy of activation for the departing bond and the geometry of lone-pair assistance. Conformationally locked model acetals experimentally demonstrate faster acid-catalysed cleavage of the axially oriented isomer, although their numerical rate ratios should not be transferred to these different substrates.^[ref]

With triethylamine present, proton transfer from thiophenol produces a more nucleophilic thiolate population. sulfur attacks the anomeric epoxide carbon C1 from the face opposite its epoxide C–O bond. Displacement by backside attack opens the epoxide, breaks C1–O, and leaves the former epoxide oxygen attached to C2. protonation of that alkoxide by thiophenol or triethylammonium gives G: SPh at C1 on the front face and OH at C2 on the back face, a trans relationship. This is inversion at C1 with retention of the C2 C–O bond; there is no need to invert every stereocentre. Rapid protonation also suppresses competing silyl transfer by the alkoxide.

Without added base, neutral thiophenol is less nucleophilic. acid-assisted cleavage at the anomeric epoxide bond can instead be accompanied by donation from the ring oxygen, giving an oxocarbenium ion with charge shared with the ring oxygen. thiophenol capture from the face that puts SPh back on the original epoxide face, followed by deprotonation, gives H with SPh and C2–OH both on the back face, the net-retention pathway. An ion-pair or highly asynchronous opening can provide this outcome; the drawing does not establish a long-lived free carbocation.

The distinction is configuration, not a mandatory fixed chair. For the closely matching trisilylated substrate, the primary study obtained both anomers with thiophenol alone, and established an unusual inverted chair for the alpha thioglycoside by NMR and crystallography. Thus H should be explained as an accessible product, not asserted to be the sole product or necessarily to have axial SPh in its preferred conformation.^[ref]

Both permitted alternatives follow the same condensation–activation–migration sequence. sodium acetate liberates a useful concentration of hydroxylamine from its hydrochloride while providing a buffered medium. nitrogen of NH2OH attacks the ketone carbonyl; proton transfer gives a carbinolamine. protonation of its carbon-derived OH and loss of water, with nitrogen lone-pair donation, then gives the oxime after deprotonation. The two C=N geometries can be separated.

For the B-to-D route, oxime O-tosylation begins when oxime oxygen attacks sulfur of tosyl chloride and chloride leaves; triethylamine accepts the released proton. The resulting O-tosyl oxime has an excellent leaving group. The $K-R_a$ bond, anti to N–OTs, migrates to nitrogen while N–O cleaves, giving a ring-expanded nitrilium ion. Its local connectivity is $R_s-K\equiv N^{+}-R_a$, with the existing scaffold still joining the two paths. water attacks the nitrilium carbon $K$. proton transfers and imidic-acid/amide tautomerization produce D, with nitrogen inserted on the aromatic side of the old carbonyl.

For the C-to-E route, the same O-tosylation activates the other oxime geometry. Now the anti bond is $K-R_s$; its migration gives $R_a-K\equiv N^{+}-R_s$, and aqueous trapping produces E, with nitrogen inserted on the spiro-junction side. Each Beckmann rearrangement expands the ketone's six-membered ring to a seven-membered lactam. The original carbonyl carbon remains the amide carbonyl carbon; nitrogen is the inserted atom. In this mechanism the ketone oxygen is lost during oxime condensation, the oxime oxygen leaves with the sulfonate group, and water supplies the new amide oxygen.

The initial nucleophile attacks silicon, not the nitrile or an alkene carbon. Each trimethylsilyl group has an electrophilic Si center. A methyl group from methyllithium attacks Si, passing through a pentacoordinate silicon arrangement; Si–O cleavage releases $\mathrm{SiM}{\mathrm{e}}_4$ and the lithium salt of the oxygen-containing fragment. Cleaving the silyl enol ether generates a lithium enolate; cleaving the aryl silyl ether generates a phenoxide. Neither operation needs a new deprotonation at a carbon stereocenter.Here $R-O^{-}$ represents either the phenoxide or the oxygen-centered enolate contributor. Excess reagent permits both cleavages. The pre-existing methyl/nitrile stereocenter retains its configuration: it has no hydrogen to remove, and neither bond attached to that center is broken.

