n organic chemistry, the Diels–Alder reaction is a chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene derivative. It is the prototypical example of a pericyclic reaction with a concerted mechanism

1. NAMED REACTIONS IN ORGANIC
SYNTHESIS: DIEL’S-ALDER
REACTION & GATTERMANN-
KOCH REACTION
By
PRUTHVIRAJ K
PRUTHVIRAJ K, MSc

2. Diel’s-Alder reaction
• The [4Π + 2Π] cyclization of a diene and alkene to form a cyclohexene
derivative is known as the Diels-Alder cycloaddition (D-A cycloaddition).
• The diene component is usually electron rich, while the alkene (dieneophile)
is usually electron poor and the reaction between them is called the normal
electron-demand D-A reaction. When the diene is electron poor and the
dienophile is electron rich then an inverse electron demand D-A cyclization
takes place
• 1) it can potentially set four stereocenters in one step; 2) if unsymmetrical
dienes and dienophiles react it is highly regioselective and stereospecific; 3)
the regioisomers are predominantly the “ortho” and “para” products over the
“meta” product; 4) if a disubstituted cis (Z) alkene is used, the
stereochemistry of the two substituents in the product will be cis and when
an (E) alkene is used, the stereochemistry in the product will be trans; 5) the
stereochemical information (E or Z) in the diene is also transferred to the
product; 6) the predominant product is the endo cycloadduct; 7) by using
appropriate chiral catalysts the cycloaddition can be made enantioselective
and 8) multiple rings can be created in one step with defined
stereochemistry
PRUTHVIRAJ K, MSc

3. PRUTHVIRAJ K, MSc

4. • Mechanism
Mechanistically the D-A reaction is considered a concerted, pericyclic reaction with an aromatic
transition state. The driving force is the formation of two new σ-bonds. The endo product is the kinetic
product and its formation is explained by secondary orbital interactions.Some of the mechanistic studies
suggested that a diradical or a di-ion mechanism may be operational in certain cases. It was also shown
that solvents and salts can influence reaction kinetics
PRUTHVIRAJ K, MSc

5. Gattermann-Koch Reaction
• In 1897, L. Gattermann and J.A. Koch successfully introduced a formyl group (CHO) on toluene by
using formyl chloride (HCOCl) as the acylating agent under Friedel-Crafts acylation conditions.1
Although the researchers were not able to prepare the acid chloride, they assumed that by reacting
carbon monoxide (CO) with hydrogen chloride (HCl), formyl chloride would be formed in situ,
• The introduction of a formyl group into electron rich aromatic rings by applying CO/HCl/Lewis acid
catalyst (AlX3, FeX3, where X = Cl, Br, I) to prepare aromatic aldehydes is known as the Gattermann-
Koch formylation
PRUTHVIRAJ K, MSc

6. Mechanism
The mechanisms of the Gattermann and Gattermann-Koch formylation belong to the category of
electrophilic aromatic substitution (SEAr) but are not known in detail, since they have a tendency to
vary from one substrate to another, and the reaction conditions may also play a role. When carbon
monoxide is used, the electrophilic species is believed to be the formyl cation, which is attacked by the
aromatic ring to form a -complex. This -complex is then converted to the aromatic aldehyde upon losing
a proton. When HCN is used, the initial product after the SEAr reaction is an imine hydrochloride,
which is subsequently hydrolyzed to the product aldehyde
PRUTHVIRAJ K, MSc

7. Synthetic application
• The benzofuran-derived natural product caleprunin A was synthesized by R. Stevenson et al. using
the Gattermann formylation as the key step.24 The starting 3,4,5-trimethoxyphenol was suspended
with Zn(CN)2 in ether and dry HCl gas was bubbled through the reaction mixture at room
temperature for 2h. The solvent was decanted, water was added and the mixture was heated for 15
minutes. The natural product was obtained by reacting the benzaldehyde derivative with
chloroacetone in DMF in the presence of anhydrous K2CO3
PRUTHVIRAJ K, MSc
Certain aromatic analogues of natural amino acids can be used as potential fluorescent probes of
peptide structure and dynamics in complex environments. The research team of M.L. McLaughlin
undertook the gram scale synthesis of racemic 1- and 2-naphthol analogues of tyrosine. The
synthesis of the 1-naphthol tyrosine analogue started with the Gattermann formylation of 1-naphthol
using the Adams modification to afford the formylated product 4-hydroxy-1-naphthaldehyde in 67%
yield

8. • Compounds containing the pyridocarbazole ring are known to have DNA intercalating properties and
therefore they are potent antitumor agents. For example, several syntheses of pyrido[2,3-a]carbazole
derivatives have been published, but these methods are often lengthy and low-yielding. R. Prasad and
co-workers synthesized 2-hydroxypyrido[2,3-a]carbazoles starting from 1-hydroxycarbazoles.26 The
key transformation was the Gattermann formylation of 1-hydroxycarbazoles to obtain 1-
hydroxycarbazole-2-carbaldehydes, from which the target compounds could be obtained via a Perkin
reaction
PRUTHVIRAJ K, MSc

9. REFERENCES
• STRATEGIC APPLICATIONS OF NAMED REACTIONS IN
ORGANIC SYNTHESIS
By- Laszlo Kurti and Barbara Czako
• REACTIONS, REARRANGEMNTS AND REAGENTS
By- S N Sanyal
PRUTHVIRAJ K, MSc