and amount of interior void space that may be enclosed by the terminal groups as
the dendrimer is grown. Branch cell multiplicity (N b ) determines the density and
degree of amplification as an exponential function of generation. The interior
composition and amount of solvent-filled void space determines the extent and
nature of guest–host (endoreceptor) properties that are possible within a particular
dendrimer family and generation. Finally, the surface consists of reactive or passive
terminal groups that may perform several functions. With appropriate functionality,
they serve as a template polymerization region as each generation is amplified and
covalently attached to the precursor generation. The surface groups may also serve
as passive or reactive gates controlling entry or departure of guest molecules from
the dendrimer interior. These three architectural components determine the physical and chemical properties, as well as the overall size, shape and flexibility of the
dendrimers. It is important to note that dendrimer diameters increase linearly as a
function of the number of shells or generations added, whereas the terminal
functional groups increase exponentially as a function of generation. This dilemma
enhances “tethered congestion” of the anchored dendrons, as a function of generation, due to the steric crowding of the end groups. As a consequence, lower
generations are generally open, floppy structures, whereas higher generations
become robust, less-deformable spheroids, ellipsoids, or cylinders depending on
the shape and directionality of the core.
Tomalia-type PAMAM dendrimers are synthesized by the divergent approach.
This methodology involves in situ branch cell construction in stepwise, iterative
stages (i.e., G ¼ 1, 2, 3 . . .) around a desired core to produce mathematically
defined nanoscale core–shell structures. Typically, ethylenediamine (N c ¼ 4) or
ammonia (N c ¼ 3) are used as nucleophilic cores and are allowed to undergo
reiterative two-step reaction sequences involving: (1) exhaustive alkylation of
primary amines (Michael addition) with methyl acrylate and (2) amidation of
amplified ester groups (Fig. 10) with a large excess ethylenediamine to produce
primary amine terminal groups.
This first reaction sequence on the exposed dendron (Fig. 12) creates G ¼ 0
(i.e., the core branch cell), wherein the number of arms (i.e., dendrons) anchored to
the core is determined by N c . Iteration of the alkylation/amidation sequence produces an amplification of terminal groups from one to two, with the in situ creation
of a branch cell at the anchoring site of the dendron that constitutes G ¼ 1.
Repeating these iterative sequences produces additional shells (generations) of
branch cells that amplify mass and terminal groups according to the mathematical
expressions described in Fig. 11.
As early as 2001, Nobel Laureate Prof. B. Sharpless popularized a modular
approach to organic synthesis that he referred to as “click chemistry” [95, 96]. This
strategy was defined in the context of four major organic reaction categories:
1. Addition of nucleophiles to activated double bonds (i.e., Michael addition
chemistry)
2. “Non-aldol”-type carbonyl chemistry (i.e., formation of amides, hydrazones,
etc.)
342
D.A. Tomalia
the dendrimer is grown. Branch cell multiplicity (N b ) determines the density and
degree of amplification as an exponential function of generation. The interior
composition and amount of solvent-filled void space determines the extent and
nature of guest–host (endoreceptor) properties that are possible within a particular
dendrimer family and generation. Finally, the surface consists of reactive or passive
terminal groups that may perform several functions. With appropriate functionality,
they serve as a template polymerization region as each generation is amplified and
covalently attached to the precursor generation. The surface groups may also serve
as passive or reactive gates controlling entry or departure of guest molecules from
the dendrimer interior. These three architectural components determine the physical and chemical properties, as well as the overall size, shape and flexibility of the
dendrimers. It is important to note that dendrimer diameters increase linearly as a
function of the number of shells or generations added, whereas the terminal
functional groups increase exponentially as a function of generation. This dilemma
enhances “tethered congestion” of the anchored dendrons, as a function of generation, due to the steric crowding of the end groups. As a consequence, lower
generations are generally open, floppy structures, whereas higher generations
become robust, less-deformable spheroids, ellipsoids, or cylinders depending on
the shape and directionality of the core.
Tomalia-type PAMAM dendrimers are synthesized by the divergent approach.
This methodology involves in situ branch cell construction in stepwise, iterative
stages (i.e., G ¼ 1, 2, 3 . . .) around a desired core to produce mathematically
defined nanoscale core–shell structures. Typically, ethylenediamine (N c ¼ 4) or
ammonia (N c ¼ 3) are used as nucleophilic cores and are allowed to undergo
reiterative two-step reaction sequences involving: (1) exhaustive alkylation of
primary amines (Michael addition) with methyl acrylate and (2) amidation of
amplified ester groups (Fig. 10) with a large excess ethylenediamine to produce
primary amine terminal groups.
This first reaction sequence on the exposed dendron (Fig. 12) creates G ¼ 0
(i.e., the core branch cell), wherein the number of arms (i.e., dendrons) anchored to
the core is determined by N c . Iteration of the alkylation/amidation sequence produces an amplification of terminal groups from one to two, with the in situ creation
of a branch cell at the anchoring site of the dendron that constitutes G ¼ 1.
Repeating these iterative sequences produces additional shells (generations) of
branch cells that amplify mass and terminal groups according to the mathematical
expressions described in Fig. 11.
As early as 2001, Nobel Laureate Prof. B. Sharpless popularized a modular
approach to organic synthesis that he referred to as “click chemistry” [95, 96]. This
strategy was defined in the context of four major organic reaction categories:
1. Addition of nucleophiles to activated double bonds (i.e., Michael addition
chemistry)
2. “Non-aldol”-type carbonyl chemistry (i.e., formation of amides, hydrazones,
etc.)
342
D.A. Tomalia