Solutions to Problems Chapter 1 1-1-8: dipolar resonance stecture has aromatic character in both rings and would be expected to inake a major contribution to the overall structure Od -~ Od 5, The “extra” polarity associated with the second resonance structure woud Soaihate 10 the molecular structure but would not be accounted for by standard group dipoles, © TREE ae thee major Factors contibuing to the overall dipole moments: (1) {he o-bond dipole associated withthe C—O and C—N bonds: (2) the w-bona dipole associated with delocalization of wr electrons from the heteroatom to the direction of the overall dipole moment, The AIM charges have been caleulated. electom ON sacions ay os ¢ i te oe ee ond O>N bona a ae Voce | unshared: 30 7008 aes os Aint chargos a09 2 Savas Pons 13.8 . The nitrogen is the most basic atom, Proven 4 Protonation on oxygen preserves the resonance interaction with the nitrogen unshared electeon pair. oH oH CHC. one! Ney NH Protonation on nitrogen limits conjugation to the diene system, Protonation 62.2) preserves a more polar and more stable conjugated iminium system, Protonation on C(3) gives a less favorable cross-conjugated system, ® —~QoOg oof i 4 Protonation on the ring nitrogen preserves conjugation with the exocyclic nitrogen unshared electrons, t i i Nt 4 ‘charge can be delocalized charge is localized on ‘exocyete nitrogen ‘The dipolar resonance structure containing cyclopentadienide and pyridinium tings would be a major resonance contributor. The dipole moments and bond lengths would be indicative. Also, the inter-ting “double bond” would have a reduced rotational barrier, ‘The dipolar oxyeyclopropenium structure contributes to longer C=O bond and lan increased dipole moment, The C=O vibrational frequency should be shifted toward lower Frequency by the partial single-bond character. The compound should have a larger p&, for the protonated foun, reflecting increased electron density at oxygen and aromaie stabilization of the cation9 ° o A- Pr ph pr Sp © There would be a shift in the UV spectrum, the IR C=O stretch, and NMR ‘chemical shifts, reflecting the contribution from a dipolar resonance structure. i ° oe Coe prefer planar geometry because of the resonance stabilization, The barrier to rotation is associated with MO terminology, the orbital with the orbital provides a stabilized Aslocalized orbital. The nonplanar form leads to isolation of the nitrogen ‘unshared pair from the C=O system, Boom — 85 a ah B09 Non, oe So b. The delocalized form is somewhat more polar and is preferentially stabilized in solution, which is consistent with the higher barrier that is observed © Amide resonance is reduced in the aziridine amide because of the strain associated with sp? hybridization at nitrogen, 2, sen] i ‘The bieyelie compound cannot align the unshared nitrogen electron pair with the carbony! group and therefore is less stable than a normal amide. 1-5. a The site of protonation should be oxygen, since it has the highest negative charge density? ® 4 Soha Pons 16. b The site of reaction of «hard nucleophile should be C(t), the carbonyl carbon, 48 it has the most positive charge © A soft nucleophile should prefer the site with the highest LUMO coefficient, {ns phenyl group decreases the LUMO coefficient, whereas an alkyl group imereases it, Reaction would be anticipated atthe alkyl-substituted carbon ATE 08s differences between the benzofb] and benzole] derivatives pera to all hee heteroatoms. The benzo[b] compounds are more stable, more romatie, and te eae thas the benzoe) isomers. This is reflected in both AH, and the HOMO-LUMO gap. Also the greater uniformity ofthe bond orders (2 the benzo[t) isomers indicates they are more aromatic. Furthermov benzenotd ati I losin the benzofb) adders, whereas it increases inthe Bence] adducts and this i reflected in the TS energy and Ai". The onder of Aff" ia in accord with the observed reactivity trend O > NH > 8. Since these dienes {cas electron donors toward the dienophile, the HOMO would be the frontier Grbital. The HOMO energy order, which is NH > S > O, does not accord with the observed reactvi [The assumption of the CH bond energy of 108kcal/nol, which by coincidence cts fame as the HH bond energy, allows the caledlation of the enthalpy ail ofthe energy diffeence resides in the central bond, rather than in eeu adjustments between the propellanes and bicycloalkanes. Let BE, be the bond ‘energy of the central bond: AH = 2(C-H) ~ BE, ~H—H = 208 ~BE, BE, (2.2. ]propellane = 104—95 = § BE,[2.1.1]propellane = 104-73 = 31 BE,[I.1.1]propellane = 10439 = 65 - 104 = 104 —BE, {iis fest indicates that while rypture of the center bond in [22.1 }propllane is nearly energy neutral, the bond energy increases with the smaller tings. The rngeriying reason is that much more strain is released by the rupture of the [2.2.1}propellane bond than in the [1.1 ]propellane bond. + The various jy values allow assigning observed Affyy and APT, @s inthe chan below. Using the standard value of 27.4keamol for a cis-duble bord allows the calculation of the heats of hydrogenation and gives a value for she ;ruin" associated with each ting, For example, the Aux of cis-eyctoostene is only 23.0keal’mol, indicating an increase of 27.4 ~23.0 = 4:4kcamel of aumin on going (0 cyclooctane, The relatively high AF» for irans-cyclovctene reflects the release of ruin on reduction 10 eyclooctane. The “strin” lor exch Sapound is & combination of tata tain minus any stabilization for conjugation {The contribution of conjugation ean be seen by comparing the conjugated 1.3 ‘isomer with the unconjugated 1, somers of eyelooctadiene and is about dé Tkeal/mol. Since the “srtn” for eyclooctatetraene fs similar to the ‘other systems, there is no evidence of any major stabilization by conjugation,® 19. 1.10, ee () — O ee 22.74 Ne 309, 4-278 C200 3s) 68) 02) j-o80 aA Oe (a9) (ray NA O ea) By subtracting the value for X=H from the other values, one finds the “additional” resonance stabilization associated with the substituent, There is Some stabilization associated with the methyl and ethyl groups and somewhat more for etheny! and ethynyl. This is consistent with the resonance coneept that the unsaturated functional groups would “extend” the conjugation, "The Stabilization for amino is larger than for the hydrocarbons, suggesting additional Stabilization associated with the amino group, The stabilizations calculated are somewhat lower than for the values for groups directly on a double bond. ‘The gas phase AG gives the intrinsic difference in stabilization of the anion, ‘lative to the corresponding acid, The reference compound, CHyCOsH, has the highest value and therefore the smallest intrinsic relative stabilization, ‘The differ, ental solvation ofthe anion and acid can be obtained from p. 5 by subtracting the solvation of the acid from the anion. The numbers are shown below. The {otal stabilization favoring aqueous ionization, relative to acetic acid, is the sum Of the intrinsic stabitization and the solvation stabilization. These tend to be in Opposite directions, with the strongest acids having high intrinsic stabilization, but negative relative solvation, x Ne sotvation| Inuiaic ‘ol a ci, MSM Msai—wTz=me a M249 249-6447 027302 260 cach, 33330 393.5050. 268 ect, 32966 427.65—55.4 403 [HC B41 MUT-os72—077809 LoaWe see thatthe final stabilization relative to acetic acid gives the correct order of pA. Interestingly. the solvation of the stronger acids is less than thet of the weaker acids. This presumably reflects the effect of the stronger intemal Stabilization, These data suggest that intrinsic stabilization dominates the relative Acidity for this series, with solvation differences being in the opposite direction I-11, These observations are the result of hyperconjugation between the nitrogen unshared electron pair and the axial C-H bonds. The chair conformation of the Piperidine ring permits the optimal alignment, The weaker CH bond reflects N= @" delocalizations. The greater shielding ofthe axial hydrogen is also the Fesult of increased electron density in the CH bond. The effect of the axial ‘methyl groups is one of raising the energy of the unshared eleeitons on nitrogen and stabilizing the radical cation. — a" s n OH OH 1-12. a-e, Bach of these substitutions involves extending the conjugated system and results in an MO pattern analogous to allyl for luoroethene and to butadiene for propenal and acrylonitie, respectively, @ © @ 8 cach cxofgg 4. The addition of the methyl group permits «+ * and m+ «interactions that can be depicted by the n-type methyl orbitals. The o orbitals can be depicted as the symmerry-acapred pairs shown, As a first approximation, one of each pair will be unperturbed by interaction of the adjacent m orbital because of the requirement that interacting orbitals have the same symmetry Roa moOFT ay LAGE ef The substituents add an additional p orbital converting the conjugated system to a benzyllke system. Inthe benzyl cation, the i, orbital is empty, ‘resulting in a positive charge. In fuorobenzene, the