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Synthesis with a twist

Naturevolume 441pages699700 (2006) | Download Citation


Amide bonds underpin protein stability, but distortion from their preferred geometry makes them reactive. An archetypal twisted amide has at last been made, and its chemistry will be revelatory.

On first appearances, 2-quinuclidone is a small, uncomplicated molecule compared with the many complex systems made by organic chemists in recent years. Yet the synthesis of this compound by Tani and Stoltz described on page 731 of this issue1, and the study of its chemical behaviour that this will enable, represents a milestone in our understanding of the properties of a special type of bond — the twisted amide.

The amide is one of the most fundamental functional groups in chemistry. It is the link between amino acids in peptides and proteins, and thus is key to the structure of many biological systems. Amides are surprisingly robust compared with structurally related derivatives, and it is believed that this linkage gains stability from electron ‘delocalization’. The amide group can be thought of in terms of two structures (Fig. 1a), one of which is apolar, and the other dipolar. These two forms — known as resonance structures — differ in the location of their double bond, and represent two theoretical possibilities of where the associated electrons could reside. In reality, the electrons in the double bond are spread (delocalized) across the amide group, and behave as a hybrid of the two theoretical distributions.

Figure 1: Electron delocalization in amides.
Figure 1

a, Standard amide bonds (where R is a hydrogen atom, or any general hydrocarbon chain) are a hybrid of two forms, known as resonance structures. The double-headed arrow indicates that the true electronic structure of the bonding lies somewhere between the extremes of an apolar and a dipolar form. The electrons are actually spread out between the nitrogen, carbon and oxygen atoms. This electron delocalization, which strengthens the amide bond, is only maximized if the atoms around the carbon–nitrogen double bond in the dipolar form are coplanar. b, For 2-quinuclidone, the geometry of the molecule prevents coplanarity of the relevant bonds (marked in red) in the dipolar form. Electron delocalization is inhibited, so the carbon–nitrogen bond is weak compared with untwisted amides. c, In the dipolar form of penicillin, the bonds in red cannot all be coplanar, again inhibiting electron delocalization through resonance, and destabilizing the amide bond.

For the dipolar form to contribute to the linkage, the chemical bonds around the amide have to lie in the same plane, in order to satisfy the geometrical requirements of the carbon–nitrogen double bond2. In circumstances where such coplanarity cannot be achieved without distortion of the structure, as would be the case with 2-quinuclidone (Fig. 1b), stabilization of the amide bond by electron delocalization is inhibited. Such twisted amides demonstrate unusually reactive chemical behaviour compared with typical amide bonds.

The 2-quinuclidone structure and reactivity problem has a fascinating historical connection. In 1941, during his studies on the synthesis of quinine, the young Harvard investigator (and eventual Nobel prizewinner) Robert B. Woodward thought deeply about the reactivity expected of this type of distorted amide3. As one of his first graduate students, I was given the problem of synthesizing 2-quinuclidone. Originally, this research was largely of academic interest, but a few years later the expected chemical behaviour of twisted amides became an important issue in the determination of the structure of penicillin.

The massive international effort to produce penicillin during the Second World War required an unambiguous structural determination of the antibiotic, so that a chemical synthesis could be attempted. There was, however, a serious difference of opinion regarding the structure among the investigators at a time when modern analytical methods were not available. The question revolved around the marked reactivity of penicillin towards decomposition with water, a process known as hydrolysis. Woodward championed a so-called β-lactam structure, which contained a cyclic amide fused to a five-membered ring2 (Fig. 1c), whereas another group, led by Robert Robinson, noted that model β-lactams did not show enhanced penicillin-like reactivity and so strongly favoured an alternative molecular arrangement. Woodward pointed out that the geometry of his suggested β-lactam forced the bonds of the dipolar contributor out of coplanarity (Fig. 1c), inhibiting electron delocalization and leading to ready hydrolysis. In other words, his suggested structure contained a reactive twisted amide. The β-lactam structure was soon accepted, in large measure owing to the logic of Woodward's arguments2.

As twisted amides can be an essential design feature of biologically useful molecules, the study of 2-quinuclidone, a model twisted amide which does not exist naturally, is of great interest. There have been a number of attempts to prepare this compound, but no successful synthesis has been previously described. Tani and Stoltz1 designed their approach so as to avoid aqueous conditions that would promote decomposition of the product. Accordingly, they focused on a route involving a molecular rearrangement, known as the Schmidt–Aubé reaction (Fig. 2), which is carried out in the absence of hydrolytic reagents. Because 2-quinuclidone is a base, and the reaction requires an acid, the product is obtained as a salt.

Figure 2: The preparation of 2-quinuclidone.
Figure 2

The precursor molecule undergoes a rearrangement in the presence of tetrafluoroboric acid (HBF4). Hydrolysis of the product is prevented by the use of a non-aqueous solvent (diethyl ether (Et2O)). 2-Quinuclidone is basic, so the product forms a salt with the tetrafluoroboric acid.

The authors outline in detail the studies leading to the optimal reaction conditions, and describe the spectroscopic and chemical properties of the product. An X-ray analysis confirmed the highly twisted nature of the amide. Tani and Stoltz's imaginative, unambiguous synthesis of 2-quinuclidone provides important confirmation of earlier predictions regarding its reactivity. This work will provide an invaluable insight into the nature of amides, and concludes a synthetic journey that began nearly 70 years ago.


  1. 1

    Tani, K. & Stoltz, B. M. Nature 441, 731–734 (2006).

  2. 2

    Johnson, J. R., Woodward, R. B. & Robinson, R. in The Chemistry of Penicillin (eds Clark, H. T., Johnson, J. R. & Robinson, R.) 440–454 (Princeton Univ. Press, 1949).

  3. 3

    Wasserman, H. H. Heterocycles 7, 1–15 (1977).

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  1. Department of Chemistry, Yale University, 225 Prospect Street, New Haven, 06511, Connecticut, USA

    • Harry H. Wasserman


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