I guess one can never know enough about the S_N2 reaction! Wester and co-workers have performed careful crossed molecular beam imagining on the reaction Cl^– + CH₃I.¹ In collaboration with Hase, they have employed MP2/ECP/aug-cc-pVDZ computations to get the potential energy surface for the reaction and direct molecular dynamics. The PES is exactly as one would expect for a gas phase ion-molecule reaction: the transition state has backside attack of the nucleophile and it connects to two ion-dipole complexes (see Chapter 5.1.1).

The experiments are interpreted with the help of the MD computations. At low energy one sees formation of the complex. At higher energies, the direct backside attack reaction occurs. And at higher energies a new reaction path emerges, as sketched out in Figure 1. As the nucleophile (chloride) approaches methyl iodide, the methyl group rotates towards the nucleophile. The methyl group then collides with the nucleophile, which sends the methyl group spinning about the iodine atom in the opposite direction. The methyl group rotates all the way around the iodine atom and when it approaches the chloride a second time, the displacement reaction occurs and product is formed. They term this process a “roundabout mechanism”, and they have some experimental evidence for the occurrence of the double roundabout (two rotations of the methyl group about the iodine)! I think we should anticipate seeing more and more interesting reaction pathways as experimental and theoretical techniques continue to allow us a more detailed and precise view of motion of individual molecules across barriers.

Figure 1. Schematic of the trajectory illustrating the roundabout mechanism.
Chlorine is yellow, iodine is pink and carbon is black.

References

(1) Mikosch, J.; Trippel, S.; Eichhorn, C.; Otto, R.; Lourderaj, U.; Zhang, J. X.; Hase, W. L.; Weidemüller, M.; Wester, R., "Imaging Nucleophilic Substitution Dynamics," Science 2008, 319, 183-186, DOI: 10.1126/science.1150238.

The bond dissociation energies (BDE) of the O-H bond of oximes R₁R₂C=N-OH) are discussed in Chapter 2.1.1.2. The controversy associated with these values originates from conflicting experimental data coming from calorimetric and electrochemical experiments. Some of the conflicting data are listed in Table 1. The electrochemical method provides energies at least a couple of kcal mol^-1 too large, sometimes much more than that. I described in the book some composite method computations (G3MP, G3, CBS-QB3 and CBS-ANO)¹ that suggest the BDE of acetone oxime is around 85 kcal mol^-1, consistent with the calorimetric results. These authors could not apply these expensive methods to other compounds and were forced to use UB3LYP, which underestimates the values of the BDEs.

Table 1. BDEs (kcal mol^-1) from calorimetric and electrochemical experiments
and ONIOM-G3B3 computations.

^aRef. 2. ^bRef. 3. ^cRef. 1. ^dRef. 4. ^eRef. 5

Fu⁶ has now applied the ONIOM-G3B3⁷ approach to this problem. This is a clever way of attacking large molecules that require rather large computations to appropriately treat the quantum mechanics. So, each step of the G3B3 composite method is split into two levels: the high level is computed with the appropriate method from the G3B3 procedure, while the low level is treated with B3LYP. These resulting BDEs are listed in Table 1 and show remarkably nice agreement with the calorimetric results. These computed BDEs confirm that the electrochemical results are in error. Fu also computed the BDEs of some 30 other oximes for which electrochemical BDEs are available and for the large majority of these compounds, the electrochemical values are again too large.

References

(1) Pratt, D. A.; Blake, J. A.; Mulder, P.; Walton, J. C.; Korth, H.-G.; Ingold, K. U., "O-H Bond Dissociation Enthalpies in Oximes: Order Restored," J. Am. Chem. Soc. 2004, 126, 10667-10675, DOI: 10.1021/ja047566y.

(2) Mahoney, L. R.; Mendenhall, G. D.; Ingold, K. U., "Calorimetric and Equilibrium Studies on Some Stable Nitroxide and Iminoxy Radicals. Approximate Oxygen-Hydrogen Bond Dissociation Energies in Hydroxylamines and Oximes," J. Am. Chem. Soc. 1973, 95, 8610-8614, DOI: 10.1021/ja00807a018.

(3) Bordwell, F. G.; Ji, G.-Z., "Equilibrium Acidities and Homolytic Bond Dissociation Energies of the H-O Bonds in Oximes and Amidoximes," J. Org. Chem. 1992, 57, 3019 – 3025, DOI: 10.1021/jo00037a014.

(4) Bordwell, F. G.; Zhang, S., "Structural Effects on Stabilities of Iminoxy Radicals," J. Am. Chem. Soc. 1995, 117, 4858-4861, DOI: 10.1021/ja00122a016.

(5) Bordwell, F. G.; Liu, W.-Z., "Solvent Effects on Homolytic Bond Dissociation Energies of Hydroxylic Acids," J. Am. Chem. Soc. 1996, 118, 10819-10823, DOI: 10.1021/ja961469q.

