Methyl Ethyl Butyl Futyl

Gunther Schlonk Imperial Editor in Chief of the Journal of Immaterial Science

Introduction

Everyone who has spent more than a year in the field of organic chemistry has heard the refrain: methyl ethyl butyl futile. This joke underlines the point of diminishing returns which is reached when making analogues of the same molecule. Because of this joke, the versatile chemistry of the futyl group has been overshadowed. This review highlights some examples in the history and applications of the futyl group.

The IOUPAC brown book defines the futyl group as a (di-sec butyl)methyl fragment, which is abbreviated as Fu.¹ The floppy, aliphatic nature of the Fu group gives its compounds a  slimy character when compared to its sleeker isopropyl and  tert-butyl cousins. The first recorded example of a futyl  molecule was the isolation of futol (1) from the plant Futilitus  owchmii by Erasmus Flunk in 1935.² The yield (0.007% w/wt)  was so low, one wonders why he bothered, but having spent a  decade working as an accountant, we can assume he was well  accustomed to pointless tasks. Flunk prepared a number of futyl  esters from futol, such as futyl acetate (2, a solvent) and futyl  benzoate (3, which is completely insolvent). 

Flunk’s futyl chemistry was cut short by his untimely death  in a cheese-slicing accident in 1942. His student, Herbert  Scrudge, inherited his legacy. Scrudge performed several functional group transformations on futol, beginning with  oxidation to forlone (4).³ Reaction of 1 with MsCl yielded futyl  mesylate (5), which could be reduced to invane (6). Bromination  of futol gave futyl bromide (7), though forceful conditions were  needed to convince futol to react. Futyl bromide is a common  entry point to futyl chemistry. By reacting futyl bromide with  cyanide, Scrudge obtained Sterile (8), a useful contraceptive  often abbreviated to FuCN. In an attempt to perform a cuprate  addition, Scrudge inadvertently synthesised difutyl (9, also  called FuFu or Fu₂). Futyl bromide can also be eliminated with  LiOH to yield futylene (10). Polymerisation of 10 yields  polyfutylene (11), while hydroformylation gave trivialdehyde  (12) in ironically low yield.  

At this stage, Scrudge’s futyl chemistry was curtailed, as despite  the prodigious nature of his work, nobody would fund him.  Scrudge left academia to become an art critic and table dancer  in 1953. Futyl chemistry was left largely untouched for several  decades until Mitsubishi and co-workers prepared  trifutylphosphine as a ligand for use in the coupling of aryl  thiahydroxylaminophenoxyphosphoryltriflates (13) and  phenylmoronic acids (14).⁴ With ligand loadings as low as 250  mol%, Mitsubishi was able to achieve a catalyst turnover of up  to 7. 

In 1990, Lasquisha and Alapisha held a competition to  publish the synthesis of the most useless compound in a  scientific journal. Alapisha struck first by esterifying futol and  futilic acid to make futyl futylate (16), which was published in 

AIR.⁵ However, Lasquisha was proclaimed the victor for  publishing the synthesis of N-futylpyrrole (17).⁶In this striking example of gilding the lily, Lasquisha suggested that pyrrole  would still win the competition, even without the futyl group.  Futyl chemistry got its first taste of popularity in 2001 when  the pharmaceutical giant Smerk brought their drug Fixitol^© to  market.⁷ Fixitol, a highly futylated molecule, was originally  intended to treat restless-breast syndrome, however clinical  trials found that the molecule mitigated the mood swings  associated with dipolar disorder in post-grads. Further studies  indicated that the highly lipophilic nature of futyl groups were  aiding transport across the blood-brain barrier.⁸ Smerk’s  competitors weren’t far behind, and released Soditol^© (19) a year later. The success of Fixitol led to  a rush for new futyl drugs. This in turn lead to a search for  futylation methodology, as Scrudge’s original futylation  conditions were hampered by low tolerance (like most things  from the 50’s).  

