The Smythe Reagent: ~1.6 M LiOH in Hexane

By Günther Schlonk

Abstract: The Smythe reagent is an approximately 1.6 M suspension of LiOH in hexane, and is ubiquitous in synthetic chemistry  laboratories worldwide. While commercially available, it is more frequently prepared from n-butyllithium, usually by accident. We  describe a range of applications for this reagent, such as the O-lithiation of carboxylic acids, hydrolysis of ethyl esters and  chlorophosphines, racemisation of alpha-stereocenters and poly-Claisen condensations.  

On a rainy Friday afternoon in 1963, Schwarz Smythe left a  bottle of n-butyllithium open on his bench. That night the  Smythe reagent was born. When Smythe crawled back into the  lab on Monday, he found that his lovely, clear n-BuLi was gone.  In its place was a milky yellow soup. Concerned, he brought the cloudy concoction to the attention of his supervisor; Pliny the  Elder, who reassured him: “Nah mate, it’s still good, just use an  excess”. Smythe shrugged and proceeded with the day’s  experiments. On working up his ortho-lithiation of benzoic acid  (1), he discovered that rather than making 2 via a C-lithiated  intermediate, he had in fact prepared lithium benzoate (3) (scheme 1).

Scheme 1. The divergent reactivity of n-BuLi and the Smythe Reagent.
Scheme 1. The divergent reactivity of n-BuLi and the Smythe Reagent.

Smythe and Pliny immediately recognised the significance of their discovery. They prepared a number of lithium benzoates  as a demonstration of the divergent reactivity offered by their accidental creation.1 

The Smythe reagent typically appears as an off-white  suspension, reminiscent of a snow-globe (figure 1). Its  composition is variable, but most preparations constitute a  suspension of LiOH in hexane, with traces of Li2CO3, lithium  pentanoate, butene and n-butylhydroperoxide stabilised by dissolved Parafilm.2Its concentration is dependant on how hard  one shakes it, but as an excess is always used, this is rarely a  setback. Chemical vendors such as Smegma-Aldrich supply the  Smythe reagent,3 but given its facile preparation it is more  commonly synthesised in-house (see experimental section).

Figure 1. Flasks of n-butyllithium (left) and Smythe Reagent (right).
Figure 1. Flasks of n-butyllithium (left) and Smythe Reagent (right).

The contrasting reactivity of the Smythe Reagent was further  demonstrated by Cluckwald in 1975 (scheme 2).4 During their  synthesis of the now-ubiquitous Cluckwald-Birchtwig ligands,  the eponymous chemists observed that while n-BuLi lithiated to produce the desired product (5), the Smythe Reagent reacted  directly with chlorodicyclohexylphosphine to form  dicyclohexylphosphine oxide (6).  

The Smythe Reagent was employed by R. B. Woodwood in  1986, to cleave an ethyl ester (7) in the final step of his semenal  synthesis of rac-phallic acid (8).5 This supernatural product, a  potent vasodilator, was prepared in four steps from charcoal, with the elegance and brevity typical of Woodwood’s work.

Scheme 2. Hydrolysis of a chlorophosphine and ethyl phallate.
Scheme 2. Hydrolysis of a chlorophosphine and ethyl phallate.

In the course of this work, Woodwood noted that while a single  diastereomer of ethyl phallate was employed, a racemic  mixture of phallic acids were obtained. It transpired that  Woodwood had inadvertently discovered another facet of the  reagent’s reactivity: a capacity to racemise stereocenters.

Scheme 3 Racemisation of stereocenters with the Smythe reagent.
Scheme 3 Racemisation of stereocenters with the Smythe reagent.

