1. Improving the Synthesis of Lidocaine: Using Arrays
Abstract:
Having improved the synthesis of α-chloro-2,6-dimethylacetanilide by using lab
arrays comparing different solvents (Taliaferro 2011), further refinement was
achieved by determining the optimum concentration with lab arrays. In this way, the
preparation of the precursor toward Lidocaine was improved from 50-66% yields to
excess of 90% yields (90-96%).
Published techniques for transforming α-chloro-2,6-dimethylacetanilide into
Lidocaine allowed for comparison of different solvents, temperatures, and reaction
concentrations. A traditional technique using refluxing toluene1 is less attractive due
to low yields (53-65%) and requires multiple extractions, while an alternative
procedure using excess diethylamine as the solvent requires at least 60 minutes2
(80-90% yields). The goal was to eliminate the use of toluene, a known carcinogen,
and minimize the reaction time.
Preparation of Lidocaine from α-chloro-2,6-dimethylacetanilide, traditionally carried
out in refluxing toluene for 90 minutes, results an average 50% yield. This reaction
was problematic for many reasons, including: health & disposal concerns of toluene,
time, & efficiency. In order to optimize the synthesis of Lidocaine, it was important to
study the use of solvent (or no solvent), the reaction temperature and heating
method, and various workup procedures.
References:
1. Experimental Organic Chemistry: A Miniscale and Microscale Approach, 4th ed., Gilbert, J.C.; Martin, S.F., Thomson
Brooks/Cole, 2006, “Synthesis of Lidocaine”, p. 733 – 745.
2. http://pages.towson.edu/jdiscord/WWW/332_Lab_Info/332LabsIRPMR/Expt4aLidocaineA.pdf
Variables: Modifications
• Temperatures: 110oC; 100oC; 70oC; 68oC; 60oC; 55oC;
• Above 70oC increased decomposition
• Below 60oC only starting material recovered
• Solvent: Toluene, CPME, THF, iPrOH, Et2NH
• CPME ineffective due to insolubility of the acetanilide.
• Heating method: Hot water bath vs Microwave heating
• 70oC hot water bath: After 5 minutes
(1.92:1.00) acetanilide:lidocaine ratio)
• 68oC Microwave: After 5 minutes
(0.49:1.00) acetanilide:lidocaine ratio
This may indicate a change in mechanism between the two heating methods.
Funding Provided By:
SFASU Department of Chemistry
Robert A. Welch Foundation (Grant Number: AN-0008)
Hank Odneal, Stephanie Aills, & Arlen Jeffery
Department of Chemistry & Biochemistry
Stephen F. Austin State University
Discussion:
Optimizing a reaction is important in industry as the efficiency of a reaction can directly
impact the cost of production. Not only must one consider the percent yield of
production, but the reaction times, cost of the chemicals involved, the waste produced,
and the hazards involved in all of the above. Industry spends a large portion of the
research and development budget testing the efficiency of their operations in order to
maximize profit and minimize hazards to limit potential liability costs.
Toluene, when used as the solvent, helps dissolve the acetanilide due to its aromaticity,
but also prevents its complete removal by extraction. NMR spectra of the product always
indicated trace amounts of toluene with the Lidocaine. The initial goal of removing toluene
as a solvent lead to investigating of CPME (cyclopentyl methyl ether) as a substitute due
to its similar boiling point (106oC). CPME failed to be a good alternative as the
acetanilide did not dissolve well enough to promote the reaction under reflux.
Studies of solvent solubility for the acetanilide lead to ionic liquids as a viable solvent
replacement to dissolve the intermediate hydrochloride salts. The ionic liquid was
thought to be ideal for solubility and temperature reasons, but isolation of lidocaine from
the ionic liquid proved to be problematic. NMR indicated lidocaine with the ionic liquid
after five extractions. Strong base extractions with an ionic liquid are not feasible due to
possible Hofmann elimination of the solvent. It is possible that a continuous extraction
cycle could minimize the lidocaine in the ionic liquid, but it would not improve the
efficiency of the reaction.
Our studies and Literature2 indicated that temperatures above 70oC increased
decomposition rates. This lead to temperature studies required to promote the reaction.
Using THF as the solvent (3mL) and and diethylamine (3 equiv.), temperatures of 55oC,
60oC, and 68oC was studied using microwave heating for 40 minutes. Only starting
acetanilide was recovered at 55oC, indicating the energy of activation was not reached.
Trace Lidocaine was observed at 60oC, but Lidocaine was the primary product at 68oC.
Using only the acetanilide and diethylamine with microwave heating at 68oC for 30
minutes, Lidocaine was produced in 95-99% yields. This prompted a study to determine
the rates of reaction at 68oC. Two five-minute reactions were performed to test the
difference between heating the reaction in a water bath or a microwave. The water bath
was heated to 70oC and the microwave was set to 68oC. The comparison of these two
reactions show a significant increased rate of reaction in the microwave. This is
illustrated in Figure 1 where the reactant/product ratio is 1.92 in conventional heating
were it is 0.49 in microwave heating. Because of the extreme difference in rates between
these two reactions at similar temperatures, the implication of different mechanisms
becomes a possibility that could also be explored.
Conclusion:
The two-step synthesis of Lidocaine was increased from 30% (55% x 55%) to a 90% yield
(92% x 98%) by simple modification of the traditional synthetic procedures. In addition,
the reaction time was reduced from 90 minutes to 10 minutes in the microwave without
compromising the purity of the products (Figure 2). Future work exploring the kinetic
enhancement of microwave heating can be explored. Through these studies, it could be
determined if the order or the rate constant of the rate law is altered.
All Reactions 0.100g α-chloro-2,6-dimethylacetanilide
Et2NH Temp. (oC) Time (min) % Yield
3 eq. in toluene 110 90 55 ± 5
3 eq. in IL * 100 60 20
3 eq. in THF 68 MW 60 60 ± 5
15 eq. (solvent) 70 60 90 ± 4
15 eq. (solvent) 68 MW 30 98 ± 3
15 eq. (solvent) 70 5 27.3
15 eq. (solvent) 68 MW 5 58.7
* IL = 1-butyl-3-methylimidazolium hexafluorophosphate
Table 1: Reaction Array
Figure 1: NMR comparison: 5 min Reactions
(Top) water bath 70oC (Bottom) MW 68oC
Figure 2: NMR of Pure compounds