find the attachment of this slide of summarized notes on physical properties of drug molecules from martin's 6th edition from page 150 to 280

1. 1
Physical Properties of Molecules
Introduction
 The physical properties of drug molecules come from
the molecular bonding order of the atoms in the
molecule and may be thought of as either:
 additive (derived from the sum of the properties of the individual
atoms or functional groups within the molecule) e.g. mass
 constitutive (dependent on the structural arrangement of the
atoms within the molecule) e.g. optical rotation as it depends on
the chirality of the molecule.
 additive-constitutive: Molar refraction of a compound is the sum
of the refraction of atoms and groups making up the compound,
however the refractive index will also depend on the
arrangement of the atoms within each molecule.

2. 2
Introduction
 Refraction is the change of direction of propagation of
any wave, such as an electromagnetic or sound wave,
when it passes from one medium to another in which
the wave velocity is different, or when there is a spatial
variation in a medium's wave velocity.
Introduction
 The following table represents how atoms and
groups contribute to the molar refraction:
2.418C─ (single)
1.733─C═ (double)
2.398─C≡ (triple)
25.463Phenyl (C6H5)
1.1H
2.211O (C═O)
1.525O (O─H)
1.643O (ether, ester,
C─O)
5.967Cl
8.865Br
13.9I

3. 3
Introduction
 For the compound C2H5─CO─CH3 the molar
refraction would be 19.998 while for the compound
CH3─CH═CH ─ CH2─OH it will be 18.7.
 Thus, although these two compounds have the
same number of carbon, hydrogen, and oxygen
atoms, their molar refractions are not the same. The
molar refractions of the atoms are additive, but the
carbon and oxygen atoms are constitutive in
refraction. A single-bonded carbon does not add
equally as a double bonded carbon, and a carbonyl
oxygen (C ═ O) is not the same as a hydroxyl
oxygen; therefore the two compounds exhibit
different molar refractions.
Dielectric constant, 
 To properly discuss dipoles and the effects of
solvation, one must understand the concept of
dielectric constant.
 Placing a molecule in an electric field is one way to
induce a dipole.
 In a capacitor (condenser), there are two parallel
conducting plates separated by a medium across a
distance (r). Electricity will flow from the battery
through the plates until the potential difference (V) of
the plates equals that of the battery supplying the
initial potential difference.
 Charge on the electrodes is +q and -q, and V
represents the potential difference between the
electrodes.

4. 4
Dielectric constant, 
Parallel Plate Condenser
Dielectric constant, 
 Capacitance is a measure of the quantity of the electric
charge stored on the plates (q, in coulombs) for a given
electric potential difference (V, in volts).
C = q/ V
 The SI unit of capacitance is the farad;
1 farad = 1 coulomb per volt.

5. 5
Dielectric constant, 
 The capacitance of the condenser depends on the
type of medium separating the plates as well as on
the thickness r.
 When vacuum fills the space between the plates,
the capacitance is C0.
Dielectric constant, 
 If water fills the space, then the capacitance
increase because the water molecules can
orientate themselves so that its negative end lies
nearest to the positive condenser plate and its
positive end lies nearest the negative plate.
 This alignment provides an additional movement of
charge because of the increased ease with which
electrons can flow between the plates.

6. 6
Dielectric constant, 
 The capacitance of the condenser filled with some
material, Cx, divided by the reference standard
,C0, is referred to as the dielectric constant, ε.
 The dielectric constant of a solvent is a measure
of its ability to maintain a charge separation in the
solution.
oC
C
 x
Dielectric constant, 
Solvent
78.5Water
42.5Glycerin
32.6Methanol
25Ethanol
4.34diethyl ether
3.1Olive oil
2.28Benzene
Dielectric constants of some liquids at 25ºC

7. 7
Dielectric constant, 
 It is 78.5/42.5 = 1.84 times easier to separate Na+ from
Cl- ions in water than in glycerin, i.e. NaCl is more
soluble in water than in glycerin.
 Polar liquids such as water and methanol have high
dielectric constants since alignment of permanent
dipoles within these liquids produces an appreciable
increase in the capacitance of the condenser.
 The polarization of non-polar liquids such as benzene
and ether produces a much smaller effect on the
capacitance of the condenser and this is reflected by the
lower dielectric constants of these liquids.
Polarity of molecules- Introduction
 A dipole is a separation of two opposing charges over a distance r. and is
generally described by a vector known as the dipole moment (µ).
 The dipole moment (µ) depends on the individual charge moments within
the molecule and the distance of separation between charges. This
magnitude is given by:
µ = q r
 The unit of dipole moment is the debye, with one debye equals to 10-18 esu
cm.
 The esu (electrostatic unit) is the measure of electrostatic charge in a
vacuum that repels a like charge one centimeter away with a force of one
dyne.