After HMPA is added, each anionic oxygen attacks the carbonyl carbon of allyl chloroformate. The C=O pi electrons move to the carbonyl oxygen, giving a tetrahedral intermediate; collapse expels chloride. The enolate becomes an allyl enol carbonate, and the phenoxide becomes an aryl allyl carbonate, each containing $\mathrm{O}-\mathrm{C}(\mathrm{O})-\mathrm{OC}{\mathrm{H}}_2\mathrm{CH}=\mathrm{C}{\mathrm{H}}_2$. oxygen acylation accounts for preservation of the enol double bond and for the two newly installed carbonate groups. carbon attack would give a different carbon skeleton. The two oxygens are trapped because they were selectively unmasked by desilylation, rather than because every ether oxygen in the molecule is equally reactive.

In the strongly acidic nitrating mixture, the dimethylamino nitrogen is predominantly protonated. The substituent is therefore $-\mathrm{NM}{\mathrm{e}}_2{\mathrm{H}}^{+}$ during aromatic substitution, rather than the neutral electron-donating $-\mathrm{NM}{\mathrm{e}}_2$ group. Its lone pair is unavailable for conjugation. Ortho or para attack would generate a sigma-complex contributor with positive ring charge at the carbon attached to an already positive nitrogen; meta attack avoids that especially unfavorable contributor.

Sulfuric acid protonates nitric acid, and loss of water produces the nitronium ion. Aromatic attack at a meta position forms a Wheland intermediate; deprotonation restores aromaticity. The bicarbonate workup then returns the amino group to its neutral form. $A$ is 3-nitro-N,N-dimethylaniline.

There are six inequivalent aromatic carbons in this unsymmetrical meta-disubstituted ring and one carbon environment for the two equivalent N-methyl groups, giving seven carbon NMR signals. The para isomer would have only four aromatic environments plus the methyl environment. An ortho isomer could also give seven signals, so signal counting supports but does not alone establish the meta assignment; protonation-dependent directing effects are essential.

Acid protonates one methoxy group of 2,2-Dimethoxypropane. methanol departure gives the oxocarbenium species $\mathrm{M}{\mathrm{e}}_2\mathrm{C}(\mathrm{OMe}{)}^{+}$, which is captured by one diol oxygen. After proton transfer, protonation and loss of the remaining methoxy group generate a second oxocarbenium center. Intramolecular attack by the other diol oxygen closes the five-membered ring; deprotonation regenerates acid. The net transacetalization exchanges two methoxy groups for the two diol oxygens, releasing two methanol molecules.

The two starred carbon centers retain their original configurations, and the two carbon side chains on the acetonide are trans. No C–O bond at either original stereocenter is broken; reaction takes place at the reagent-derived CMe${}_2$ acetal carbon. The apparent change in wedge/dash presentation comes from redrawing the backbone into the five-membered ring, not inversion at a starred center. In the planar pentagon used in the diagram, draw the alkynyl-bearing side chain behind and the $\mathrm{C}{\mathrm{H}}_2\mathrm{OPMB}$ side chain in front. The unstarred methyl-bearing center also retains its configuration. The acetal carbon itself is not stereogenic because its two methyl substituents are identical.

The reactive fragment is the C6 amidine-like portion of the purine ring; the N9–ribose attachment is retained. Write it locally as $N1=C6(\mathrm{N}{\mathrm{H}}_2)-$, with the rest of the fused ring understood. One productive acid catalysis route protonates N1, making C6 more electrophilic. water then adds at C6 while the C6=N1 pi electrons move onto N1. Subsequent proton transfers generate a carbinolamine and then a protonated amino leaving group:These are local bonding fragments: C6 retains its bond to the adjoining ring carbon at every step. In the addition step, an oxygen lone pair forms C6–O and the C6=N1 pi bond opens. During collapse, an oxygen lone pair reforms C6=O and the C6–N6 bond breaks toward the departing nitrogen. Solvent mediates each proton transfer; no direct unsupported transfer across a long distance is required.

water supplies the new C6 oxygen, and ammonia is expelled after protonation of the leaving group. Final deprotonation gives the lactam form of inosine. In acidic bulk solution the released ammonia is largely trapped as ammonium. The catalytic proton transfers regenerate acid around the substitution cycle; ammonium trapping separately affects the net proton balance. This is hydrolytic deamination, not cleavage of the glycosidic bond.