(6) Chong, S. S.; Fu, Y.; Liu, L.; Guo, Q. X., "O-H Bond Dissociation Enthalpies of Oximes: A Theoretical Assessment and Experimental Implications," J. Phys. Chem. A 2007, 111, 13112-13125, DOI: 10.1021/jp075699a.

(7) Li, M. J.; Liu, L.; Fu, Y.; Guo, Q. X., "Development of an ONIOM-G3B3 Method to Accurately Predict C-H and N-H Bond Dissociation Enthalpies of Ribonucleosides and Deoxyribonucleosides," J. Phys. Chem. B 2005, 109, 13818-13826, DOI: 10.1021/jp0508204.

What happens when antiaromatic rings stack? One can draw an MO interaction diagram for π-stacked cyclobutadiene dimer (Figure 1) and recognize at once that this cluster should be stabilized. In fact, it is reminiscent of an orbital diagram for an aromatic species!

Figure 1. MO Interaction diagram of stacked butadiene (modified from Ref 1).

Houk had examined just this dimer (1) in 1996 and located a D_4h critical point at CASSCF(8,8)/6-31G* (see Figure 2).² This structure is energetically below two isolated cyclobutadiene molecules; however, it is a second-order saddle point.

1

Figure 1. CASSCF(8,8)/6-31G* optimized structure of 1.

Schleyer has examined a series of superphanes constructed from anti- and aromatic rings linked by methano bridges, 2-7.¹ These structures were optimized at B3LYP/6-311+G** and their magnetic properties computed at GIAO-PW91. The optimized structures of 3 and 4 are shown in Figure 3.

3

4

Figure 3. B3LYP/6-311+G** optimized structures of 3 and 4.¹

The inter-ring separation (D) in these compounds is quite interesting (Table 1). It decreases in the series 2-4, with the distance in the latter compound of only 2.002 Å. The inter-ring distance is much larger in 5, which has two (aromatic) benzene rings. All of the other comounds (except 2) have shorter distances and these all involve antiaromatic rings. These short distances for the antiaromatic superphanes suggests stabilizing interactions between the rings, as indicated by the MO diagram of Figure 1.

Table 1. Inter-ring distance and NICS values for 2-7.¹

^aDistance (Å) between the carbon of one ring and the closest carbon of the second ring.

The NICS values are also interesting. Schleyer computed a variety of different NICS values, and we list here the isotropic NICS value at the cage center (NICS_cage) and the zz-component evaluated 1 Å above the ring on the outside face NICS(1)_zzring). The NICS(1)_zzring is perhaps the best measure of magnetic properties related to aromatic/antiaromatic character. All six compounds have rings that have negative values of NICS(1)_zzring, indicating of aromatic character. In fact, the value for 5 is less negative than for isolated benzene alone. This suggests that the stacked antiaromatic rings become aromatic, while the stacked aromatic rings become less aromatic. For all six compounds, the NICS_cage value is negative indicating diatropicity, associated with aromatic character – again consistent with the MO argument presented in Figure 1. To answer our lead off question, stacked antiaromatic rings are aromatic!

References

(1) Corminboeuf, C.; Schleyer, P. v. R.; Warner, P., "Are Antiaromatic Rings Stacked Face-to-Face Aromatic?," Org. Lett. 2007, 9, 3263-3266, DOI: 10.1021/ol071183y.

(2) Li, Y.; Houk, K. N., "The Dimerization of Cyclobutadiene. An ab Initio CASSCF Theoretical Study," J. Am. Chem. Soc. 1996, 118, 880-885, DOI: 10.1021/ja921663m.

InChIs

2: InChI=1/C9H6/c1-4-6-2-7-5(1)9(7)3-8(4)6/h1-3H2/q-2

3: InChI=1/C12H8/c1-5-7-2-8-6(1)10-3-9(5)11(7)4-12(8)10/h1-4H2

4: InChI=1/C15H10/c1-6-8-2-9-7(1)11-3-10(6)14-5-15(11)13(9)4-12(8)14/h1-5H2/q+2

5: InChI=1/C18H12/c1-7-9-2-10-8(1)12-3-11(7)15-5-16(12)18-6-17(15)13(9)4-14(10)18/h1-6H2

6: InChI=1/C21H14/c1-8-10-2-11-9(1)13-3-12(8)16-5-17(13)21-7-20(16)18-6-19(21)15(11)4-14(10)18/h1-7H2/q-2

7: InChI=1/C24H16/c1-9-11-2-12-10(1)14-3-13(9)17-5-18(14)22-7-21(17)23-8-24(22)20-6-19(23)15(11)4-16(12)20/h1-8H2

In Chapter 5.3.2, I extensively discuss the organocatalyzed aldol reaction. Barbas and List have pioneered the use of proline to catalyze this reaction, and Houk has performed a series of computational studies to discern the mechanism. The mechanism is essentially the attack of the enamine on the carbonyl with concomitant proton transfer from the carboxylic acid to the forming oxyanion.