p, orbital on fluorineQoQ wil we cnste with he sem a wl lo is ets ’ in cece foe eon dey Yon hoa cksheegane carat Moone wl ps he obec aga ane itn a omc ove ergy Wane cea oa fest A a peti he he a met Gi wit etn ogee wi. ee i ih — we wa Comment, With the availability of suitable programs, these orbitals could be calculated, Siena Pris 1.13. a. The resonance interactions involve a -> 1° hyperconjugation in the case of ‘methyl and —+ 1° conjugation in the case of NH, OH, and F, as depicted beiow. K \ He. Ho we Tw eee Q # 7 H XH CHpsCH-x: —~ cH, VB description of interaction with donor substivsnis, ome Bi MO cesciption of interaction win donor substtuents >. There are two major stabilizing factors at work. One is the 1 delocalization depicted for both the methyl group and heteroatoms, The order of this effect should be NH, > OH » CH, which is in accord with the observed order of the inevease in stability. The other factor is the incremental polarity of the bonds, where an increment in stability owing to the electronegativity difference should occur. This should be in the order F > OH > NH, but this ‘onder seems to be outweighed by the effect of the ar-electran delocalization, “ws% ? The NPA charges are in qualitative agreement with the resonance/polar dichotomy. The electron density on the unsubstituted carbon C(2) increases, as predicted by the resonance structures indicating delocalization of the heteroatom unshared electron pair. The charge on the substituted carbon C(1}) increases with the electronegativity of the substituent. As is characteristic (and based on a diflerent definition of atomic charge), the AIM charges are dominated by elecironegativity differences. There is some indication of the st-donor effect in that C(2) is less positive inthe order NH, < OH =F. 1:14 a In the strict HMO approximation, there would be two independent and 4 ‘orbitals, having energies that are unperturbed from the isoleted double bonds, which would be +8 in terms of the HMO parameters b. There would now be four combinations. The geometry of the molecule tilts the orbitals and results in better overtap of the endo lobes. should be stabilized, Whereas Y» will be somewhat destabilized by the antibonding interactions between C(2) and C(6) and C(3) and C(5). Ys should be slightly stabilized by the cross-ring interaction. The pattern would be similar to that of 1,3-butadine, but with smaller splitting of Wy and tly and Hy and ty © The first IP would occur from Ws, since it is the HOMO and the second IP ‘would be from yy. The effect of the donor substituent is to lower both IPs, but |P, is lowered more than IP. The electron-withdrawing substituent increases both IPs by a similar amount, The HOMO in the case of methoxy will be dominated by the substituted double bond, which becomes more electron rich 48 a result of the methoxy substituent. The cyano group reduces the electron density at both double bonds by a polar effect and conjugation, ty fe te OY ay “ ‘The HMO orbitals would each have energy a oe “p — =e 1115: a Since there are four a electrons in the pentadienyl cation, yy will be the HOMO, b. From the coefficients given, the orbitals are identified as and yy, shown below. Ye is a bonding orbital and is antisymmetric. yy is a nonbonding orbital and is symmetric oft> 1-16. The positive charge on the benzylic position increases with the addition of the 9 EWG substituents, which is consistent with the polarity of these groups. There —___) is relatively lite change at the ring positions. All the cations show that q imi Pons substantial part of the overall cationic charge is located on the hydrogens. There is a decrease in the positive charge at the para position, which is consistem: vith delocalization to the substituent, All the structures show very significant bond length alterations that are consistent with the resonance structures for delocalization of the cation charge tothe ring, especially the para position 1.17 a In terms of « the four linear homogeneous equations for butadiene take the Form: axtay ay +ajxtay a tasetay ay tax where x = ~1.62, 0.618, 0.618, and 1,62. For y, x= 1.62, and we obtain =1.62a, +4; =0 4, ~ 1624; +a, =0 4; — 1.024, tay =0 44-1824, =0 ‘The first equation 1.62a, Substitution of this value for ay into the second equation gives 0 4, ~ 1.62(1,62a,) +4; 4; = 1,62, From the last equation, we substitute the a; in terms of a, and obtain 62a, ~ 1.624, =0 We must normalize the eigenfunction: ae tae tagdy 10 ‘Making the appropriate substitutions gives Shei Praena 4? +2.62a7 42.624, 44, and W =0:372p, +0.602p, +0.602p, +0.272p, ‘To obtain the coefficients for Ys we use the value of x, = 0.618, and ‘CAMTY oUt the same procedure that is illustrated above. The tesulis are a; = 06184, 4 =~0618a, and. _ 4,7 40.3824)? +-0,382a,? +a; = @ and 372 an .602p, +0.372p, ~ 0372p, ~0.602p,” a e 118, a, Using the values x = 0.618 and 1.62, we repeat the same procedure for ‘and thy. The four eigenfunctions for butadiene are: 1 =0.372p, +0.602p, —0.602p, -0.372p, 0602p, +0.372p; ~0,372p; ~0.602p, Ys = 0.602p, +0.372p, ~0.372p, -0.602p, = 0372p, +0.602p, ~0.602p; -0.372p, The MO diagram can be constructed using the Frost Circle, The energy of the occupied orbital is «+28, so there isa stabilization of 2B, nominally the same as benzene, suggesting substantial stabilization for this ion, ‘The longest UV-VIS band should correspond to the HOMO-LUMO gap. For 1.3,5,7-octatetraene and 1,3,5-hexatriene the HMO orbitals are as follows 135hoxavione 1,98,7cctteraene 0.445042 0.387298 vel Tm ‘The energy gap decreases with the length of the conjugated system, and therefore the 1,35,7-octatetraene absorption should occur at longer wavelengths. ‘The adcitional strain in spiropentane relative to cyclopropane is due to the fact that there can be no relief of strain by rehybridizaion of the spiro carbon, By symmetry itis tetrahedral and maintains sp° hybridization These values provide further indication of the strain in spiropentane. The intemal angle is close to that of an equilateral triangle (asin eyelopropane), ‘The 137° value indicates considerable strain from the ideal 109° for an sp? carbon. Ths strain induces rehybriization in the C(2) and C(3) carbons Using 0.25 as the 5 character in the spiro carbon, we find the s character in the C(1)—CQ2) bond to be 20.2 = $50(0.25)(x). The s character is 14.5%, For the C(2)—C(3) bond, 7.5 = $50("). The fractional s characteris 11.7% ‘This reaction would be expected to be unfavorable, since cyclopropane is tore acidic than methane. The increased character ofthe cyclopropane C_-H. bond makes it more acidic. A gas phase measurement indicates a difference in AH of about Skeal/mol ‘This comparison relates t0 the issue of whether @ cyano group is stabi- lizing (delocalization) or destabilizing (polar) with respect to a carbocation (see p. 304). The results of a HF/3-21G calculation in the cited reference indicate a net destabilization of about 9kcal/mol, in which ease the reaction will be exothermic inthe direction shown12 Saas 120, 121. 122, 123, The polar effects ofthe fluorine substituents should strongly stabilize negative charge on carbon, suggesting that the reaction will be exothermic Aw MPASDTQU-31+4(d\p) calculation finds a difference of ~ 48 kcal/mol. ‘Because ofthe antiaromaticity of the cyclopentadienyl eaton (p. 31) the first Faction would be expected to be the slower of the two. The reaction has not been observed experimentally, but a timit of < 10°* relative to cyclopentyl iodide has been placed on its rate 5 The exclopropenyl anion is expected 0 be destubilized (anaromatic) ‘Therefore, K should be larger forthe first reaction. An estimate hused on the {ale of deuterium exchange has suggested that the pk difference is at lean 3 fog units © Tie Second reaction will be the fastest. The allylic cation is stabilized by delocalization, but the cyclopentadienyl cation formed in the frst reaction 1G destabilized ‘Tre diminished double-bond character indicates less delocalization by conju gation in the carbene, which may be due to the electrostatic differences. In the cirbocation, delocalization incurs no electrostatic cost, since the net positive charge of | is being delocalized, However in B, any delocalization has an electro, ie energy cost. since the locelized sp" orbital represents a negative charge In the overall neutral carbene. Ze results ae relevant 0 a significant chemical issue, namely the stability of i ines with N-n-donor substituents. such as oximes (OXTHO) and hydrazones (YX = HN), are more stable to hydrolysis than alkyl (YX= HC). The classical explanation is ground state resonance stabilization, Ye-ne=ch, —~ vhen-onye [Tie Sibilzation i greatest for the F > OH > NH series of substituents. The sill sroup (ERG) is destabilizing, and the conjugated EWG groups ere moderately Stabilizing, The most significant structural change isin the bond angle, which implies a change in hybridization at nitrogen. The NPA charges show a buildup of charge on carbon for NH, OH, and F of about the same magnitude for each. This sould result from the 7 delocalization. The charges on N are negative (except {orf where it neu) and seem to be dominated by the elecroncgatvity of {he substituent atom with the order being Si> C > N > O> F. These recalta indicate that as the substituent becomes more electronegative, the unshared pair orbital has more s character. (Results not shown here for X= Li and Ne indicate that the lone pair is p in these compounds.) At least part of the siailization Would then be due t0 the more stable orbital for the unshared electron pei, A second factor in the stabilization may be a bond strength increment from the slectronegativity difference between X and N. The NPA charges indicate thatthe planar (conjugated) structures have charae- leristies associated with amide resonance. The oxygen charge in formamide fs tno Zao inthe planar form and —0.620 in the twisted form. For the NH, uroup, the charge is ~0.080 in the planar form and —0.182 in the twisted form, There differences indicate more N to O charge transfer in the planar form, For 3, aminacrolin, the coresponding numbers at Ona !