**5. Mechanisetic aspect of Ru(II)-catalyzed C-H/N & C-H/N-H alkyne annulation reactions**

#### **5.1 Nature of the C-H bond activation**

Ruthenium(II)-catalyzed alkyne annulation reaction started via the activation of the C-H bond *ortho* to the nitrogen atom of the directing group thereby forming a C-Ru species. In this C-H bond activation, whether the C-H ruthenation step is reversible or irreversible can be confirmed by a deuterium-scrambling experiment (**Figure 4**) [22]. If the deuterium exchange on a specific substrate in the absence or presence of alkyne under the standard reaction condition in a deuterated solvent (ionisable) did not afford any H/D exchange or undergoes a minor exchange at the *ortho*-C-H position, suggest an irreversible C-Ru bond formation. On the other hand, if the H atom of the *ortho*-C-H undergoes a significant H/D exchange then the ruthenation step might be reversible.

#### **5.2 Kinetic Isotop effect (KIE) study**

In Ru(II)-catalyzed oxidative alkyne annulation reactions the rate-determining step can be explained on the basis of kinetic isotop effect [23]. This can be done by an intermolecular competitive experiment between a non-deuterated and corresponding deuterated substrates with an internal alkyne under the standard reaction condition (**Figure 5a**) or from two parallel reaction involving nondeuterated and corresponding deuterated substrates individually (**Figure 5b**).

*Access to* N*-Heterocyclic Molecules* via *Ru(II)-Catalyzed Oxidative Alkyne… DOI: http://dx.doi.org/10.5772/intechopen.95987*

#### **Figure 4.**

*Deuterium-scrambling experiment.*

**Figure 5.** *KIE determination experiment.*

If these experiments provide a kH/kD > 1.0 than it is suggests that the initial C-H bond cleavage, *i.e*., the C-Ru (reversible or irreversible) bond formation is the rate determining step. The KIE is determined from the ratio between the kinetic constants for the non-deuterated (kH) and deuterated (kD) substrates. Nevertheless, it is also estimated indirectly by the measurement of the ratio of individual yield of the corresponding undeuterated product and deuterared analogues or from their 1 HNMR spectra in the case of a mixture of products on the basis of their integration ratio.

#### **5.3 Regioselectivity of the alkyne annulation**

The regioselectivity of these Ru(II)-catalyzed oxidative alkyne annulation can be determined by the reaction of an unsymmetrical internal alkyne having an alkyl and an aryl substituent such as 1-phenyl-1-propyne. It has been found that the internal

**Figure 6.** *Regioselectivity of the internal alkyne.*

alkyne inserts into the C-H bonds through the carbon atom towards the alkyl part while the aryl substituted carbon center of the internal alkyne is connected to the nitrogen atom (**Figure 6**). This preferential reactivity of the nitrogen atom at the benzylic carbon of an unsymmetrical internal alkynes leading to regioselective annulation is quite similar to that of C-H/O-H C-H/S-H annulation reactions [24, 25].