The all-carbonyl hydride, HCo(CO)${}_4$, is more acidic. Loss of ${\mathrm{H}}^{+}$ gives $[\mathrm{Co}(\mathrm{CO}{)}_4{]}^{-}$, whose negative charge is stabilized by pi backbonding into four carbonyl ligands. Replacing one CO by triphenyl phosphite reduces the net electron-withdrawing character of the ligand set relative to four carbonyls. The substituted hydride is more electron rich and its conjugate-base anion is less stabilized against protonation.Both conjugate bases have a conventional 18-electron count, so the difference is not a missing-electron argument. It is the relative stabilization of acid and base by the ligands in coordination chemistry. This concerns heterolytic deprotonation, not the homolytic Co–H bond-dissociation energy.

Pyrrolidine and 2-methylcyclohexanone first form an enamine, through carbonyl addition, carbinolamine formation, dehydration to an iminium ion, and alpha deprotonation. The less hindered enamine carbon is on the side opposite the methyl-bearing alpha carbon. It attacks the terminal beta carbon of methyl vinyl ketone, while the conjugated $\pi$ system shifts to oxygen. Protonation gives an alkylated iminium species; aqueous acid then hydrolyses it back to the ketone.

The result is a Michael addition product: the previously unsubstituted alpha carbon bears $-\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{COC}{\mathrm{H}}_3$. In drawing the arrows, start the new C–C bond at the enamine carbon, not at nitrogen. The iminium bond is restored during addition and removed by hydrolysis. The sequence is an enamine-mediated conjugate addition, rather than direct addition to the methyl vinyl ketone carbonyl.

Protonation of a spiroacetal oxygen makes the adjacent C–O bond easier to cleave. Reversible opening gives an oxocarbenium ion, in which the spiro carbon is locally planar. The tethered alcohol can attack either face; deprotonation closes the acetal and regenerates acid. Repetition interconverts the spiro epimers while retaining the other stereogenic centres. Methanol can participate in reversible proton transfer or trapping, but there is no need to invert the remote carbon centres.

$A=[\mathrm{Co}(\mathrm{N}{\mathrm{H}}_3{)}_5(\mathrm{OH}){]}^{2+}$, $B=[\mathrm{Co}(\mathrm{N}{\mathrm{H}}_3{)}_5(\mathrm{ONO}){]}^{2+}$, $C=[\mathrm{Co}(\mathrm{N}{\mathrm{H}}_3{)}_5(\mathrm{N}{\mathrm{O}}_2){]}^{2+}$, and the by-product is $\mathrm{HN}{\mathrm{O}}_2$. The first transformation is deprotonation of coordinated water, not loss of an ammonia ligand. The hydroxo ligand in $A$ is then nitrosated at oxygen, retaining its original Co–O attachment in the initially formed O-bound nitrito ligand. Atom and electric charge balance giveThe relative molecular mass of nitrous acid is approximately $1+14+2(16)=47$. Heating converts the O-bound nitrito ligand to the N-bound nitro ligand; these are linkage isomers, with Co remaining in oxidation state $+3$ throughout.

First hydrolyze the benzylidene acetal. Protonate one acetal oxygen and break its bond to the Ph-CH centre, giving one free alcohol and a benzylic oxocarbenium ion. Water attacks that centre; proton transfers give a hemiacetal. Protonate the remaining acetal-derived OR group and cleave it to release the second alcohol and benzaldehyde.

The resulting unsaturated hydroxy ester isThe OH on the allyl-substituted methine is gamma to the ester carbonyl. Protonation of that carbonyl enables intramolecular OH attack to give a five-membered tetrahedral intermediate. Proton transfer to methoxy and collapse expel methanol, followed by deprotonation to give the alpha,beta-unsaturated gamma-lactone.