~0.665, Opn 0.625 and NE! 0.060, NH siusy | ~0-149. These values indicate somewhat{ess Polarization associated with the (vinylic) resonance in this compound. For squaramide, the magnitude of the charges is similar O() jij! 0.655; OM uives ! 0.609 and NHsirigu 0.001, NH:yuinuy : 0.095; The differ. ences in the "0 chemical shifts and the rotational barrier also indicate greater fesonanee interaction in formamide than in 3-aminoacrolein and squaramide ‘The interaction maps show that the nitrogen is repulsive toward a positive charge in the planar forms, but becomes attractive in the (wisted form. The attractive ‘region is associated with the lone pair on the nitrogen atom in the twisted form Chapter 2 2.1. a, diastereomers: £. enantiomers. 22. a. S: CH(C), > CH,CH{C), > CH,CH, > H b. RSi>O>C>H ©. RO >C=0>C(C), >H . RO > C(C), > CH, > H © 5:0 > C(C)sC(C)sH > C(C),C(C)H, > C(C).H £ RIN > C(O), > C(O),H> CCH, & RO >C(C), > CH, > : (electron pair) mers; ¢, enantiomers; d diastereomers; ¢, enantiomers; 23. 24. a Pre ani PB — —— Paco "co. sasition a” Sco racemic (tiso) ——racomie _ Ph, Bee ang ‘con 4 davon racemic (ert) come 13 Bie Pts4 Sia Pons b. er OCH 90H, 2 cama ' : 97% 3% ‘enantiomeric excess = 94% 2.8, The solution to this problem lies in recognizing that there are steric differences for the phenyl group in the axial and equatorial conformations. In the equatorial Position, the phenyl group can adopt an orientation that is more or less “perpen- diculae” to the cyclohexane ring, which minimizes steric interactions with the 2,6-equatorial hydrogens. In the axial conformation, the phenyl group is forced to rotate by about 90°, which adds to the apparent —AG, for the phenyl group. ‘When a I-methy! substituent is present, the favorable “perpendicular” is no longer Available and this destabilizes the equatorial orientation relative to phenyleyclo- hexane, Sp ey prefered confarmation preferred conformation ty group precludes pratered ‘9109 t-phonyleyclohexane of ax tphenyeycherane conformation ane adds a desteizing Iniracton with 26-69 hogan Commen. This i a challenging question but can be approached effectively by MM modeling, 8 was done in the original and subsequent references, As discussed on p. 148, the preferred conformation of acetone is the C-HIC-=0 eclipsed conformation. Tis is stabilized by a ¢ — 1 interaction. For 2-butanone the C(4YC=O eclipsed is prefered, as discussed on p, 148 and illustated by Figure 2.12. For 3-methyl-2-butanone, four distinct conformations aise. The ‘maxima at 60° and 180° represent the CH,/CH, ectipsed conformations, which give tise (0 a barier of about 2.5 keal/mol. This is somewhat less than Tor the CHs/CH, eclipsed conformation of butane and presumably reflects the absence (of additional H/H eclipsing. An analysis of the 3-methyl-2-buianone spectrum is available in Ref. 36, p. 149,Hy cH, CHy__gOHs Ce oss So owt othe W i on, ‘oy 0% 240° CHyC=0 60%, 180", staggered 120%,H1CuO 300, staggered cipeed CHYCHs ecipsed—golpind hiv ecpeod 2.7, The stereochemistry of all of these reactions is governed by steric approach contol +o oy oom = : psc) ad am ye sgt ° 2 : eet « yon in Ry Iyegeraten 7%, oe . reagent spproach (0 ayer soe K Ay CCH aan omy NINO On = seat o meat \ © Zoe non mom ro en a 28. a,b. The conformers of 2-methylbutane differ by one “double” gauche inter- action. The conformation of 2-methylbutane that avoids this interaction is favored by 0.9 kcal. There is good agreement between experimental and ab ‘o results. Surprisingly, the two conformations of 2,3-dimethylbutane are virtually equal in energy, by experimental, MM, and ab initio results. The Qualitative “double” gauche argument fails in this ease. ©. This is an example of the 3-alky! ketone effect (p, 161), by which the conforma tional free energy of a 3-atkyl substituent is smaller than that in cyclohexane. ‘The AG. has been estimated as 0.55 keal/mol Comment. Assuming availability of a suitable program, this question can framed «as an exercise fo calculate and compare the energies of the two conformations of ‘h compound, 2.9. An estimate can be made by assuming additive 4G, and adding an increment (3.7 keal/mot) for |.3-diaxial interactions between methy! groups. The reference takes a somewhat different approach, summing gauche interaction terms 10 stimate the energy differences,> & wad sh = aA Saeegs -AG=9.4-1,7-97 254 H96=3.4-1.7=1.7 8G93.7+3.4-1.7 84 Comment. This problem would be amenable to an MM approach, 2.10. The conformation equilibria shown below have been measured, cH, os, CH, 079 GH, 1.00 HOW, 1.28 ie, 23 yy >100 ‘The wend sa eter modest increase wih size forthe primary groups though isobutyl Ther isa slighly lager change with the scoonduy hoppy eae, 8 followed by avery large factor favoring thesis conformer for poy he very lage Inerease going to buy osur because thee fe Ngee iydrogen tat cn oecpy the postion eclipsed withthe BCH ihe ea conformation omy ox” eR wa 2.11. The product stereochemistry can be predicted on the basis of the Felkin model, ° 5 7 CHy Ph, CH Ph, oh na) aN Wren on 4" Prger ‘threo or syn ° or on os ote myfow mt Po ArH H a ion of Crain's rule and uses an Comment, The reference is an early formula alternative conformation of the reactant.> ‘center. 2.12. The a. B-double bond is held in proximity to the catalyst center by the acetamido Substituent, while the .8-double bond is not brought near the coordination 2.13. cout con go = HORA 00H Hofh = wo K cou bab come c 2nss Gc 250n gout 03H cout = Hoe con HOH W064 ‘cout eae ase ne 2naA CHeCOH 25.5 2M. a ws 108 pos X pos 9 on) i WGC Ta con pee — 3 ent senator th roc wit viene contin iin b. sie vowed fromthe ep 4 i iromine top ©. The reaction proceeds with retention of con! figuration at C(3). Inversion occurs at CQ2). CoH Ch omy cose yy 4 é aN % 4 . mF OS E00 cn SH cg tow ad On We Ron Wy 3828 anas snan 3828 4 mom - Cs, ee ee 7 iain Patens entie 18 2s. 2.16. 2.17. 2.18. ‘An achiral tetramer with a center of symmetry results if the wo enantiomeric mers nonactic acids are combined in a structure that contains a center of symmetry. 4 (@) The cis isomer is achiral while the rans isomer is chiral. The chirality of {he wans-substituted ring system makes the benzyl hydrogens diastereoropic and nonequivalent. This results in the observation of geminal coupling and the appearance of an AB quartet. (b) Hyperconjugation with the nitrogen lone Pair moves axial hydrogens to high field in piperidines. The trans isomer has oe equatorial hydrogen, which appears near 2.8 ppm. Inthe cis isomer, only axial hydrogens are present and they appear upfield of the range shown, b. Isomer A is the cis.cis-2,6-dimethyl isomer, The benzyl singlet indicates that there is no stereogenic center inthe ring and the relatively narrow band at 3.4 icates that there is only eq-ax coupling to the C(I) hydrogen. Isomer B is the trans, trans-2,6-dimethy! isomer. The benzyl singlet indicates an achiral Steueture but now the larger ax-ax coupling that would be present in this isomer is seen, Isomer C isthe chiral cis, rrans-2.6-dimethyl isomer, The AB {quartet pater of the benzyl hydrogens indicates thatthe ring system isthe chiral cis, trans isomer. The splitting of the signal at 3.0 is consistent with ‘one equatorial and one axial coupling, ‘The data allows calculation of ~AG,. The interpretation offered in the reference is that hydrogen-bonding solvents (the lst two entries) increase the effective size of the hydroxy group. The potential donor solvents dimethoxyethane and tetrahydrofuran seem to have ltl effec This result seems to be due to 7 -» 0" and o> 1 hyperconjugation between the oximino and chloro substituents. Since hyperconjugation is also present in the ketone, the issue is rnised a8 to why the oximino ethers are more prone ‘0 the diaxial conformation. The fac thatthe oximino ethers adopt the dial conformation indicates thatthe hyperconjugative stabilization is greater forthe ‘oximes than the Ketones. This implies that the » | @ more