Recognition of Important Components in Complex Compounds

Thalidomide

"Thalidomide rapidly epimerizes under physiological conditions rendering bioassay of enantiomers difficult."

Y. Takeuchi et al. Organic Letters 2000, 1, 1571.

Other Components:

 

Review of Basic Functional Groups in Organic Compounds

(see notes from Lecture I)

Goal:

  1. Recognize basic functional groups.
  2. Recognized major subunits that are present in pharmaceutical compounds.

Assignment: Compound information treasure hunt.

Each person is assigned compound. You are asked to find the following pieces of information on your compound:

Product name

Chemical name (common)

Therapeutic use

Compound class *Chiral atoms, rac or pure enantiomer?

 

 

Major structural units (draw and name)

 

 

Acid/Base properties Solubility

 

Structure of ionized derivative

 

Stability (Oxidative, Thermal, Photochemical)

 

Sources: PDR, Merck Index

Example:

 

Product name: Fluothane

Chemical name (common): 1,1,1-trifluoro-2-bromo-2-chloroethane

Therapeutic use: inhalation anesthesic

Compound class *Chiral atoms, rac or pure enantiomer?

Halogenated hydrocarbon

Organofluorine

Major structural units (draw and name)

CF3 - trifluoromethyl group

 

Acid/Base properties Solubility

Neutral at physiological pH alcohol, chloroform, ether, organic solvents

pKa ~ 15

Structure of ionized derivative: NA

Stability (Acid/Base, Oxidative, Thermal, Photochemical)

Stable toward warm mildly basic solutions

Reactive toward Al, Cu, Pb, brass in presence of moisture.

 

Acid/Base Chemistry

Fundamental Role in synthesis, analytical behavior, reactivity including phsyiological behavior.

General Equation:

Strengths of Acids:

  1. Inverse relationship rule:

  2. Periodic effects:
  1. Acidity increases from left to right:

    2. CH < NH < OH < FH

  2. Acidity increases from top to bottom:

HI > HBr > HCl > HF; H2S > H2O

  1. Acid Strength depends on the ability of the conjugate base to stabilize a negative charge.

a) Presence of electronegative elements:

  1. Resonance stabilization:

 

Measure of Acid/Base Strength

Aqueous systems - pKa, pKb

Scale: 0 to 14, neutral = 7

Base strength is often reported in terms of pKa which is the strength of the conjugate acid.

Example: Pyridine, pKa = 5.19 (Merck Index)

 

Rank the following compounds in order of relative basicity:

Basicity trends for amines:

  1. Resonance stabilization

    2. Cyclohexylamine vs. aniline

     

    Amides are very weakly basic (pKa = -1)

     

     

  2. Solvation effects:

    3. Explanation: (CH3)3NH+ is less solvated in H2O

  3. Explain imidazole:

 

Protonation of Basic Pharmaceuticals

 

Why?

 

What is the actual structure?

 

 

 

Expanded Scale of Acid/Base Strengths

H2O has leveling effect

Design a scale that is solvent independent.

Abbreviated scale is listed on next page.

How to read scale:

  1. Acids will react with bases listed at or below the acid.
  2. Bases will react with acids listed at or above the base.

 

Pick a base game:

Choose a base that

  1. will completely deprotonate 1,3-pentanedione

    2.  

     

  2. will partially deprotonate 1,3-pentandione

 

 

 

 

Retention of Ionizable Components in Reverse-Phase HPLC

Ref: R. LoBrutto, Y. Kazakevich*, in Practical Problem Solving in HPLC, S. Kromidas, Ed., Wiley-VCH, in press (available a 2000 Pitt-Con)

See also Prof. Kazakevich's homepage @ Seton Hall University: http://hplc.chem.shu.edu

Chromatography Theory - separation of analytes is based on the relative attraction of analytes between mobile and stationary phases.

 

 

Mobile phase: hydrophilic

Stationary phase: hydrophobic

Simple rule of retention: the more hydrophobic the component is the more it is retained.

Ionizable organic compounds: longer retention times when they are in the neutral form.

pH of mobile phase has a strong affect on separation!

 

 

 

 

Retention vs. pH Profile for a Basic Organic Cpd.

To be inserted.

 

 

 

 

 

 

 

 

 

 

 

 

 

A - fully protonated, low retention

B - partially protonated/deprotonated

Poor peak shape

Unstable retention times

Slight Change in mobile phase pH or composition greatly affects retention

C - neutral form, long retention

Silica columns are unstable > pH 8.5

 

 

Retention vs. pH Profile for Acidic Organic Cpds

To be inserted

 

 

 

 

 

 

 

 

 

 

 

 

 

A - not ionized, long retention

B - partially protonated/deprotonated

C- fully deprotonated, low retention

Silica columns are unstable > pH 8.5.

Questions:

  1. Do you need to adjust the pH with a nonionizable compound?
  2. How do you analyze something like an amino acid?