The other liberated OH remains CH${}_2$OH. Both C=C units survive: one is the allyl substituent and the other becomes the lactone's conjugated double bond. Hydrolysis to a hydroxy acid followed by lactonization is an alternative sequence under the aqueous acid; direct acid-catalysed intramolecular ester exchange gives the same atom mapping.

ethanol undergoes proton transfer with the methoxide produced. The oxygen lone pair of methoxide attacks the hydroxyl proton of ethanol, while the ethanol O–H bond pair returns to its oxygen:The alcohol acidities are similar, so this is an equilibrium, not an overwhelmingly one-way deprotonation determined solely by intrinsic acidity. The large ethanol reservoir and initially small methanol concentration nevertheless matter. This exchange means that lithium ethoxide need not be consumed stoichiometrically in the net transesterification. Neutral ethanol can also participate in proton shuttling; it is not acting as a reducing reagent or as a substrate for elimination under these conditions.

Begin with the same ammine deprotonation and amido-assisted weakening/cleavage of the Co-S bond, but now SCN${}^{-}$ is already beside the metal. A solvent-caged pair of five-coordinate cobalt amido species and the departing thiocyanate can reorient and recombine through nitrogen before the ligand diffuses into bulk solution. Reprotonation restores the five ammines and gives A.

Thus the essential sequence isWater capture competes to give Co-OH, but rapid internal return of the already associated ligand accounts for the high yield of A. The slower entry into the reactive conjugate-base/dissociation sequence is followed by faster reorientation, capture and proton transfer. This is linkage isomerization, not oxidation or reduction of cobalt.

Low-spin Co(III) is substitution-inert. In acid, coordinated ammine deprotonation is suppressed, so the strongly donating amido conjugate base that assists ligand loss is not generated appreciably. Direct aquation/linkage change consequently remains very slow.

The persistence of the starting S-bound complex therefore supports a base-activated kinetic pathway. It is consistent with the rapid rearrangement in base and does not mean that the S-bound form must be the thermodynamically preferred linkage isomer under every condition.

First the tertiary amine attacks the primary allylic bromide carbon by SN2 reaction, giving the quaternary ammonium salt. The less hindered nitrogen face is favored by the pre-existing fused-ring stereochemistry.

DBU removes the proton at the carbon alpha to both the ammonium nitrogen and the ester carbonyl. The resulting ammonium ylide undergoes a concerted 2,3-sigmatropic rearrangement: the N–CH${}_2$(allyl) bond breaks, a bond forms between the ylide carbon and the aryl-bearing terminal allyl carbon, and the double bond moves to give $-\mathrm{CH}(\mathrm{Ar})-\mathrm{C}(\mathrm{Me})=\mathrm{C}{\mathrm{H}}_2$. Nitrogen becomes neutral again. An ordinary alkyl substitution would attach the wrong end of the allyl unit.

An envelope-like five-membered transition structure keeps Ar outside the crowded bicyclic framework. With the pre-existing OMe dash and ring-junction geometry fixed, place the newly installed side chain on the solid-wedge face at the former ylide carbon and choose the benzylic configuration that places Ar outward, as in the displayed intermediate. This is diastereoselective, suprafacial allyl transfer.

Finally methanesulfonic acid protonates the methyl acetal. Methanol leaves to give an oxocarbenium/iminium-stabilized electrophilic centre, which is attacked intramolecularly by the electron-rich arene at its available ortho position. Deprotonation restores aromaticity and closes the bridge. The terminal isopropenyl group survives; it is not the bond consumed in this final Intramolecular Friedel-Crafts reaction. The constrained tether selects the displayed bridged diastereomer.

The kink indicates that two pathways with different leaving-group sensitivities compete: one dominates for good leaving groups and another for poorer ones. A single straight-line free-energy relationship is insufficient. The additional hydroxide-order information can be accommodated by rapid phenol deprotonation,Two rates are then possible. A route with one hydroxide equivalent in its overall kinetic dependence contributes $k_2[\mathrm{C}][\mathrm{O}{\mathrm{H}}^{-}]$. Attack of a further hydroxide on phenoxide ester contributesThus $k_3=k_{\mathrm{add}}{K}_{\mathrm{OH}}$. The third-order term need not involve a simultaneous collision of three molecules: sequential acid-base equilibration followed by bimolecular attack produces it.

The three regions represent competing pathways whose leaving-group sensitivities differ.

The bend in the upper plot is a crossover of mechanisms, not a discontinuous change in the identity of the leaving group. The lower plot is the separate hydroxide-on-phenoxide pathway.