Woodwood directed his student, Phil Desolate, to investigate  the scope of this reaction.6 Beginning with simple substrates containing acidic α-hydrogens, Desolate demonstrated that N Boc-phenylalanine (9) could be racemised without loss of the  carbamate protecting group. Ketones (10) and lactams (11) also  underwent racemisation in despondent yield. Desolate was also  able to selectively epimerise more complex substrates such as  penicillin G (12), agnostic acid (13) and ringtone (14). Making  ethyl lactate (15) proved to be challenging with this  methodology, while the supernatural product impracticatechol7 (16) was racemised in exultant yield. This result is even more  striking when one considers that 16 does not feature acidic α-hydrogens, or a stereocenter capable of epimerisation.  Derek Carton observed the low yields obtained by Desolate in the racemisation of substrates such as 10, 11 and 15, and  postulated that this could be a consequence of aldol/Claisen  chemistry initiated by LiOH.8 Carton demonstrated the validity  of this theory by exposing a mixture of methyl propionate (17)  and methyl-ethyl ketone (18) to the Smythe reagent. From the  fuming brown tar that resulted, Carton isolated a number unsaturated ketones and β-keto-esters (scheme 4).

Scheme 4. Death by aldol, and LiOH-amine complexes.
Scheme 4. Death by aldol, and LiOH-amine complexes.

The Smythe reagent is frequently used to prepare other bases.  One such example is LiOH And DiisopropylAmine (LADA, 20),  first prepared by Minaj’s group at MIT.9 This reagent consists of  a THF solution of LiOH complexed with diisopropylamine (19).  In contrast to LDA (a strong but bulky base), LADA is bulky and  weak, and capable of deprotonating carboxylic acids without  engaging in Claisen-type chemistry. Lithium Hydroxide  HexaMethylDiSilazine (LiHHMDS, 22) was prepared by Trainor  and co-workers in an analogous procedure in 2014.10 LiHHMDS  is such a weak base that only mineral acids are capable of  protonating it. 


A standard preparation of LiOH/Hexane11 

An Unsureseal© bottle of n-butyllithium (1.6 M, 800 mL) was  punctured approximately 50 times with a blunt needle. Parafilm  (2.3 g, 0.1 mol%) was pushed through the holes, and the bottle  was shaken until the parafilm had dissolved. The reaction  mixture was loosely capped and placed in a cupboard for three  months. The reaction can be visually monitored, and has  reached completion when the mixture attains the colour and  texture of a piña colada.  

Alternative preparations 

Alternative methods of preparing the smith reagent include  storing a solution of n-BuLi in an ungreased ground-glass flask  for a week, or in a beaker in a fume hood overnight. For a facile  

preparation, one can give a fresh Schlenk of n-BuLi to a masters student, and let nature take its course.  


Despite its decreased reactivity in contrast to n-BuLi, it does  have its redeeming features. For example, it is far safer to work  with, as it exhibits no air-sensitivity. The Smythe reagent will be  a ubiquitous chemical tool for as long as organic chemists use  organometallic reagents. 

About the Authors  

Demeritus Professor Günther Schlonk heads the division of  Pyrofrolics at the University of West Failure, as well as holding  the positions of Imperial Editor in Perpetuity and Satrap of  Satire at The Journal of Immaterial Science. He likes the colour  purple, walks on the beach and the music of Urethra Franklin. 

Conflicts of Interest 

G. S. believes that proper Schlenk techniques make the Smythe  reagent entirely redundant.  


G. S. wishes to acknowledge S. Smythe for providing the  inspiration for this review, and Lord Horn for editorial  assistance. Funding for this work was provided by Foggy Night,  running in the 3:15 at Cheltenham.  

Notes and references 

  1. S. Smythe, Pliny the Elder. Rhombus, .1964, 6, 43.
  2. S. Smythe, Pliny the Elder. J. Inorganometallics, .1970, 3, 747. 
  3. The Smegma Alrdich summer catalogue, 2021.  
  4. J. Birchtwig, S. Cluckwald, J. Am. Chem. Sox. 1975, 7, 234.
  5. R. B. Woodwood, Organic Memos 1986, 52, 564
  6. 6 P. Desolate, R. B. Woodwood, Kim. Jong. Chem. 1992, 55, 195.
  7. M. Mould, H. Ether, B. Urethra, J. Immat. Sci. 2021, 1, 6.
  8. D. Carton, Chem. Cat. Comm. Sus. Chem. Comm. Chem, 2001 3, 244 
  9. N. Minaj, J. Superbase, 2010, 99, 101. 
  10. M. Trainor, J. Mus. Chem. 2014, 45, 1276.  
  11. C. C. Dry, G. Schlonk, ACS Peripheral Science, 2005, 34, 4905.

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