Meperidine has analgesic properties. To improve its properties, the butyric acid analogue was synthesised but was found to have low analgesic but good sedative properties. The analgesic properties were further minimised by the synthesis of haloperido (6 marks) 2) C3 Merperidine Merperidine butyric acid analogue Cl Haloperidol a What effect would the chlorine substitution in haloperidol have on the compounds solubility in water? What effect would the chlorine substitution in haloperidol have on the compounds ability to enter the brain? b) b) What effect would substitution of the N-methyl group with the butyric acid group have on the compounds distribution? d) Suggest roles for the fluorine and chlorine substitution in haloperidol. Solution a) The lipophilicity of the molecules caused by chlorine substituents is well known. In the case of Haloperidol is even more notorious. The chlorine group adds electrons into the phenyl group causing a mesomeric +M effect and overall the electron density of the substituent is increased causing even more London dispersion forces. In this sense, the solubility in water of the compounds decrease. b) The improved lipophilicity of the chlorine substitution of the compounds enrich its ability to permeate the membrane of the brain cells more effectively. Also, chlorine ions permeate the membrane naturally post-synaptic to raise the excitation, so haloperidol takes advantage of this to permeate as well by its chlorine group. c) This substitution improved the ability of the compounds to travel faster due to its increase in polarity, which cause them to increase its distribution, this is why butyric acid is well known for its anesthetic properties. d) The halogen substituents on haloperidol play a very important role in the synaptic mechanism of brain cells. Chloride substituents permeate the membrane via the excitatory process while fluoride manage the brain response blocking the chloride channel in the cells. .

1. Meperidine has analgesic properties. To improve its properties, the butyric acid analogue was
synthesised but was found to have low analgesic but good sedative properties. The analgesic
properties were further minimised by the synthesis of haloperido (6 marks) 2) C3 Merperidine
Merperidine butyric acid analogue Cl Haloperidol a What effect would the chlorine substitution
in haloperidol have on the compounds solubility in water? What effect would the chlorine
substitution in haloperidol have on the compounds ability to enter the brain? b) b) What effect
would substitution of the N-methyl group with the butyric acid group have on the compounds
distribution? d) Suggest roles for the fluorine and chlorine substitution in haloperidol.
Solution
a) The lipophilicity of the molecules caused by chlorine substituents is well known. In the case
of Haloperidol is even more notorious. The chlorine group adds electrons into the phenyl group
causing a mesomeric +M effect and overall the electron density of the substituent is increased
causing even more London dispersion forces. In this sense, the solubility in water of the
compounds decrease.
b) The improved lipophilicity of the chlorine substitution of the compounds enrich its ability to
permeate the membrane of the brain cells more effectively. Also, chlorine ions permeate the
membrane naturally post-synaptic to raise the excitation, so haloperidol takes advantage of this
to permeate as well by its chlorine group.
c) This substitution improved the ability of the compounds to travel faster due to its increase in
polarity, which cause them to increase its distribution, this is why butyric acid is well known for
its anesthetic properties.
d) The halogen substituents on haloperidol play a very important role in the synaptic mechanism
of brain cells. Chloride substituents permeate the membrane via the excitatory process while
fluoride manage the brain response blocking the chloride channel in the cells.