Spine disease? No, just a rigid backbone, but it keeps from flippin’ the ring!

For this one I must begin with a little personal background information due to my special relationship to the scaffold of the target compound. During my diploma thesis I investigated gold(I) phosphine complexes as catalysts for the intermolecular hydroamidation of olefins.^[1] I found that dinuclear gold complex showed superior reaction times and yields compared to mononuclear complexes, like Ph₃PAuCl. This particular dinuclear complex [xantphos(AuCl)₂] (1) was kicking the reaction of norbornene (2) and tosyl amide (3) and made my first academic publication possible (scheme 1).

Scheme 1. Mono- vs. dinuclear gold catalyzed intermolecular hydroamidation of norbornene.[1]

By the way, as our work group owned only a very little amount of J Young NMR tubes at the time, I had to work with headspace vials and mointor the reaction via GC analysis. (See Think Inside the Box - Running NMR in the Glovebox as an alternative!) That caused a heavy time- and material-consuming sample preparation.

Now, almost 5 years after my EJOC paper was published, I found myself doing chemistry with the xanthene scaffold again. I let you guys guess which analytical instrument I worked with this time. Here is a hint: I did not have to walk to another level, just two steps over to the other bench.

Let’s get down to the nitty-gritty. Today’s recommendation of the chef: “A two step organic synthesis of 9-phenylxanthene-1,8-dione (9) staring from dimedone (5) and benzaldehyde (6)” (scheme 2) adapted from a J. Chem. Educ. article published by A. M. Reeve^[2]. We recently posted an Applications Note dealing with this chemistry, so I will give you a quick summary in this blog entry.

Scheme 2. Two-step synthesis of xanthene 9.[2]

This is an exciting, but simple, synthetic experiment accompanied with some in-depth analytical exercises using NMR spectroscopy and it is very well suited for an undergraduate practical course. I really enjoy its straight forward character. We are dealing with basic aldol chemistry here, but I still want to discuss the mechanism a little bit. The first step involves an aldol reaction of the β-diketone (pK_a ≈ 9)^[3] 5, which forms stable enolates under basic conditions and attacks the electrophilic benzaldehyde (6). After formation of a Michael acceptor intermediate 7 via an initial Knoevenagel reaction, another nucleophilic attack of the diketone 5 (two equivalents are employed) follows, leading to diol 8. Under acidic conditions xanthene 9 is formed by a second condensation reaction.

The signals of the enol species in the ¹H NMR spectrum corresponds to a symmetric molecule. The reason for this is that a rapid intramolecular proton exchange from one oxygen atom to the other oxygen center is taking place. As this dynamic process is faster than the NMR time scale, both species are in equilibrium and the two CH₂ groups of the enol 5a are observed as a broad singlet.^[4]

Figure 1. 1H NMR (60 MHz, CDCl3) spectrum of dimedone (5).

For the exact same reason, the chemical shifts of all the CH₂ groups in the aldol condensation product 8 are the same and they appear as a singlet that integrates for 8 protons (figure 2). For the CH₃ groups a broad singlet was observed. This is due to the small difference in the chemical shifts of the pseudoaxial and pseudoequatorial methyl groups of the different ring conformers.^[2]

Figure 2. 1H NMR (60 MHz, CDCl3) spectrum of diol 8.

While the diol 8 gives a symmetric ¹H NMR spectrum, the signals of the CH₂ and CH₃ groups of xanthene 9 are no longer equivalent as a result of the rigid, fused heterocycles in the xanthene scaffold (figure 3, left).

Figure 3. 1H NMR (60 MHz, CDCl3) spectrum (left) and Chem3D model (right) of xanthene 9.

Due to the fixed ring confirmation, the signals of the CH₃ groups split up to separate singlets due to its chemical inequivalence. This situation can be confirmed by considering the positions of the CH₃ groups relative to the phenyl substituent in a 3D model of xanthene 9 (Figure 3, right).

In this cool experiment 9-phenylxanthene-1,8-dione (9) was obtained in a straight forward two-step synthesis, employing basic aldol chemistry starting from dimedone (5). Please check our Applications Note if you want to know more details about the experiment and don’t hesitate to contact us if you have any questions.

References

^[1]J. M. Serrano-Becerra, A. F. G. Maier, S. González-Gallardo, E. Moos, C. Kaub, M. Gaffga, G. Niedner-Schatteburg, P. W. Roesky, F. Breher, J. Paradies, Eur. J. Org. Chem. 2014, 2014 4515-4522.
^[2]A. M. Reeve, J. Chem. Educ. 2015, 92, 582-585.
^[3]http://evans.rc.fas.harvard.edu/pdf/evans_pKa_table.pdf (accessed November 2018).
^[4]J. Clayden, N. Greeves, S. Warren and P. Wothers, Organic Chemisry, Oxford University Press, Oxford/Berlin, 2001, p. 530.