Botafogo, Brazil's Campeonato Carioca champions in 2013, and Chilean outfit Union Espanola will meet at the Estadio Jornalista Mario Filho on Wednesday with just one point separating both teams after four matchdays.
Eduardo Hungaro's men have collected seven points from their opening four games, while Union Espanola have six points thus far.
The Brazilian outfit edged Independiente del Valle two weeks ago but that is the team's only win in eight previous outings, while Union Espanola have tasted defeat just once in their last eight games.
Uruguay's Defensor Sporting can close the gap on their Chilean opponents when they play host to Peruvian outfit Real Garcilaso, who sit bottom of the group, on Tuesday.
Since losing to Mineiro on the opening matchday, Santa Fe have lost and drawn to Venezuela's Zamora in reverse fixtures to fall three points adrift of the qualifying spots.
Ecuador Primera A leaders Emelec will be aiming to bounce back from their league defeat to El Nacional when they go head-to-head against Brazil's Flamengo in Group 7 action on Wednesday.
Meanwhile, Brazilian club Gremio can leapfrog Newell's Old Boys into top spot in Group 6 with victory over Atletico Nacional of Colombia on Wednesday.
