Archive for September, 2011

Electrophilic aromatic substitution is really addition-elimination

We have all learned about aromatic substitution as proceeding via the following mechanism

(Worse yet – many of us have taught this for years!) Well, Galabov, Zou, Schaefer and Schleyer pour a whole lot of cold water on this notion in their recent Angewandte article.1 Modeling the reaction of benzene with Br2 and using B3LYP/6-311+G(2d,2p) for both the gas phase and PCM simulating a CCl4 solvent, attempts to locate this standard intermediate led instead to a concerted substitution transition state TS1 (see Figure 1).


Figure 1. PCM/B3LYP/6-311+G(2d,2p) optimized transitin state along the concerted pathway

However, this is not the lowest energy pathway for substitution. Rather and addition-elimination pathway is kinetically preferred. In the first step Br2 adds in either a 1,2 or 1,4 fashion to form an intermediate. The lower energy path is the 1,4 addition, leading to P3. This intermediate then undergoes a syn,anti-isomerization to give P5. The last step is the elimination of HBr from P5 to give the product, bromobenzene. This mechanism is shown in Scheme 2 and the critical points are shown in Figure 3.

Scheme 1







Figure 2. PCM/B3LYP/6-311+G(2d,2p) optimized critical points along the addition-elimination pathway

The barrier for the concerted substitution process through TS1 is 41.8 kcal mol-1 (in CCl4) while the highest barrier for the addition-elimination process is through TS3 of 39.4 kcal mol-1.

Now a bit of saving grace is that in polar solvents, acidic solvents and/or with Lewis acid catalysts, the intermediate of the standard textbook mechanism may be competitive.

Textbook authors – please be aware!


(1) Kong, J.; Galabov, B.; Koleva, G.; Zou, J.-J.; Schaefer, H. F.; Schleyer, P. v. R., "The Inherent Competition between Addition and Substitution Reactions of Br2 with Benzene and Arenes," Angew. Chem. Int. Ed. 2011, 50, 6809-6813, DOI: 10.1002/anie.201101852

electrophilic aromatic substitution &Schaefer &Schleyer Steven Bachrach 27 Sep 2011 4 Comments

Structure of 1-Methyl-Piperidone

The combined supersonic jet expansion and Fourier transform microwave spectroscopy provides an excellent opportunity for the synergistic workings of experiments and computations. This is nicely demonstrated in the study of 1-methyl-4-piperidone.1

The careful microwave study allows for the full structural characterization of the equatorial form 1e along with obtaining a good deal of information concerning the axial form 1a. To help evaluate the experimental data, the authors have optimized the structure of the two isomers at MP2, B3LYP and M06-2x using the 6-311++G(d,p) basis set.

The rotational parameters computed with the three methods are in very fine agreement with the experimental values. Of particular note is that the three computations predict a different sign for the nuclear quadrupole coupling tensor elements χaa and χbb, and this is observed in the experiment as well. It is perhaps the critical identifier of the axial isomer. The computed and experimental geometries of 1e are in fine agreement, with the largest deviation of a few degrees in the dihedral angle of the carbonyl to the ring. The experiment suggests an energy difference of 11.9 kJ mol-1, which is corroborated by MP2, B3LYP and M06-2x computations. In fact, these first two methods predict an enthalpy difference within a kJ of the experimental value.


(1) Evangelisti, L.; Lesarri, A.; Jahn, M. K.; Cocinero, E. J.; Caminati, W.; Grabow, J.-U., "N-Methyl Inversion and Structure of Six-Membered Heterocyclic Rings: Rotational Spectrum of 1-Methyl-4-piperidone," J. Phys. Chem. A, 2011,
115, 9545–9551, DOI: 10.1021/jp112425w


1: InChI=1/C6H11NO/c1-7-4-2-6(8)3-5-7/h2-5H2,1H3

Uncategorized Steven Bachrach 20 Sep 2011 No Comments

Fantastic host-guest complex

Check out this an incredibly cool host guest complex: the [10]-cycloparaphenylene ([10]CPP) hoop encapsulating C60!1

(Be sure to click on this image to bring up the 3-D interactive structure – as with all structures in my blog!)

