Nitrogen containing organic compounds
Nitrogen containing organic compounds Lecture-4
Stereochemistry
The properties of many drugs depends on their stereochemistry
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Nitrogen chirality center
Stereochemistry → \rightarrow → Nitrogen chirality center → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Nitrogen chirality center
Stereochemistry → \rightarrow → Nitrogen chirality center → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Ambident nucleophile
Nucleophiles which have more than one (generally two) suitable atoms through which they can attack the substrate
Stereochemistry → \rightarrow → → \rightarrow → Ambident nucleophile → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Reaction
R Br + AgCN ⟶ s l o w \overset{slow}{\longrightarrow} ⟶ s l o w ↓ + [ R + + C N − ] ⟶ f a s t \downarrow+ [R^{+} + CN^-] \overset{fast}{\longrightarrow} ↓ + [ R + + C N − ] ⟶ f a s t R − N ( + ) ≡ C ( − ) ; S N 1 R-N^(+) \equiv C^(-) \quad ; \quad S_N 1 R − N ( + ) ≡ C ( − ) ; S N 1
R− - − → {\rightarrow} → ∣ N C δ − — R — B r δ + ∣ T S \underset{TS}{\underset{}{| \overset{\delta -}{NC} — R — \overset{\delta +}{Br} |}} TS ∣ NC δ − — R — B r δ + ∣ → \rightarrow → R − C N ; S N 2 R-CN \quad ;\quad S_N2 R − CN ; S N 2
A g + \mathrm{Ag}^{+} Ag + R + \mathrm{R}^{+} R + A g X p p t \mathrm{AgX} \hspace{1mm} \mathrm{ppt} AgX ppt
N u − Nu^- N u −
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → Reaction → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Reaction
R − B r + A g N O 2 \mathrm{R}-\mathrm{Br}+\mathrm{AgNO}_2 R − Br + AgNO 2 → slow \xrightarrow{\text { slow }} slow A g B r ∣ + R ( 1 ) + [ N O 2 ] → fast R − O − N = O ; S N 1 \mathrm{AgBr} \mid+\mathrm{R}^{(1)}+\left[\mathrm{NO}_2\right] \xrightarrow{\text {fast }}\mathrm{R}-\mathrm{O}-\mathrm{N}=\mathrm{O} ; \quad S_N1 AgBr ∣ + R ( 1 ) + [ NO 2 ] fast R − O − N = O ; S N 1
R − B r + N a N O 2 \mathrm{R}-\mathrm{Br}+\mathrm{NaNO_2} R − Br + NaN O 2 ⟶ ∣ O 2 N ^ R B r 5 + ∣ \longrightarrow\left|\begin{array}{lll}\mathrm{O}_2 \hat{\mathrm{N}} \mathrm{R} \stackrel{5+}{\mathrm{Br}}\end{array}\right| ⟶ O 2 N ^ R Br 5 + ⟶ R N O 2 ; S N 2 \longrightarrow \mathrm{RNO}_2 ; \quad S_N2 ⟶ RNO 2 ; S N 2
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → Reaction → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Reaction
Reduction of Nitriles, Oximes, and Amides
Reduction of any of these functional groups by catalytic hydrogenation or lithium aluminum hydride ( L i A l H 4 ) \left(\mathrm{LiAlH}_4\right) ( LiAlH 4 )
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → Reaction → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Discovery of sulfanilamide
In 1936, Ernest Fourneau of the Pasteur Institute in Paris showed that prontosil breaks down in the human body to produce sulfanilamide, the active agent
In the following years, many thousands of structural variations of sulfanilamide were synthesized in the search for additional drugs
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Discovery of sulfanilamide → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Proto alkaloids
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Proto alkaloids → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Classification of alkaloids
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Classification of alkaloids → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Classification of alkaloids
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Classification of alkaloids → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Nicotine
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Nicotine → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Arecoline
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Arecoline → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Lobeline
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Lobeline → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
The hofmann elimination
In the late 19th century, the prominent German-born chemist, August W. von Hofmann (1818-1895), discovered that quaternary ammonium hydroxides on heating undergo an elimination reaction to produce an alkene
Hofmann made many important contributions to organic chemistry as a professor at the Royal College of Chemistry in London
In the traditional Hofmann elimination a primary amine with a β \beta β
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → The hofmann elimination → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
The hofmann elimination
Hofmann Elimination, An E2 Reaction
The 4 0 4^0 4 0 200 ∘ C 200^{\circ} \mathrm{C} 20 0 ∘ C E 2 \mathrm{E} 2 E 2
The availability of a β \beta β
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → The hofmann elimination → \rightarrow → → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Regioselectivity in the hofmann elimination
In quaternary ammonium hydroxides that have two or more nonequivalent β \beta β
The major product results from abstraction of
the more or most acidic-β H \beta H β H
This is what is called the Hofmann rule
Since alkyl groups are electron-donating relative to H \mathrm{H} H β − H \beta-\mathrm{H} β − H
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Regioselectivity in the hofmann elimination → \rightarrow → → \rightarrow →
Nitrogen containing organic compounds Lecture-4
The cope elimination
Essentially a variation of the Hofmann elimination, the Cope starts with a 3 0 3^0 3 0 4 0 4^0 4 0
The Cope is a syn elimination that proceeds through a cyclic transition state
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → The cope elimination → \rightarrow →
Nitrogen containing organic compounds Lecture-4
The cope elimination
An Example
Cyclohexylmethyl dimethylamine oxide ⟶ 160 0 \underset{160^0}{\longrightarrow} 16 0 0 ⟶ + ( C H 3 ) 2 N O H + (CH_3)_2 NOH + ( C H 3 ) 2 NO H
98%
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → The cope elimination → \rightarrow →
Nitrogen containing organic compounds Lecture-4
Reaction
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Reaction
Nitrogen containing organic compounds Lecture-4
Reaction
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Reaction
Nitrogen containing organic compounds Lecture-4
Reaction
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Reaction
Nitrogen containing organic compounds Lecture-4
Reaction
Stereochemistry → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → → \rightarrow → Reaction
