Metalation reaction of 3,5dichloroNethylbenzamide

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Metalation reaction of 3,5dichloro-N-ethylbenzamid
e

• Adam Clarke
• Dr. Bradley
• CPSRP 2005

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Background

• Benzamides have known biological activity as
  insecticides and fungicides. The most widely
  used of this family is 3-methyl-N,N-diethylbenzami
  de, more commonly known as DEET. Analogs of this
  compound have been synthesized in order to find a
  new, possibly more effective biologically active
  molecules.

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Background

• Benzamides have been observed to direct
  metalation to the ortho site.

• In has been shown that 3,5-dichloro-N-N-diethylbe
  nzamides undergo almost complete para
  substitution after benzaldehyde electrophile
  quench

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Abstract

• In order to study the directing effects of a
  3,5-dihalogenated benzamide a series of
  experiments were designed with variable
  electronegativity of the 3,5 halogens (Cl or F)
  and variable degree of substitution of the
  nitrogen (secondary or tertiary)

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Experimental

• Reaction is water sensitive, acyl halide reacts
  to form benzoic acid counterpart.
• Reaction run under nitrogen with dry glassware.
• Measuring acyl halide proved difficult.

N2
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ReactionFormation of benzamide
First, ethylamine adds to the carbonyl carbon via
nucleophilic attack, creating a tetrahedral
intermediate which then collapses, displacing the
chlorine anion. The resulting, protonated amide
is then deprotonated by the second equivalent of
amine.
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Data and Observations

• Compound confirmed by
• 1H-NMR
• IR
• GC/MS
• 13C-NMR
• Melting Point
• Isolated in approximately 85 yield

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1H-NMR of Benzamide
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Experimental

• Reaction run at -78ºC in an acetone/dry ice bath
• Sec-butyl lithium is water sensitive, so the
  reaction was run with dry glassware under
  nitrogen
• N,N,N,N-tetramethylethylenediamine was used to
  prevent sec-butyl lithium from complexing

Low Temp Thermometer
N2
Acetone/Dry Ice
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Reaction
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Workup and Purification

• Reaction solvent removed by rotary evaporation
• Reaction mixture was separated into two compounds
  by column chromatography with 85 petroleum ether
  15 ethyl acetate
• Characterization by IR, GC/MS, and 1H-NMR
• Peak at 1776 cm-1 indicative of lactone carbonyl

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GC/MS of Lactone
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1H-NMR of Lactone
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Conclusions

• Benzamide was successfully synthesized and fully
  characterized
• Lactone was synthesized, as shown by Mass Spec
  and IR
• 100 Ortho substitution observed with dichloro,
  monoethyl compound
• Purification methods not adequate, as shown by GC
• Metalation is not 100 efficient, needs driving
  force to completion

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Other Random Things

• Synthesized 3,5-diflouro-N-ethylbenzamide via
  same method as dichloro analog
• Synthesized salicylaldehyde phenylhydrazone, and
  used as an indicator for the titration of
  sec-butyl lithium
• Assembled Krugelrohr distillation apparatus,
  Bucci Rotavap, and solvent stills

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Acknowledgements

• Brad Hutnick
• Maryll Geherty
• Dr. Bradley
• Dr. Hunt
• Alyza Szajna
• CPSRP students and Chemistry faculty
• Provost Briggs

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References

• Demas, M. Javadi, G.J. Bradley, L.M. Hunt,
  D.A. J. Org. Chem., 2000, 65, 7201-2
• Patel, Minal The Metalation Reaction of
  3,5-dichloro-N-ethylbenzamide 2002
• Fleming, Tina Metalation Studies of the
  Substitution Reactions of 3,5-dichloro-N-ethylbenz
  amide 2001