1H and 13C NMR and fluorescence quenching spectrometry clearly indicate that this complex is formed when [10]CPP is mixed with C60 in toluene. In fact, when C60 is mixed with a mixture of nanohoops ranging from 8 to 12 phenyl ring, only the [10]CPP hoop complexes with the fullerene. The experimental binding energy is between 38 and 59 kJ mol-1.

M06-2x/6-31G* computations give the structure shown above. The computed binding energy is 173 kJ mol-1, but the computations do not include solvent. So this overestimation might be somewhat due to the difference in gas phase vs. solution complexation.

(Check out this post for other interesting nanohoops.)


(1) Iwamoto, T.; Watanabe, Y.; Sadahiro, T.; Haino, T.; Yamago, S., "Size-Selective Encapsulation of C60 by [10]Cycloparaphenylene: Formation of the Shortest Fullerene-Peapod," Angew. Chem. Int. Ed., 2011, 50, 8342-8344, DOI: 10.1002/anie.201102302

nanohoops Steven Bachrach 13 Sep 2011 3 Comments

trans-Cyclooctene as a Click Alternative

The click reaction, the copper-assisted cycloaddition of an azide with an alkyne, has been extended to biological systems by use of a strained alkyne (cyclooctyne) thereby eliminating the need of the toxic copper agent.1 Fox has extended this analogy with the reaction of strained trans-cyclooctene 1 with tetrazine 2.2

The interesting new twist here is to add more strain to trans-cyclooctene to perhaps make the cycloaddition even faster. Bach3 had pointed out that the half chair conformation of 1 is almost 6 kcal mol-1 higher in energy than the ground state (Figure 1). Fox suggests that fusing a cyclopropyl ring to the eight-member ring would create a ring in the half chair 3. Since 3 would be even more strained than 1, it should undergo a faster cycloaddition reaction.


1 (half chair)


Figure 1. M06L/6-311+G(d,p) optimized structures of 1 and 3.

Though Fox did not estimate the strain of 3, I have computed the structure of 1 constrained to the geometry of 3, with the two hydrogens that replace the bonds to the cyclopropyl carbon allowed to optimize. This restricted geometry is in fact 6.1 kcal mol-1 (M06L/6-311+G(d,p)) higher in energy than 1 – so the fusion of the 3-member ring does net the strain increase expected by Bach.

Fox reports estimates of the free energy of activation (at M06L/6-311+G(d,p)) for the reaction of 1or 3 with 2. The barrier for the raction with trans-cyclooctene 1 is 8.92 kcal mol-1, while the barrier for the reaction with 3 is 6.95 kcal mol-1. A methylenehydroxyl derivative of 3 was synthesized and it does react 180 times faster than the reaction with 1. Furthermore, the differences in the experimental free energies of activation is 3.0 kcal mol-1, in excellent agreement with the computed difference.


(1) Agard, N. J.; Prescher, J. A.; Bertozzi, C. R., "A Strain-Promoted [3 + 2] Azide-Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems," J. Am. Chem. Soc., 2004, 126, 15046-15047, DOI: 10.1021/ja044996f

(2) Taylor, M. T.; Blackman, M. L.; Dmitrenko, O.; Fox, J. M., "Design and Synthesis of Highly Reactive Dienophiles for the Tetrazine-trans-Cyclooctene Ligation," J. Am. Chem. Soc., 2011, 133, 9646-9649, DOI: 10.1021/ja201844c

(3) Bach, R. D., "Ring Strain Energy in the Cyclooctyl System. The Effect of Strain Energy on [3 + 2] Cycloaddition Reactions with Azides," J. Am. Chem. Soc., 2009, 131, 5233-5243, DOI: 10.1021/ja8094137


1: InChI=1/C8H14/c1-2-4-6-8-7-5-3-1/h1-2HInChIKey

2: InChI=1/C12H8N6/c1-3-7-13-9(5-1)11-15-17-12(18-16-11)10-6-2-4-8-14-10/h1-8H

3: InChI=1/C9H14/c1-2-4-6-9-7-8(9)5-3-1/h1-2,8-9H,3-7H2/b2-1+/t8-,9+

cycloadditions Steven Bachrach 07 Sep 2011 No Comments