8. 8
Polarity of molecules-Introduction
 A molecule can maintain a separation of electric charge (i.e. get polarized)
either:
 By having a permanent charge separation within a polar molecule
(permanent dipole moment).
 Through induction by an external electric field or surrounding ions. Induced
polarization can occur for both polar and nonpolar molecules (induced
dipole moment).
Induced Polarization of nonpolar
molecules
 When nonpolar molecules are placed in an electrical field, the
electron clouds of their molecules become distorted so that a
temporary charge separation occurs that is they become polarized.
This effect is termed induced polarization. On removal of the
electric field, the molecules revert to their original state.
 So, the molecules acquire an induced temporary dipole moment,
the magnitude of which is proportional to the applied field strength
(E) and the induced molecular polarizability (αp).
µ ind = E αp
 Induced polarizability is defined as the ease with which an ion or
molecule can be polarized by external force. Polarizability is a
characherstic property of a molecule associated with the structure
of that molecule. Its unit is 10-24 cm3 or Å3
 The polarizability of a medium determines the refractive index, the
dielectric constant and the optical rotation.

9. 9
Induced Polarization of nonpolar
molecules
 The induced molar polarization Pi represents the induced
dipole moment per mole of nonpolar substance when the
electric field strength of the condenser is 1 V/m.
 Pi (cm3 mol-1) is defined by the Clausius-Mossotti equation as
 Where:
  is the dielectric constant.
 M is the molar mass (molecular weight) (g mol-1)
  is the density (g cm-3).

 M
Pi
2
1



Induced Polarization of nonpolar
molecules
Example:
The dielectric constant and density of benzene (molecular
weight 78.11) are 2.28 and 0.08787 gcm-3 respectively at
20ºC. Calculate the induced molar polarization.
Pi = 265.8 cm3mol-1

10. 10
Polar molecules
Permanent dipole moment
 In a polar molecule, the separation of positively and negatively charged
regions can be permanent , and the molecule will possess a permanent
dipole moment, .
 Dipoles therefore don’t have a net charge, but this charge separation can
often create charge-like interactions and influence several physical and
chemical properties.
 The dipole moment is a vector property where the symmetry of the
molecules affects generally its dipole moment. For example, carbon
dioxide has no net dipole.
 Another example: Benzene and p-dichlorobenzene are symmetric planar
molecules and have a dipole moment of zero. Meta (m-) and ortho (o-)
dichlorobenzene are not symmetrical and have significant dipole moment.
Polar molecules
Benzene p-dichlorobenzene
o-dichlorobenzene m-dichlorobenzene

11. 11
Polar molecules
Dipole moment
(Debye units)
Compound
0Benzene
0p-dichlorobenzene
1.5m-dichlorobenzene
2.3o-dichlorobezene
1.45Ammonia
1.84Water
2.07Acetylsalicylic acid
Dipole Moments of some compounds
Polar molecules
Polarization of polar molecules
 The molecules of polar liquids experience two
effects when subjected to an applied electric field.
 As with nonpolar liquids, there is an induced
polarization which is proportional to the field
strength and the polarizability.
 A second effect arises because of the alignment
of the permanent dipoles in the applied field
(orientation polarization).

12. 12
Polar molecules
 The total molar polarization is now the sum of the
induced polarization, Pi, and the orientation
polarization, Po
P = Pi + Po
 Where k, the Boltzmann constant, is 1.38 X 10-23 J
K-1,  is the dipole moment, T is the temperature, N
is Avogadro’s number.
Tk
NPo
1
)
33
4
(
2


Polarization of polar liquids
Orientation of dipoles in an applied electric field (Absolute perfect
orientation can never occur due to the thermal energy of the
molecules which contributes to agitation against the molecular
alignment).

