What is Medicinal Chemistry (section 8)
Section 8: How Scientists Identify Drug Structures
In medicinal chemistry, after a
compound is discovered or isolated from natural sources, one of the most
important tasks is to identify its chemical structure. The chemical
structure tells us what atoms are in the compound, how they are bonded, and how
the molecule is arranged in space.
Knowing the exact structure is
critical because:
- It helps understand how the drug works (mechanism of
action)
- It is necessary for making copies (synthesis)
- It ensures purity and avoids unwanted side effects
In this section, we will explore the
tools and techniques used by scientists to find out what a drug looks like at
the molecular level.
1.
Why Structure Identification is Important
Before using a drug in patients or
manufacturing it:
- Scientists must confirm the exact chemical
structure.
- Small changes in structure can change how the drug
behaves in the body.
- Regulatory bodies (like FDA or CDSCO) require
structural information.
2.
What is a Chemical Structure?
A chemical structure describes:
- Atoms present
(carbon, hydrogen, oxygen, etc.)
- Types of bonds
(single, double, triple)
- Functional groups
(like -OH, -COOH, -NH₂)
- Arrangement in 3D space (stereochemistry)
3.
Techniques Used to Identify Structures
There is no single method that can
provide all details. So, scientists use a combination of techniques:
|
Technique |
Purpose |
|
UV-Visible Spectroscopy |
Detects presence of double bonds
and conjugation |
|
Infrared (IR) Spectroscopy |
Identifies functional groups
(e.g., -OH, -COOH) |
|
Nuclear Magnetic Resonance (NMR) |
Determines molecular skeleton
(carbon-hydrogen framework) |
|
Mass Spectrometry (MS) |
Finds molecular weight and
structure fragments |
|
X-Ray Crystallography |
Gives 3D atomic structure (used
for crystals) |
|
Elemental Analysis |
Gives percentage of carbon,
hydrogen, nitrogen |
4.
UV-Visible Spectroscopy
Principle:
- UV-Vis measures how much ultraviolet or visible
light a compound absorbs.
- It is used for compounds with π-electrons or conjugated
double bonds.
What it tells us:
- Presence of chromophores
- Degree of conjugation
Example:
- Aromatic compounds show absorption at around 260–280
nm.
5.
Infrared (IR) Spectroscopy
Principle:
- IR spectroscopy measures how molecules vibrate
when exposed to infrared light.
- Different functional groups absorb IR radiation at
different frequencies.
What it tells us:
- Functional groups like alcohol (-OH), amine (-NH₂),
carbonyl (C=O), etc.
Example IR signals:
- O–H stretch: 3200–3600 cm⁻¹
- C=O stretch: ~1700 cm⁻¹
- N–H stretch: ~3300 cm⁻¹
6.
Nuclear Magnetic Resonance (NMR) Spectroscopy
NMR is the most powerful tool for
determining a molecule’s structure.
Principle:
- When placed in a magnetic field, hydrogen and carbon
atoms absorb radio waves.
- The pattern of absorption tells us the environment
of atoms.
Types:
- ¹H NMR (Proton NMR):
Information about hydrogen atoms.
- ¹³C NMR:
Carbon atom framework.
What it tells us:
- Number of hydrogen or carbon atoms
- Their neighbours
- Their electronic environment
- Stereochemistry (e.g., cis/trans)
Example:
- A peak at ~7.0 ppm in ¹H NMR indicates aromatic
protons.
7.
Mass Spectrometry (MS)
Principle:
- In MS, molecules are bombarded with electrons and
broken into fragments.
- The instrument measures the mass-to-charge ratio
(m/z) of each fragment.
What it tells us:
- Molecular weight
of the compound
- Structure
from fragmentation pattern
- Isotope patterns
(helps with halogens like Cl, Br)
Types of MS:
- Electron Impact (EI)
- Electrospray Ionization (ESI)
- Matrix-Assisted Laser Desorption/Ionization (MALDI)
Example:
- If molecular ion peak appears at m/z = 180, the
compound likely weighs 180 g/mol.
8.
X-Ray Crystallography
Principle:
- X-rays are passed through a crystal of the compound.
- The pattern of diffracted rays is used to calculate the
3D arrangement of atoms.
What it tells us:
- Complete 3D structure including bond angles and lengths
- Exact positioning of atoms
Limitation:
- Requires high-quality crystals, which may be hard to
grow
Used for:
- Complex natural products
- Proteins and enzymes
- Confirming absolute configuration (R/S)
9.
Elemental Analysis (CHN Analysis)
Principle:
- Determines the percentage of Carbon (C), Hydrogen
(H), and Nitrogen (N) in a compound.
What it tells us:
- Helps calculate empirical formula
- Confirms the purity and composition
10.
Combining Techniques
Each method gives a piece of the
puzzle. Scientists combine all data to determine the full structure.
Example:
- UV suggests aromatic ring
- IR shows OH and COOH groups
- NMR gives carbon-hydrogen layout
- MS gives molecular weight
- X-ray gives 3D confirmation
Together, these create a complete
structure map.
11.
Software and Databases Used
Modern laboratories use software to
interpret data:
- ChemDraw:
Draw and predict structure
- MestReNova:
NMR data processing
- MassHunter:
MS data analysis
- SciFinder, PubChem, Reaxys: Search known compounds
12.
Challenges in Structure Identification
|
Challenge |
Reason |
|
Mixture of compounds |
Difficult to isolate single
compound |
|
Overlapping peaks |
In NMR or IR, makes interpretation
harder |
|
Unstable compounds |
Decompose before analysis |
|
Need for expensive equipment |
Advanced machines like NMR and MS |
13.
Case Study – Structure Elucidation of Morphine
- Isolated from opium poppy
- IR:
Showed OH and aromatic ring
- MS:
Molecular weight ~285
- NMR:
Complex hydrogen pattern confirming its structure
- X-ray:
Confirmed 3D structure
This analysis helped in
understanding how morphine interacts with the brain’s opioid receptors.
14.
Summary Table – Key Techniques
|
Technique |
Main
Use |
|
UV Spectroscopy |
Conjugated systems, double bonds |
|
IR Spectroscopy |
Functional groups |
|
NMR Spectroscopy |
Hydrogen and carbon framework |
|
Mass Spectrometry |
Molecular weight and structure
fragments |
|
X-Ray Crystallography |
3D structure |
|
CHN Analysis |
Empirical formula |
Conclusion
Understanding the structure of a
compound is one of the most important steps in medicinal chemistry. It tells us
what the molecule is, how it might behave in the body, and how we can modify or
improve it. With the help of modern analytical techniques, scientists can
decode the mystery of molecules — even those as complex as proteins and
antibiotics.
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