The first such example was reported by Cupid Stunt from the  University of Llanbobbl, Old South Wales.⁹ Stunt developed a  procedure for the palladium-catalysed futylation of  phenylmoronic acids. The appeal of this reaction lies in the  availability of moronic acids (they seem to be everywhere these  days). This work was followed up by Barabbas with an atom 

transfer-radical-futylation,¹⁰ and by Nebuchadnezzar with the  hydrofutylation of alkenes.¹¹ More recently, Johan Birchtwig  reported the rhodium-catalysed directionless C-H futylation of  arenes.¹² This protocol exhibits the high yields, simple  purification, and complete lack of selectivity characteristic of  directionless C-H activations. While this would be a most useful  reaction, no one else can afford to try it until the rhodium  market settles down again.  

The pinnacle of futyl chemistry was reached in 2020 when  the Morrison lab prepared futyl potassium (20, FuK) by refluxing  futyl bromide in potassium metal.¹³ Often referred to as an “uberbase”, FuK is capable of deprotonating hexane, making it  somewhat difficult to handle. Despite this handicap, FuK is now  commercially available from both Smegma-Aldrich and DuCont  Chemical.¹⁴ 

Conclusions and Outlook 

It can be expected that plenty more futyl chemistry will be  published, but nobody will notice. After all, what would be the  point?  

About the Author  

Demeritus Professor Günther Schlonk was born in the small  Austrian town of Fucking in 1905. He received his BSc from the  back of a serial box in 1925, and commenced his doctoral work with Herr Doktor Professor Claus Graf von der Plonk at the  Universität von Wankendorf. There he worked on the chemistry  of purine and conducted the first synthesis of 2-purylarsole. He  undertook postdoctoral work with Victor Grignard in 1927, but  drew the short straw and had to work with strontium instead of  magnesium. In 1938, Schlonk moved to ETH in Zurich to study  the chemistry of gold. Positions at Oxford, Cambridge, UC  Berkeley, and Oxford again saw him through to his current  position as the Fritz Haber Chair of Chemistry at the University  of West Failure.  

Conflicts of Interest 

Günther Schlonk is the Imperial Editor in Chief of The Journal of  Immaterial Science. That didn’t stop reviewer two from being  an arsehole, though.  

Declaration of Funding 

This work was funded by the proceeds of crime. 

Acknowledgements  

G. S. acknowledges The Porphyrogenitress and Lord Horn for  editorial assistance, and himself for helpful discussions.  

References 

1. The IOUPAC Brown Book, 2005, pg 666.  
2. E. Flunk, Jerkin Transactions, 1935, 12, 5375. 
3. H. Scrudge, Faraday Musings, 1943, 19, 76. 
4. M. Mitsubishi, H. Toyota, I. Hyundai, Octahedron, 1982, 4, 676. 5 K. DeShanessa, D. Alapisha, Ann. Improb. Res, 1990, 45, 125. 6 Z. Lasquisha, J. Irrep. Res, 1990 7, 34.  
5. The Smerk Index, 2001.  
6. M. Jackson, W. E. Houston, J. Self. Med. Chem, 2002, 6, 294. 9 M. Hinge, C. Stunt, Chem. Miscomm, 2005, 12, 364. 10 P. Pilate, J. Barabbus, Isr. J. Chem, 2007, 5, 3434. 
7. N. Nabopollassar, T. G. Nebuchadnezzar, Babyl. J. Chem, 56, 56. 12 W. Horse, J. Birchtwig, PNAS, 2012, 4456, 12.  13 P. C. Dutton, B. Joyce, S. J. Morrison, Aus. J. Polit. Chem, 2020, 1, 1. 14 The Smegma-Aldrich Summer Catalogue, 2021.

If you enjoyed this Immaterial Science article please like, share, and subscribe with your email, our twitter handle (@JABDE6), our facebook group here, or the Journal of Immaterial Science Subreddit for weekly content.