polar environment, accounting for the shift toward more of the syn conformation. There does not seem to be stabilization of the 90° conformation, Which would presumably optimize C-X > m hyperconjugation. The anotnalous behavior ofthe nitro group is attributed to the somewhat different spatial orien, tation of the substituent, vty is consistent with a chelated TS. ~ 4 bts ole on Tae OAK —py Rt = ». The observed stereoselectivity is consistent with a Felkin-Ahn model. Siar Pros COCK it 2.24, Application of the oxazaborolidine (p. 196) and (Ipe)sBCI (p. 194) models correctly predict the R configuration of the chiral center. Phs: : p-wrn Ph. OH ; , fe oN CHOC eV’ co,cr 225, ‘The two methyl groups are enantiotopic. Pro-S CHy CH pros ° b. The two methy! groups are enantioto ° post pon cub, €. The metys inthe grpy! group ar dasteretpie as Potts Pro Ne cn & ky pos2.26, 227, 2.28, © diastereotopic, CH pros HNO" por Ky © Both the benzyl and glyeyl methylene hydrogens are diastereotopic. The ethoxy methylenes hydrogens are diastereotopic. The bromomethylene hydrogens are enantiotopic () chiral; (&) chiral, but note that inversion of the configuration of the methyl fsroups on one ring would give a molecule with a center of symmetry; (e) chiral, (@) achiral, plane of symmetry dissecting any ring and a ring junction: (e) achiral, center of symmetry and a plane of symmetry; (f) chiral; (g) chiral by virtue of helicity; (b) chiral; (i) chiral; (j) chiral; (k) chiral; (I) achiral, plane of symmetry aligned with the two C=O bonds; (m) chiral. ‘The following predictions are made by fiting the alkenes to the TS model in Figure 2.27. (a) DHQD (&); DAQ (Ss) (b) DHQD (5); DHQ (R) (e) DHQD (2,8); DHQ (5,5) (@) DHQD (8,8); DHQ (5,5) 4 The TS model on page 196 predicts configuration. Pn meh on ove Ae Sy crc Pn oy 8 b. The TS model on page 194 predicts R configuration, 2 oH oN tpe-200N “Serta,or SS OF> 22 © The empirical predictive scheme on p, 198 predicts thatthe 2R,3S-cpoxide Soe will be formed, *s eS, jour t 2A.35 729, (9) Classical resoltion; (b) kinetic resolution; () chiral chromatography; (4) enantioselective synthesis, 2:30. The original reference analyzed the barrier in terms of o-m hyperconjugation, However, as suggested by the analysis of ethane in Topic 1.1, the rotational barrier is affected by adjustments in molecular geometry, which will lead to changes in all components of the total energy. The analysis ofthe acealdehyde ‘otational barrier given on p. 148 shows that nuclear-nuclear and electron, . The enthalpy of oxidation can be obtained by a simple thermochemical calcu lation, since the 41, for O, the element in its standard state, is 0 PROH=0 + 1120, ——~ Phoo,H SH=-88 sho. SH, = 70.41 = 70.1 ~(-8.8) 61.3 © The difference in 11, between 2-methyl-l-pentene and 2-methylpentane corresponds 0 the heat of hydrogenati imethyleyclohexanol that would be dehydrated to the three alkenes shown, on CHy om ang The formation of a stereoisomeric mixture of 1,2-dimethyleyelohexane from each is in accord with these assignments. The H-catalyzed equilibration would establish the thermodynamic equilibrium so that the structures can be assigned fon the basis of relative stability. The relative stability of the alkenes should be C> B> A, based on the number of double-bond substituents, A plot of In K versus 1/7” gives a good straight line with a slope of 2428. By ‘use of Equation (3.1), this give AW =4,80kcal/mol and AS = —12.2¢u TempC Temp temp Kak AG” a as 728° M02 O.00870-169_aRIaI—1s18@ ~aNOTIey IRIE NS 284.9 Ooms 1.0 2397m8 13527 Lasoned Lis ia0 $81 2912 ooss3 84 ZID8282 “1297.1 Laos _ia 2088 219 3950 ooM0 79 2omoH 23 ond 000331 s—sTia02 2073 4807.64 12.2047 11208 —4su7.68 121921 32 M51 0028 61140828 “Ho924 agones Lise 389 3oRd 000025 5:7 E7404 © —tO614 —aRO7et ~IBLe 32-3103 oom 531647707 mae Dagoes Liat S25 M6 omualT 46 seo oma —worer ietsLnikvs. . fees : 24. —— a Rae 0 ae Oonsr come adm edi aos atm oc Gio " P30, em Baa eeeez~C~CZ~CE___ ime Taek a 250 DRI 0000355136807 —I8aI D008 BBNTT 982 a3 400 313.1 Oousi9e 850807 “13978 23008 22387 Be6s LS 501 3232 o.003094 2728.0 12815 23008 22307 4200 Be 5843319 0.03013 7368-06 “ina 23008 22359 FHI6 ABD Link vs. 177 of fp 3 ye 1620023188 = R= 0.9908 5 | -20 8.003 0.008 0.0081 0.0081 6.0082 0.0082 o0083 0.0083 OoGes o90s4 Ww Fig. 2.Pa, Plot of fa & versus 1/7 for seta of -ehlroheney tosylate, b, B Tempo Temp tks Ink Ea ant sat ast 03.1 o003008boed030—10.1143 27H 26TH asey SDE 70 MBI 0.G02915 ou0097 9.2408 27439 26760 GIT? 3D 25 MB 8002873 ooGOI79 R528 27439 26750 S917 G9 §0 353.4 o.cu2¥92 oun —¥0822 27439 derad S081 997 S03. mon7s4 com0K92 “70229 37439 A6mU AOR OT 2S MB.1_wO2TI7_ov01s90 64490 27439 26710 40979926 iso Plas nk ve. 7 0 2 xt 38683 + 3174 54 ta a3 0.9997 = “10 2 S.on27 0.00275 0.0028 0.90285 0.0029 0.00295 0.003 0.00305, ww Fig Pb, Plotofln vers 1/7 forthrmolyssof3-cloro-33-cloopteny) sine, 3.5. & The reaction profile would show a depression for the diradical intermediate for mechanism (a), but would show only a TS for mechanism (6). . An isotopic labeling study could determine ifthe exoeyclic methylene carbon and the C(3) methylerie had exchanged. Exchange would be expected for the diradical mechanism, but not for the concerted mechanism, Deuterium labeling showed that there was interchange of these carbons on the reaction path, indicating that the two-step mechanism is occurring, Fg. 39.5, Reaction nergy profiles fr dirs! and concerted echanism, 3.6, The reaction can occur by migration of either of the bridgehead carbons, which are in sterically similar environments. The data show that polar EWGs favor migration of the more remote carbon. The same trend is evident, although with ‘alenuated magnitude, in the substituted phenyl derivatives, Thus EWGs disfavor tnigration ofthe adjacent bridgehead carbon, whereas ERGs favor such migration. Migration is facilitated by the group's capacity to donate electrons Io peticipate in the migration process. The cited authors favor hyperconjugation as the cease for the substituent effect, but it could also be formulated in terms of the effect of the bond dipole.7 ac? es a . ype. arog cramieanenie aetna Deller able tomigrate seperated 3.7. & The data and plot show a somewhat higher correlation with « than with a= ‘The p value is +1.23, indicating that EWGs favor the reaction. The magnitude of the p, which is modest, and the poorer of correlation with o~ suggest a relatively early TS, occurring before full conjugation of the phenolate anion leaving group has developed. Group Rate iy Lop kik, « o ry 23 057 ~o2e “097 ~026 cH 24 0682 0192 017 “oy H a4 ' ° ° o Br 95.1 254 ows 023 02s NO, 130 us 161 078 ur Log k/k0 vs. Sigma 12 kiko “04 02002 04 06 084 ‘Sigma Log k/ko ve. Sigma 3 ° 8 7 15 Sigma . The correlation with a” is considerably better and the faily large negative p of $8 is consistent with substantial cationic character atthe teansition state.> 28 Substtent k Key tog ke, ° o Saar a Pons $CHO4RKE-03—Ga2EFO2_———-aDe cH, LOWE—OF — 200B+01 305 ot? “ua 4 SIE—05 ove +09 0 ° ° 41 3I8E-06 — 392E-01 040723 tt NO, M4468 L7RE~03 27st mk Log kiko vs. Sigma 4 3 2 21 #2 2 3 a 46, Log k/to vs. Sigma. Log kiko dobsbosmos 4 5 0 05 1 Sigma+ 6: The correlation is much better with @ than with a. The pis modestly negative (1.14), consistent with the expected qualitative substituent effect, The modest value of p and the lack of correlation with o* indicate that the substituent effect is primarily polar in nature Substivent lop Wop Ky ° ° 2cH,0 932 “099 0a OTe “+CH, 90 “019 017 “on sci, ~905 <00r D1 an 1H 903 00 uo 0 +r ~a98 0.09 0.06 007 40 883 020 023 ou cl ~86r 036 037 on ENO, 819 ost a7 on NO, a x9 on 0799 Log k/ko vs. Sigma 29 7 og 08 go B02 ao 02 4 “04-08 002 oa 08 08 Log k/ko ve. Sigma 1 os 08 204 202 Boo -02 34 28 + “05 ° cr 1 ‘Slgmay 38a. The first step can be treated as an equilibrium and the concentration of the anion expressed in terms of the reactants, How we RN =e senscag. er an [An] = KiBrCH-CHENIRAN) rai {AN = keKIB1CHeCHBH\FAN) "A10 = kp BICH=CHBAAN} > This represents an example ofthe classical Sy reaction Rate = AIR —XI. The ratio of products would be given by ks/ky. k, Ar-H+Bry {_UAHBr*] + Bris rate controlling Steady state approximation for [AcHBr*] leads to Ka(ArH] [Bro] = k_[APHBr”}[Br“]-+-ky[ArHBr*] and Bry = RUAPHIPB | (artery = KIB] +k, The effective [Br] is determined by the tribromide equilibrium = [BHI * BeBe]a 30 39, 3.10. Substituting gives 1 kekyfAPHIIBr) TER Be}* kB] +k, When ky[ArHBr] >> k_[AcHBr this simplifies to [Beslows 1 oe = RSA) a This can be formulated by using a steady state approximation for the enol (Eno! &y[Keto] =k_,[Enol] + 4(Cr]{Enol] __kilKeto] (Eno) = Ae ‘The rate then is Rate = k{Enol]{Cr} = x*lKetollCe} ky FRICH] THe apparent stabilization is given by [Arh (cyclic system)} ~ [Ay (ret)] ‘The following are the apparent stabilizations: ee System Apparent ssblation Cyetopropeny cation 239 Gyetopeopeny anion Cyetobuadiene Cyclopenaieny ation Cyetopentacienyl enon Benzene Cyeobeptaviony eatin ‘Cyeloeptnienyl anion This computation scems to emphasize