13. 13
Polarization of polar liquids
 The orientation of permanent dipoles becomes
less effective as the temperature is increased.
 The thermal motion of the molecules tends to
destroy the alignment of dipoles.
 The molar polarization of a polar liquid therefore
decreases with increase in temperature, in
contrast to molar polarization of nonpolar liquids,
which is independent of temperature.
Polarization of polar liquids
 A is a constant that is equal to
Where k, the Boltzmann constant, is 1.38 X 10-23 J K-1,  is
the dipole moment, N is Avogadro’s number.
k
N
9
4 2

T
APP i
1


14. 14
Polarization of polar liquids
 Importance of being aware of polarity and polarization:
1- for ionic solutes and nonpolar solvents, ion-induced
dipole interactions have an essential role in solubility
phenomena.
2- for solids composed of molecules with permanent dipole
moments, the dipole force contributes to crystalline
arrangement (ice crystals).
3- drug-receptor binding: dipole dipole interactions are
essential noncovalent forces to enhance the
pharmacologic effect. (e.g. insecticidal activity of three
isomers of DDT).

15. 15
Refractive Index
 Light passes more slowly through a substance than
through a vacuum. As light enters a denser
substance, the advancing waves at the interface
are modified by being closer together owing to their
slower speed and shorter wave-length.
 If the light enters a denser substance at an angle,
one part of the wave slows down more quickly as it
passes the interface, and this produces bending of
the wave toward the interface. This phenomenon is
called refraction.
Refractive Index
Waves of light passing an interface between two substances
of different density

16. 16
Refractive Index
 The relative value of refraction or bending of light between
two substances is given by the refractive index, n:
 In which sini is the sine of the angle of the incident ray of
light and sinr is the sine of the angle of the refracted ray.
 Normally the numerator is taken as the velocity of light in
air, and the denominator is the material being investigated.
substancesecondinlightofvelocity
substancefirstinlightofvelocity
sin
sin


n
r
i
n
Refractive Index
 Refraction varies with temperature and the wavelength of
light; nD
20 is the refractive index using the D-line
emission of sodium at 589nm, at a temperature of 20ºC.
 The refractive index can be used to identify a substance.
 Typically, a refractometer is used to determine refractive
index.

17. 17
Refractive index
 Example: The refractive index for quinoline is 1.627
at 20°C using light from the D line emission of
sodium. If the incident light has an angle of 45°
from the perpendicular to the surface of the
quinoline liquid, what is the angle of its direction
inside the quinoline?
Answer: ~ 25° 75´
Refractive Index
 The molar refraction, Rm, is related to both the refractive
index and the molecular properties of the compounds
being tested.
M is the molecular weight and  is the density of the
compound.
)(
2
1
2
2

M
n
n
Rm




18. 18
Refractive Index
 Molar refraction, Rm, is a constitutive property yet has
some measure of additivity (Table: slide 4).
 Molar refraction of a compound is the sum of the
refraction of atoms making up the compound. The
arrangements of atoms in each groups are different,
and so the refractive index of two molecules will be
different; that is, the individual groups in two different
molecules contribute different amounts to overall
refraction of the molecule.
Refractive index
Q1) The refractive index of methanol is 1.326, its
molecular weight is 32.04 g/mol, and its density is
0.7866 g/cm3 at 25°C. Calculate the molar refraction of
methanol, Rm.
Q2) Calculate the refractive index using the table in
slide 4.
Answer 1: Rm = 8.218.
Answer 2: Rm = 8.343.

19. 19
Refractive Index
 Light incident upon a molecule induces vibrating
dipoles due to energy absorption at the interface.
 The greater the refractive index at a particular
wavelength, the greater is the dipole induction.
 i.e. The interaction of light photons with the
polarizable electrons of a dielectric causes a
reduction in the velocity of light.
Refractive Index
 The dielectric constant, a measure of polarizability,
is greatest when dipolar interactions with light are
large.
 The refractive index for light of long wavelengths,
n, is related to the dielectric constant for a non-
polar molecule,, by the expression
2
n

20. 20
Refractive Index
 Molar polarization, Pi, can be considered roughly
equivalent to molar refraction, Rm, and can be written
as follows
 From this equation, the polarizability p of a nonpolar
molecule may be obtained from a measurement of
refractive index.
pi N
M
n
n
P 
 3
4
)
2
1
( 2
2





