Chemistry beyond carbon: the heteroelements

Introduction

Organic chemistry is often teased as ‘elementally boring’, a joke among inorganic  chemists, because of its reliance on C, H, O and N. While organic chemistry is broadly defined as the study of carbon containing compounds, this overlooks the role of heteroelements in synthetic chemistry. 

Heteroelements, defined as elements other than C or H, frequently include the p-block  elements. Their diversity in chemical properties often enables exotic functional group  transformations; inaccessible with ‘traditional elements’. Therefore, this article will explore the roles of selenium, phosphorus and sulphur in organic synthesis, highlighting how their  unique reactivity expands the synthetic toolbox.  

Selenium

Selenium’s unique position within Group 16 underpins all of its reactive behaviour.  Selenium’s polarisability means it can act as both a nucleophile and electrophile  depending on the context. Its larger atomic size stabilises lower oxidation states making Se (IV) compounds readily accessible, while the orbital mismatch between selenium and  oxygen explains why selenoxides are prone to decomposition. 

Selenium anions readily undergo nucleophilic substitution (S_N2) with halogenoalkanes to  form alkyl selenides (Se-C). Upon oxidation (i.e. H₂O₂), selenium is oxidised to form a  selenoxide which undergoes syn elimination to form alkenes. This provides a useful  alternative to E₁ and E₂ eliminations, as no leaving group is required. See Figure 1.

Selenium dioxide (SeO₂), a direct analogue of CO_2, enables allylic oxidation of C-H bonds. This reaction has been used widely across industry and academia as a method of  functionalising otherwise inert positions. 

Sulphur

Just above Selenium in the periodic table, sulphur chemistry parallels many of the  chemical properties of selenium. Thiols (C-S) can readily participate in S_N2 reactions to generate thioethers. Under oxidising conditions, these species can form disulfides, an  important feature of the tertiary protein structure.  

The nucleophilic character of sulphur can also be exploited to functionalise ketones without reducing the carbonyl group. The ketone can undergo a reaction with 1,3 - propanedithiol to generate a dithiane. This dithiane intermediate can then perform further  S_N2 reactions under basic conditions before addition of HgCl₂ to remove the dithiane and  unmask the ketone. 

Additionally, sulphur can also react to form sulfonium ylides. An ylide is a neutral molecule  in which adjacent atoms carry a positive and negative charge. These compounds are  formed from nucleophilic attack followed by base deprotonation of one of the adjacent C H bonds. These species are ideal reactants for forming strained rings.

Phosphorus

The chemistry of phosphorus is largely dominated by its ability to form stable compounds in the +3 and +5 oxidation states. Again, phosphorus largely acts as a nucleophile and, like  sulphur, is able to form ylides. This is central to one of the most important alkene forming  reactions; the Wittig Olefination. 

The Wittig reaction selectively forms both E and Z alkenes from a phosphonium ylide and  either a ketone or an aldehyde. To synthesise the ylides, the same procedure is used as  described with sulphur, with the nucleophilic species typically triphenylphosphine (PPh₃). The adjacent positive and negative charges form a polarised bond which matches the  dipole of the carbonyl.  

The carbonyl species then aligns with its respective opposite charge on the ylide to form an oxaphosphetane intermediate after a [2+2] cycloaddition. The ring strain of this  intermediate means it decomposes to form an alkene and a strong P=O bond. 

Phosphonium ylides are also key intermediates in the Corey-Fuchs reaction. The ylide is  crucial to the formation of a dibromoalkene intermediate from a starting aldehyde. Under  basic conditions and slow heating, the alkene decomposes to form an alkyne from an  aldehyde in a single step.  

Conclusion

Heteroelement chemistry plays a vital role in expanding the scope of organic synthesis, enabling transformations that would otherwise be difficult. The importance of this field is  reflected industrially where sulfonamide formation and the Wittig reaction rank among the 20 most commonly used reactions in drug discovery. While this article has focused on the roles of Se, S and P in ionic mechanisms, both silicon and boron are also central to modern organic synthesis, especially catalysis and cross coupling mechanisms.

Written by Antony Lee

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