the antiaromatie character more than the aromatic character. Note, for example, that the cyclopentadiene anion is calculated to be slightly destabilized by conjugation, which runs counter to the Observed relative acidity of the eyclopentadiene cing. The qualitative agreement with Hckel’s rule is exceltent but the agreement with the calculated 8 values is Poor. This treatment makes no explicit separation of stain. For example in the Cr system, the reference point is the allyl system. so the strain associated with losing a three-membered ring is subsumed into the calculated (destabilisation Thclusion of a separate term for strain would increase the apparent stabilization Of the cyclopropenyl cation and decrease the destabilization of the anion by the ‘amount of strain assigned, 4a. The very large heat of hydrogenation ofthe eyclobutadiene reflects the anti present in this molecule. The more or less normal heat of hydrogenation of the second step indicates that tere isnot much change of strain in this step. ‘b. The larger exothermicity of the first sing cleavage is the result of the rehydridization that is possible in the dimethyleyclopropane product. The relief of strain is greater in the first step than in the second because of the ‘adjustment in hybridization© The successive steps reflect: (1) change from di- to tri-substituted double bonds (2) relief of strain resulting from reduction of sp? carbons in the ring from one to two; (3) further relief of strain by removal of the sp carbon from the ring: (4) the final heat of hydrogenation is slightly lower than I-butene, Suggesting a small stabilization of the double bond by the cyclopropyl ring. 3.11, The mechanism is believed to involve rate-determining hydride donation from hydrated benzaldehyde. The lack of exchange with solvent protons indicates that it is the formyl hydrogen that is transferred, Reversible formation of the aldehyde hydrate and its conjugate base accounts for the appearance of "0 in both products. The third-order rate expression is also consistent with involvement of the hydrate, The role of aromatic substituents could be complex. The extent of hydration and the reactivity of the aldehyde to hydride transfer would be favored by EWG substituents. On the other hand, the hydride transfer itself would be retarded by an EWG in the hydrate. The positive p indicates that some combination of the former two factors must be dominant. The inverse and is consistent with 'y of “OD compared to “OH. The observations are Consistent with a mechanism in which the aldehyde hydrate acts as the hydride donor. AcHoO + -on SH AHO bu voy necro som arco aco, EL. ArcHoH + Arcos Nee A 7 312. t step must be rate determining, since the aromatic hydrogens exhibit 4 primary isotope effect, whereas there is no isotope effect for elimination of hydrogen from the styrene reactant, which occurs in Step 3. Step 2 would not be expected to exhibit a primary isotope effect because the aryl hydrogens are not directly involved in the reaction, but should exhibit a secondary isotope effect for styrene-f-ds. 3.13. 1, The larger substituent effect in the gas phase is due to the “leveling effect” in solution. In the gas phase, the adjustments to changes in the electron distribution resulting from ionization must be accommodated internally, so substituent effects are large. In solution, much of the effect of the negative charge is stabilized by solvation, and this reduces the relative importance of the substituent effects, 2. The larger and more polarizable benzoic acid molecule is able to better accommodate the charge of the anion in the gas phase. 3. Stabilization of the anion in solution causes solvent organization, which Appears as an entropy contibution, Substituent effects are translated into differences in solvation. Anions beter stabilized by internal substituent effects resull in somewhat looser solvation, 3:14, The correlation with o~ is marginally better than for @ and both ae significantly better than with o~. This indicates that the chemical shifts result from a mixture of polar and resonance effects that weight resonance slightly higher than for 319 32 Saar Proms the standard ionization of benzoic aci resonance o id. The data were used to assign “pure” flues by using a dual substituent parameter correlation Sutswent ae * 7 © Ma ~one arr 8 CHO “195 § a9 cH, 259 a 205 br -162 cr, 33 cn 3480 CHo.c 42 cco 8 cHso, 464 “on 0.06 017 023 023 ost 0.86 ass 030 on 026 “003 017 ou as 065 oo om oa 1 No, 333 o78 an van a Chemical Shift vs. Sigma i a + do[- = 15 a “5 g oo 1 Sigma Chemical Shift vs. Sigma+ 0 “10 Chemical shin. & 4 a & 15, Chemical shit Sigma315: The correlation with ois somewhat better than with a, although a diet resonance interaction does exist. Both A and AS show good linear correla, tions with AG. indicating that the substituent effect operates by both electroni stabilization and solvati Subsinen pk, K a6 i, cH. 89 68 027-078 cH, a2 6 017 “91 H mas oo 00 cr 3236 023 aur Br sis 02 ous cn ~pka vs. Sigma ° : Pe ] = aston ane as ae : sions Te ° s a: = z . rasan aa Sone ih ee ‘tomes Dt @ve.Deta son [Sara es wo wane eerie ure 33 Bare Pies34 Soha Pons Delta G vs. Delta S Dota s 3416. The absolute (unsigned) deviation fr MM isquitesmall PMG gives sigh high Values forall compounds, especially for nortrieycane and quadieylene- AMT issystematally high exept fornorborane, andisespecally high for novtney. lane and quadricyclane. MNDO is systematically high, excep for norborane and quacricycane, Thus it appears PMB3 gives the best results ofthe semiens, Pirical methods, bt all have some dificult with te stained tiny compounds b. The ab initio results are in quite good agreement with the experimental valoeg although norbornene and norticyelane ate consistently about 3-4 keal/mol less than the experimental value. The B3LYP results ate about IDkealhvol 100 high forthe bicyclic compounds, but somewhat closer although sl for nortcyelane end quackcyelae, The heats of hydrogenation results ffom the semiempirical calculations are similar tothe AH, celulations, withthe AMI results most seriously in eer 37. The order (CH)N > (CiH,),N > (CyH,.,)5N presumably is mainly a sere effect. There is a small variation of the longer-chain compounds inthe onder 4.2 8> 3> 6,for which there is no obvious interpretation. Pyridine i comparable the longer-chain trialkylamines because the sp? trogen is less nucleophilic than the sp? nitrogen. There is further reduction with quinoline, which is probably largely due to the steric effet of the C(8)-H. N.N-Dimethylaniline fs ail ene reactive, The phenyl group would exert both a polar and resonance withdraeeh Of electron density from nitrogen and there is more steve hindrance then pyridine. esse Temp (MeN (EDN (PsN (Bu)sN (Hex),N (OethN PHIM, Pyridine Quinoine co eee 2 ae 502 oe 0 Ler 0.35% 0371 0250 0336 58 30 107 0633 aH 0366 0570 0337 asi @ 451 105 124 0860 0912 os OBI aus 70 149 176 1M LSE 0283 ss w 301322262 27038) 2a ” oe om0 $FTemp KT Me © 9) aH Gas 35 Spry QU 382° “o00038 78009 108] DNTa) aT Sane Fo Zr oo1%66 502 aaosen 759691 torre wat 00399 728 oonors = “a zs21 ta ana Imereept 1464294 slope SU8I4 aH AG ss a M32 wom a9 ‘Temp K vt BAN k 0h) aH ac as 3310003194167 1696-05__ 1.0001 tora) sao) ae 331 00309307 307808 t0.912 todas a B31 ooo se 4 54E05 10 terol) nase 81 aoogsis 7497498 © 949916 taedd ease tek Tmtereept 5.831199 slope SW1I6 aH 8G as fa 4oss392 0725820 ta Temp K we PN x ma) aH aos 3100031960354 3.S4E06 128514 om de166 ae 0.003095 0633 6336-06 003002 105. osE-08 Dooss 176 1.76605 Lho.9e76 yomm2 304 SOMES to Imtereepe 6226278, slope 882.95, Es 689.83 or ro700 1680 toa an 10700 29598 27138 27682 208s ac mm 93, a =394 493 as #3 Temp K it Bun x nak) on Gas 311 G0oni9¢ 0am 47006 _—123658 1074025988 an 3231 0003095 omts Base 6825 333.1 os002 241.2405 “aL 2o7e, M31 002915194 L405 Llo.aso2 35.1 000832322 3maEns _joa3s Imercept 4.26121, slope =317009 0272.97 tox0 10700 eso 10690 an 0700 26464 27018 27595 25044 ac 02s a487 49.1 092 492 as 190 ‘Temp K WT Regn x i) aH aos 331 003d 9.39” 298-06 _—iaas0e Yara ae299) ae 323.1 0003095546 S.66E-06 BB. ono os 8-06, 38.1 omgis isi si-as 3831 one 22 2gE OS Tnx slope Ee 10gat = 11.6637 Host 10.5898 anes w720 10700 180 160 aH 0700 26720 27290, ams 2518 aa ons 495 “98 “97 46 as ~69 36 k me) aH ass Sansa Prone ‘Temp K Wt Onn 3B Oousi9s 0336 3.3606 12a Iona) Reread 321 oomsees as S706 = Liners wana ogete a 381 ooos0: 912 9.1206 1605 to 352 nae AB1 ones 6 aoenmI6 110s Inman ator ak 3u1 om? 2m AMOS §— -02 4 ~04 <= 08, S.002e 0.0028 0.008 0.0037 0.0032 oG0a3 " PhINMe2 Log k vs. 1/7 9 ~o2} 04 = 2048.5x7 6728 Logk 08 og }—— }0027 0.00275 0.0028 0.00885 0.0029 0.60285 0.00 4.00008 ww Pyridine Log k vs. 177 4 ®.c0a7 “0.0088 0002s 0.003 00081 ovoae ww 3.18. The slopes of the line increase with the number of cyano substituents, This indicates there is successively more solvent attenuation, with the increasing stabilization by cyano substituents. This may be because the charge is more localized on the benzylic carbon, permitting more effective solvation39 