Shininisha and Sunoj have examined a number of bicyclic analogues of proline (1-11) as catalysts of the aldol reaction.¹ They computed the activation energies for the reaction of the enamine derived from acetone with p-nitrobenzaldehyde with the various catalysts. All computations were performed at B3LYP/6-311+G**//B3LYP/6-31G* with the solvent effects modeled using CPCM.

As Houk has demonstrated, there are four possible transition states: the attack can come to either the re or si face of the aldehyde and either the syn or anti enamine can be the reactant. The four transition states for the reaction of 8 are shown in Figure 1. These TSs are representative of all of the transition states involving the different catalysts, including proline itself. These TS are characterized by proton transfer accompanying the C-C bond formation. Their relative energies can be interpreted in terms of the distortions about the enamine double bond (the more planar, the lower the energy) and the arrangement of the carboxylic acid and the incipient oxyanion. These arguments were made by Houk and are described in my book.

8-anti-re 0.0	8-anti-si 2.12
8-syn-re 8.15	8-syn-si 7.28

Figure 1. B3LYP/6-311+G**//B3LYP/6-31G* optimized structures and relative energies (kcal/mol) of the transition states of the enamine derived from acetone and 8 with p-nitrobenzaldehyde¹

The enantiomeric excess predicted by the computations for the aldol reaction using the 11 different bicyclic catalysts is presented in Table 1. All of the catalysts except 11 give high enantiomeric excess, with a number of them predicted to produce an ee above 90%. The authors conclude that these catalysts are worth exploring, since they are predicted to perform better than proline (which has a predicted ee of 75%).

Table 1. Predicted ee for the reaction of the enamine derived
from acetone and catalyst with p-nitrobenzaldehyde.

References

(1) Shinisha, C. B.; Sunoj, R. B., "Bicyclic Proline Analogues as Organocatalysts for Stereoselective Aldol Reactions: an in silico DFT Study," Org. Biomol. Chem., 2007, 5, 1287-1294, DOI: 10.1039/b701688c.

InChIs

1: InChI=1/C8H13NO2/c1-5-4-6-2-3-8(5,9-6)7(10)11/h5-6,9H,2-4H2,1H3,(H,10,11)

2: InChI=1/C8H13NO2/c1-5-4-8(7(10)11)3-2-6(5)9-8/h5-6,9H,2-4H2,1H3,(H,10,11)

3: InChI=1/C6H9NO2/c8-5(9)6-2-1-4(3-6)7-6/h4,7H,1-3H2,(H,8,9)

4: InChI=1/C6H9NO3/c8-5(9)6-2-1-4(7-6)10-3-6/h4

5: InChI=1/C5H7NO3/c7-4(8)5-1-3(6-5)9-2-5/h3,6H,1-2H2,(H,7,8)

6: InChI=1/C6H9NO2S/c8-5(9)6-2-1-4(7-6)10-3-6/h4,7H,1-3H2,(H,8,9)

7: InChI=1/C5H7NO2S/c7-4(8)5-1-3(6-5)9-2-5/h3,6H,1-2H2,(H,7,8)

8: InChI=1/C7H11NO2/c9-6(10)7-2-1-5(3-7)4-8-7/h5,8H,1-4H2,(H,9,10)

9: InChI=1/C7H11NO2/c9-7(10)6-4-1-2-5(3-4)8-6/h4-6,8H,1-3H2,(H,9,10)

10: InChI=1/C6H9NO2/c8-6(9)5-3-1-4(2-3)7-5/h3-5,7H,1-2H2,(H,8,9)

11: InChI=1/C6H9NO2/c8-6(9)5-3-1-4(5)7-2-3/h3-5,7H,1-2H2,(H,8,9)

The norbornyl cation has been a source of controversy for decades. Just what is the nature of this cation? Should one consider it a classical cation A or of some non-classical character B? A recent computational study adds further fuel to this fire.¹

The B3LYP/6-311G(d,p) structure of the norbornyl cation is shown in Figure 1, and this structure is little changed when reoptimized at PBE1PBE/6-311G(d,p) or CCSD/6-311G(d,p). Application of the topological method (sometimes referred to as atoms-in-molecules or AIM) reveals a bond path network that resembles the bicyclo[3.2.0]heptyl cation C. The C₁-C₂ distance is 1.75 Å and a bond path does connect these two atoms, though the density at the bond critical point is only 60% the value at the other C-C bonds in the compound. There is no bond path connecting C₁ to C₃ that would close up a three-member ring. The C₁-C₃ distance is 1.955 Å. So, the non-classical structure is not a proper description of this unusual species.

Figure 1. B3LYP/6-311G(d,p) optimized structure of the norbornyl cation.

References

(1) Werstiuk, N. H., "7-Norbornyl Cation – Fact or Fiction? A QTAIM-DI-VISAB Computational Study," J. Chem. Theory Comput., 2007, 3, 2258-2267, DOI: 10.1021/ct700176d.