ov e80- w- ow Lr0~ z0 wo #0 Biorees 900 OD's>¥ os wo Oona ony fo oe sro be 0 Noe 90 390 Now owe io fone aie font aco fone tp 4 o 4 a es aon ‘steuoworeuysaaya ~¢ sag syaorcn eng = sagt 9 40 0 7 Sitar Prag Yet42e0n. 21078 Mo. . yo2.195804 29817 Parets [- Pasar]3:18. There is no corelation with a: The plot has a roughly parabolic shape with the greatest reactivity at the two exitemes. The vinyl group, despite its tow value, is among the strongest rate-enhancing sulstituents, The 4-phenyl and ‘Amethylthio substituents are also rate enhancing. The reaction is believed to Proceed by rearrangement of an intermediate diradical, in which case the radical. stabilizing substituent effect should govern the relative reactivity. Indeed, this reaction was used to establish such a substituent scale, : CHy ee \y r 7 : aon oe a 7 oe ‘e ‘3 a ; a om 7 ‘e oo - Sen" 41 Ri Pros) 42 3.20. These data relate to the general acidifying effect of cyano groups, as manifested in the pK values of the “cyanocarbons.” The referenced papers point to several Properties of the eyano group, which is a strongly polar EWG, combining the clectronegativity of sp carbon and nitrogen, The group is also rather undemanding sterically, allowing several groups to be accommodated without ‘mutual steric repulsions. Richard, Williams, and Giao in the reference cited gue further that the effect is more polar than resonance and cite the relatively high energy of the ketimine resonance form as an explanation. Merrill, Dahlke, ‘and Kass point to hyperconjugation as contributing to the @-stabilization, citing the lengthened C(B)-CN bond. 3.21, The two transition structures shown below ate derived from reactant confor= tations 21-A and 21-B, respectively, As the attacking radical becomes larger, the steric repulsion with the methyl substituent becomes more significant and forces the TS to react through the less favorable reactant conformation 21-B, ‘The product ratios can be used to estimate the difference in the AG? values, as shown in the figure, 3.22. The SAH results show some of the characteristic features of aromat ‘substituents, reflecting the mixture of resonance and polar components. For example, 4-F is less acidie than 3-F and 4-OCH, is less acidic than 3-CHO, reflecting the 7-donor effects ofthe 4-, but not the 3-substituents. The conjugated EWGs 4-CN and 4-NO, are mote strongly acidifying than the corresponding 3-substituents, since they can enhance acidity by resonance. The charge differ. ‘ences that are computed are relatively small. The charge difference on H is a range of 0.007 wnits, about 3% of the charge in the unsubstituted compound. Similarly the ranges of charges on the CO;H and COs groups are about 5 and 3%, respectively. of the charges on the unsubstituted compound. The HOMO ‘energy Of the anion might be expected to be a good indicator of acidity, since it reflects the ability of the stcueture to accommodate the negative charge, Here9 4 the range is about 15% of the unsubstituted compound. The correlation between B44 and the HOMO energy is high. As might have been anticipated for gas phase data all substituents lower the energy of the HOMO relative to hydrogen, but the effect of methyt groups is small. The broad general conclusion that ‘can be drawn is that anion stability, as indicated by the HOMO energy, is the major factor. The rather poor correlation with «, which is derived from aqueous ionization of benzoic acids, indicates that a considerably of substituent effects operates in the gas phase, “Gmp 9 MN Eee Sa gH gO," C0; HOMOGY) Grupa #0000 om) 00803 —1a57 —aasan $F 005 366 02 eons 1329 “dass 3F 038-402 0231 “0041s 1204 3.8487 #Ct 023 3.110239 p0m60 “1397 “aes 31037-3110 0239 0.440 “1326 “aes93 SEN 066-795 0232 “omnes <1215 463 3CN 056-749 0232 00297 “in? “ggasi $NO; 078 =1298 0234 0.0297 “i199 “3108 BNO, 071 has 0385 “aoa? 1207 “Saas 4CHy -017 044 0228 00519 1337 a sea SCH, 007 022 oz 00514 “i237 ass CHO -027 01s 0228 —o0s20 “1257 3000 CHO 012-036 028 00190 13% “43047 GH vs, dottatt a Lr 4 0.226 0228 023 o2a2 0204 026 aH 008 -005 004 003 008 001 0 ‘acozH 43> C02 ve. ea 2 of 7 2 4, is Se ae —— -10 a R07 a4 a S| “124 123-128 4212.10 ‘qco2- HOMOev vs. dotatt 2 ° -2 -4 6 -3 10 “2 a4 2 “04-02 0 02 04 06 08 + sigma OBE 3.23. The reactions are all faster in DMSO than methanol, except for SCN~. This can be the result of @ combination of two factors—less solvation of the anion in DMSO and greater solvation of the transition struture in DMSO. The effect is greatest for CI" and Teast for ~ among the halides, which is consistent with stronger solvation of the harder chloride by methanol. The S* in DMSO becomes mare ‘negative in the order CI” < Br” 46 9 orvoMs0 aaa fm 0548+ 20401 ee 4 crmeoH 5 0.0082 oodses 0.0059 0.00808 O00 odes $$’ Ff Yoon Bata wT NyroMs0 f8 conse aodses O00s9 Ome antsy oedoAE aps 2p 3p 4p yo-97872 20888 wNy7MeOH 1S actee 00025 0609s oat%as ootea onfoss = 1 y=-10960%+ 26.221 “4 ~104 2 wr Brouso 5 0.002 0.00325 0.003 0.00095 0.0084 a0g04s pa COO 0.0099 0.00085 0.0034 0.00 ep a BriMeOH NS 0.0082 a00s25 0.009 0.00805 0.0034 p.odaas +7 pa J J y=—11001% + 27.080 we 47 Sienna PonsYy « ‘SCN7OMSO Salsts 0.002 000325 0.0033 cotess 008 oOgsss S| ee ¥4p—_ : ve-solom + 24109 Pp verrovorn autos -10 “2 - — — SCNMeOH 07 0.04815 0.0082 0.00325 0.0083 0.00985 p.onse oodos ya10280x + 22.698 rouso ° 0.04805 0.0081 0.00815 0.0082 0.00825 0.0083 o.daa5, ———$__$_— 2 2 | -4| 6 { 2-6 [yeaa 7586‘ oofers 0.0082 codees 0.005 cadees oovas nods 2s wr 3.24. a. Cyclooetatetraene is strained by 14.5 kcal/mol, relative to butadiene. on ~908.96208 4x ~78.41192 «-913.64708 iyelo[1.1.0] is strained by 66.1 keal/mo © + sey — aononoy «enn ~195.62205 5.x-70.62661 =~ 998,19208 2x-116.85022 = -297-70044 2 18807751 = -216.15500 © 0.10594 = -66.1 kealino! ©. Quadricyelane is strained by 71.3 keal/mol 2 + TOCHCH, —~ CHCH.CH, + 6 (CHui,CH ~27090520 10%-79.62641= 79626641 ~110.8002 6 x-168.07761 = 048.40506 E=-71.9kealmel = 0.1196 Chapter 4 ‘41. a. The observed order reflects the relative carbocation-stabilizing effect of the Substituent groups: cyclopropyl > phenyl > alkyl. The small differences 49> « Bitar Poems i among the alky! groups correspond to the electron donor capacity 1-C,Hy > E-C\H; > CHy and may also reflect steric acceleration, ‘The increasing magnitude of p reflects increasing electron demand in the TS in the order CH, < CF, GCL —— cronpr—cryen je Ct cy Pcp ——= (CHO},PCHPR bon, These stereospecific rearrangements occur by participation of the C-C bond anti the departing brosylate ion. The rearrangement is driven by relief of strain associated with the four-membered ring oe ohm ot LoS LA ott Bed Hy CH, a - a Bue Cry CH (So Se This reaction occurs by chorine participation resulting in an S-exe cyclization, Followed by ring opening of the chloronium ion at the 5p"! carbon in preference (0 the sp carbon, Heny a) — nok y)-o.00, —- enero I tYY 4. These contrasting rearrangements reflect the relative conformational prefer ences in the diazonium ion intermediates and imply panicipation ‘nthe {Rigration process. The hydroxy groups favor the migration by carbonyl bond formation. tn the conformationally biased r-butyl derivative, preferential ‘migration of the anti hydrogen occurs, wrse- ro © The bridging oxygen can assist a o migration, leading to an oxonium ion, and then to hemiacetal that can open to the observed produet. &.-&- PA 1 F. An achiral aziridi displacement, but thi ium ion can be formed from the endo isomer by back-side pathway is not open to the exo isomer. Alternatively, a the racemization might involv actoy patcplon CH Oy t Ohny yoo oe — dA Boe "x cha Yee te ae 2 ee be 55 Gy achtal &: This rearrangement can occur by pauticipation of one of the imide carbonyl ‘groups, aon, ml wa ata “eb — ae? — oa pbenenc.en ol 43.4, The 2,2.2«rfhioroethy|sulfonate isa somewhat better leaving group and reacts about 175 times faster in the example cited Sl eae Pens9d 52 44, 4S. > fe conor efit ofthe ERG CH favors reaction, whereas the polar effect of TEEN group CF, retards the reaction. The difference is & felon of shove 1000 in the example cited. While ther is some strain atthe 7 postion, the bridgehead position is very the rate scehe fae ratios reported tobe 16:1. According to one analysis (see {he references), the strain associated with ionization of 1-7, ana 2-norborny! Gevivatives are 30. 16.5, and 4 kealimol, respectively. Furthermore mele, ‘philic solvent participation is precluded for the 1 isomer, & Reactant stain (B-stain) increases reactivity in the t-butyl case by @ factor of 39,600 over the CH, compound. & he exo methylene derivative is 8.8 x 10" slower. The double bond is held Perpendicular to the ionizing bond and cannot participate by electron deloc. carbons af a_TS. Additional sain and the unfavorable polar efect of the sp Sarbons of the vinyl group also contribute to the diminished rate {The a-sulfonyl chloride is less than one-twentieth as reactive asthe B-sulfonyl {alle This i de toa steric effect of the branched sulfonyl. perhaps cohaveed by the partial negative charge (repulsive to iodide) associated with ihe sulfonyl oxygens & Je cxclopropyearbiny| structure is about 100 times more reactive asa result ofthe cation-stbilizing effect of the eyetopropyl group. bye unsalurated compound is nearly 100 times more reactive andthe products inate Favorable geometry for neighboring-group participation, 4 The onto isomer is more than 150 times ‘more reactive because of intramolecular neighboring-group participation ion. The rate of exchange measures the rate of internal teture of sulfonate with scrambling of the tosylate oxygens. The rate shone « slight Frere ( Fetum of the original oxygen (k, > h.,), which may be dneere CAtfrential solvation ofthe oxygens. Conversion tothe final racemic produ by Fenuion of the eation with acetic acid occurs at about one-fifth the vate of ie, formation, that is, about four out of five ofthe phenonium ion pass saten reactant, oro v a SEH Aon, OW ‘a Sco, b,com 05 The nonpolar solvent and use of «soluble azide salt promote an $y? mechanism ‘over ionization, as demonstrated by the inversion of conti Sisenoe of any rearrangement, The reduced rate relative to eyclohenyl brosylate ‘iso implies that there is no kinetic entancement from or patcipation aqw oF ake endo and 80% of the exo isomer reacts via a back-side displacement. ‘The nortricyclane must be formed by ‘concerted attack of azide on the exo Ci AS Ny 46, 4 bimolecular process as well, perhaps a (6) hydrogen, m= — cs Fos = He, " = = Pt s oN ais Dog ae Odom es | ray mo, = PA Ci on ‘The results are consistent with the formation of a Z-allylic cation from both eactants, followed by isomerization ‘The normal deuterium isotope effect to the E-cation and product formation, for the diene indicates rate-determining Protonation, whereas the inverse isotope effect for the alcohol results from the higher extent of proton: step is the ionization of the protonat mn in the deuterated solvent. The rate-determining ted alcohol. The £, values refer to the fate-determining step and indicate that the isomerization must occur with a lower energy requirement. The barrier to isomerization would be expected to be significantly reduced, as observed, by the presence of the phenyl group, which brovides alternative (benzylic) stabilization of the carbocation. An approximate reaction energy profile is sketched in Figure 4.6P on page 54. 47. Le oni or Deprotonati sesulting di ~@ of the phenol group permits effective aryl participation and the none has moderate stability Comment. The authors remark on the very surprising chemical shift equivalence of the a and B-cyclohexadienone proions in the 60 MHz spectrum. So far as can be determined, hhas not been pursued is aspect of the propenties of spiro{2.S]octa-d,7-dien-6-one ‘48, The syn isomer can ionize with « participation that leads to analy ion, 0. 2 ~ & = & 5354 Free energy lrans-alcohol Feaction coordinate Fig. 4.6%. Approximate reaction energy profile for fomerzation reactions. Reproduced from J. Am. Chem. Soc. 93, 69 (1971), by Fermission ofthe American Chemie Society 4.9. The following ions are the most stable structures that are isomeric with the initial carbocation that would be formed. See pp. 436-438 for discussion of carbocation structures under stable ion conditions. "By "Opes *Opaee 4 ob oS ‘cs 4-10. The ratios of solvolysis to exchange are 4.55, 4.47, 0.83, and very large, respec- Lively, The relatively unhindered secondary systems represented by i-propyl and cyclopentyl indicate only about 20% internal ion retum, This presumably results from major solvent participation. Note tht the ratio is virtually unchanged, even though the absolute rates differ by a factor of 100. The extent of ion pair rlumn becomes larger in the more hindered 2-adamantyl system, where nucleophil Solvent participation is decreased by sterie factors. The 3,3-dimethy!-2-bity] system rearranges to a tertiary carbocation faster than internal return oceurs. Thes Suggests the possiblity of concerted ionization and rearrangement. ‘411, The smaller p and r values inthe Yukawa-Tsuno equation forthe I-arylpropeny! cation indicate a reduced electron demand, which must be due to the electros- releasing character of the methy! group, OR, — Ox, — OR, 4:12 a. The dependence on [Nj] withthe EWGs reflects a shit from an wacoupled ‘© coupled mechanism in response to lower carhcation stability.3 4d ‘is result is consistent with little direct nucleophilic participation in the reactions that proceed through discrete carbocations TRS test indicates greater selectivity for Ni by more stable (longerlived) carbocations, Less stable carbocations may collapse so rapidly that solvent Geplure is more favorable in competition with the anionic nucleophile ‘This tesult is as atcipated, since the Ny is acting directly asa mucleophii participant ‘The retention of configuration in both cases indicates participation. The Stealer rate enhaneement in 13-A. indicates that the isolated double bond is imore effective at stabilizing the TS than an aryl ring. This can be explained in terms of the -bond order of the participating bonds, which is 1.0 im 13-A 8s opposed (0 0.5 for 13-B. This implies higher electron density to the back side of the bromine in 13-A, The aromatic 7 electrons are also “harder: The cyclopropylearbinyl character of 13-D reduces the electron demand. ‘The product array from reactant 13-E is consistent with formation of the cyclopropylcarbiny! carbocation 13-G. kk 136 1346 Reactant F evidently has a more favorable pathway tothe stabilized ion 13-H, ‘hich ean also account for the observed stereaspecificty. LA. — EA — wt TEPC tae [Js suggested that the ring expansion preference is related to reactant confor- ‘mation, Reactants 13-1 and 13:f have configurations that permit formation of eyclo- Propylearbinyl cation 13-L, On the other hand, the syn relationship of the leaving group to the double bond in reactant 13-K precludes participation 134 Thess results illuswate the effect of remote substituents on adamantyl solvolysis, The EWG fluoro substituent promotes retention inthe sym isornee, whereas the ERG substituent (CH,),Sn leads to retention in the ant! isomer Hess felts have been explained in terms of preferential ¢ bridging of the most electronich C—C bonds. The rate retardation for the anti fear derivative is consistent with this explanation. The nearly complete racen tation forthe ant isomer indicates nearly asymmetsc solvation, Both sana derivatives are much more reactive, which is consistent with the ERG character of the stannyl group, but there is litle rate difference between the two stereoisomers. The extensive inversion with the sym isomer must 55 Sire Pros4.14, 4.15, 4.16, 47, ons ors =o & ant on Dost bridging for best bridging for ERG substituent ERG substivent Ton 1 is an aromatic cyclopropenium ion, Jon 2 is allylic and can also be considered to be the homoaromatic analog of cyclopropenium ion, Jon 3 can be stabilized by conjugation withthe adjacent double bond, fons 4 and $ are isomeric rrepabilic cations that benefit from resonance stabilization. Theie relatively high energy is rather surprising. No conventional stabilization is evident for icy 6, which is a vinyl cation, ‘The highly reactive endo-anti isomer benefits from optimal alignment of the ¢yclopropy! orbitals and can lead to a bridged ion A. This structure also accounts {or the stereospecifiity of the reaction. The exo-syn isomer can benefit Irene ‘Eearrangement to a eyclopropylcarbiny! cation B. The exo-anti and eno-syn ers rem aligned wal fo eyclopops pepe a be = Ay w a> ptm eyclon earangementisaas io ® ‘cyclopropyl ortitats = = a ‘The first two cations benefit only from direct aromatic stabilization, This stabi- lization increases with the donor cha in the thitd cation, the most effective stabilization is from the 2.3-double bond, as can be seen from the very large upfield shifts. This stabilization becomes Zelatively less important, as the aryl substituent becomes more stabilizing, This {Gan be seen in the case of the 4-methoxy substituent, where the chemical shift iS now similar o the other two cations. The strongly bridged carbocation might be formulated as m complexes, as forthe norbornyl cation (ee Section 4.4.5) Ar Zhe T-norbory! system suffers angle stain on ionization and o participation is ‘minimized by the strain involved. The exdo-2 isomer can be taken on ihe “norial” rate forthe system, The exo-2-system benelits from C(5)—C(6) Participation to give the bridged norbornyl cation. The «nti-7-norborn4.18, 49, 420, 4a 422. 423, ‘ystems benefits from 7 participation. The two tricyelic systems benefit from cyelopropy! participation, with additional relief of strain in the ease of the bieyelo[3.2.0.0 }heptan-3-y! system, Ute first-order reaction represents rate-limiting Sy 1 ionization, As substituents become less electron donating, the first-order process becomes negligible in comparison with the second-order reaction. This is consistent with the need for Sarbocation siabilization in the ionization reaction, The curvature in the Yukawe, ‘Tauno plot forthe second-order reaction suggests continuous change inthe “exwfa” resonance component. As the aryl group becomes less able to sablize Poriave charge, the TS becomes more concerted and tighter, with less charge buildup and therefore less substituent sensitivity he 7 values suggest increasing “extra” resonance in the order (CH, CH.) < CH,,H The second set of reactions pertains to aryL-assisted processes, The resonance component is now somewhat smaller, but in the same direction, since the CF, sroup will sgn increase the need for resonance pacicipation, ‘his is considered to be a ease of opposing resonance and polar effects. While the eyano group is a strong polar EWG in both the a- and postions, the substituent ean also provide esonance stabilization. This stabilization is qual Latively similar to propargyl resonance, but less favorable because of the more electronegative character of nitrogen, don 37Yy 58 Bai Proms For the branched system, the potential for forma by rearrangement favors migration, The donor cap ‘migration of the sily-substituted methylene in prefere n of a tertiary carbocation Of the silyl group favors, nce (0 the methyl groups, gs P, sory west Ep oTes OP oo PL cad ae [ites Eonons oH ony body, foes a 10 —~ Compound 25-€ is well alig nortricyclane is observed. rehome a Compound 25-D may ret by an nvamolcuar ennaion reaction - Aeon a are HO "CH, ned for concerted participation and a high yield of FerpPoun 25-8 shows 1 evidence of panicipation and gives only a very low Zicld of apparent oxidation products, Evidently, the primaty toryte sence only by direct displacement.4.26. Compound 25-F is favorably aligned for fragmentation of the“ eyelopropane formation. ro btw ats a ots oak. G probably lies in steric interactions between the ring and the methyl ide” conformation in 25-G, Note, however, that the Participation does retain its stereospecificity, dae ono von, ‘oncHy Gram rgemaniion | famaabymigaten tomes by tagraniaton wah Sens awit serecspecte sftmd ogre sing. tipeas sat ‘Sylpropanetomatan expanse 4 The viny! cations are less stable than the ethyl and thus benefit more from electron donation by substituenis, 5 The sp carbon in vinyl cations is more electronegative than the sp? carbon in chy! cations. This results in a more unfavorable polar interaction with the iMate Clestronegatve substituents, which pantaly cancels the stabilization by sm donation, © The vinyl cations would be expected to be more electronegative than the cyt cations and therefore would lose less eletron density to polar EWG substituents, such as cyano and wifluoromethyl, 4: The order of stabilization is OH > Br > C1» F> CF, > CN, which, except for OH. is inthe order of the potariy ofthe subsiens, indicating that « polar effect is dominant, All the CH,-X groups except CH, CN remain sabi izing, although less so than methyl. This suggests that the dominant effec ie alkyl Group hyperconjugation, attenuated, but not dominated, bythe polar effect ot the substituent group, © These m-donor substituents are all strongly stabilizing in both ethyl and funy! cations. The order is NHy > OH ~ SH for ethyl and NH, > SH OH for vinyl. These substituents presumably have opposing resonance and polar compounds, 59 Iry 60 4.27, Sitoar a Frain Hy om, Invasion aon ce) sf f ance) s +6 seat oy pectin we josesto forte becouse tin mona ‘stoebunon 5) ° oo fo tetorton 316) = | | Chapter 5 51.4 THe dub stew i soit 90 tn re reaive bese of he unui ces of te cleste-dnatng yt pte se > ‘Table 52, whch weld ast omer aera se b Be i home, heh ha the CBr tea win het ah in ons (Cre Forge poner dis-isoner trans-isomor The EWG carboxy group destabilizes the carbocation intermediate and the Bat sited compound is about 100 times more reactive in 20% H,S0,. & Roth alkenes will give the same carbocation, which is tertiary od Siso benefits from cyclopropylcarbinyl stabilization, Under these circumstances, seaman eperBy should determine the relative, and the less stable exocyelic compound is about 23 times more reactive, © The sulfonyl isa much poorer teaving group than the sulfonate and is substan- tially less reactive, f, The EWG methyl stabilizes the B-chlorovinyl carbocation intermediate and is about 65 times more reactive, 8 The bridgehead structure prevents the oxygen from providing any stabilization '0 the carbocation intermediate. Under these circumstances, the polar EWcharacter of the oxygen is dominant and the bridgehead compound is about 61 10 tes reactive, Normally the strain assoiated with the bridgehead dole bond would lead wo enhanced resctivity, so the electronic factor is greater than the observed difference of 10°, 4 This alkene would be expected to give an S-exo cyclization product as a result of intramolecular nucleophilic participation. The preference between the two alternative cyclization TSs is small and a 2:1 mixture of products is formed, ocr ZOX.chete HOH HOGtH, HOCH, a4 HOCH M2 OO ue a “oles °° b. The regiochemisty is controlled by the stability ofthe cyclopropylearbinyh cation, The addition is syn, reflecting involvement of a relatively stable carbocation, There is a modest preference for attack ant o the eyclopropy!- ‘methylene group, which can be attributed to a steric effect. o2 @. & §. fe © This action would be expected to proceed by removal of the acidic proton ‘(0 the carbonyl group. Elimination to the less sterically congested E-nomer is expected and observed. e CM whew whe ao == HOO HO 47 geen peter ested ere aan us i Hy L7H ¢: The product composition corresponds to net substitution, suggesting a carbo- «cation process. The observed product can be accounted for by terminal allone62 Siar Patios 53. 54, Feaation. wih the regiochemistry governed by the eyelopropyl group followed by ring opening and deprotonation, co, oo, oo ° ong oe Oe, 5 MCh os EP BRE — op one Ey cn ie oy? 0 Yo bm F The highly hindered base leads to &3:1 preference for the exocycle alkene OF st O- Qe 2 "minor & These reaction conditions lead to the isolation of the methoxymercuration Product as the chloride, The methoxy group is located atthe benzylic postion 1) Hg(OAC)y CHOH Cty cH=cH SO oy, CHCH Hct 2) Nach i och, 1 Because the reaction can proceed through « phenyl-sabilized vinyl eaton, A rinture of anti and syn addition is expected. Both the dichloride and the solvent incorporation products are nearly a 1:1 mixture of syn and ant addition Fr phat ScleAt incorporation product regiochemistry is controled by the phenyl substituent Pho Pr Cay Pri Ph Gly oot * a? * ancora * anoor™e, The trans isomer can attain art alignment ofa B-hydrogen only in adaxial chai Sintra Conformation, thus disfworing the elimination. Evidently the sym elimination mechanism is also strongly disfavored, because this would inewecge torsional strain, N(CH as (OC LF —N CH, os ‘rane Ihe elatvely large postive p valves are consistent with an Elebstike TS for the quater Holope effects, suggesting more synchronous ‘Ss, None of the eliminations ‘ppear to be El-ike, since the p would be expected to be negative for an Bl-tke ans ietope effect near 7 forthe bromide suggests an TS near he midhoina Sisal ond breaking. An ineresting point is thatthe tosylate sroup, nhroin a Beuter leaving group in Sy2 reactions than bromide. seems to be a soma Poorer leaving group by these criteria$5. In the erythro isomer, the deuterium is ant tothe bromine in the conformation that gives rise to E-2-butene. The primary isotope effect should increme the ‘amount of Z-2-butene and I-butene at the expense of E-2-butene 56. The order of reactivity is expected to be governed by carbocation stability and therefore is in the order shovn, The reported second-order rate constant, (M~'S"") are given with the structures, og Se an > cHy0" 75x10? 20x10 37x10 495x40% 61x10 517. a. The observed regiochemisty isthe result of phenyl stabilization ofthe carbo- ation intermediate, The syn addition is also consistent with the involvement of a stabilized carbocation with rapid nucleophilic capture. The protonation ‘cccurs from an axial direction to maximize the overlap with thew electron density. The reactant conformation is controlled by the #-buty! substituent D ° Dear — Ne BA) wath ie Wor ra '. The regiochemisty is controlted by phenyl stabilization of the carbocation intermediate, The preferred syn addition isthe result of phenyl stabilization ot the ion pair, which collapses faster than dissociation or stereorandomization ‘There is a larger driving force for rotation to relieve strain in the Z-isomen, 4nd this results in a higher degree of stereorandomization © This reaction proceeds from the sterically preferred exo direction, with Markovnikov regioseletivty, There is no need to invoke a bridging carbo. Galion, because ter-earbocations are of suftcient stability to avoid bridging, 4 The stereochemistry results om diaxial addition, with the t-butyl grove Sontoling reactant and product conformation. Although reglochemisty not an issue with the symmetrical reagent, the nucleophilic attack would be ‘expected to occur at the more-substituted end of the bromonium ion 8 HL on, 63