\makeatletter
\@ifundefined{HCode}
{\documentclass[screen,CRCHIM,Unicode,biblatex,published]{cedram}
\addbibresource{crchim20250988.bib}
\newenvironment{noXML}{}{}
\def\tsup#1{$^{{#1}}$}
\def\tsub#1{$_{{#1}}$}
\def\thead{\noalign{\relax}\hline}
\def\tbody{\noalign{\relax}}
\def\endthead{\noalign{\relax}\hline}
\RequirePackage{etoolbox}
\usepackage{upgreek}
\def\hyphen{\text{-}}
\def\jobid{crchim20250988}
%\graphicspath{{/tmp/\jobid_figs/web/}}
\graphicspath{{./figures/}}
\newcounter{runlevel}
\let\MakeYrStrItalic\relax
\csdef{Seqnsplit}{\\}
\def\botline{\\\hline}
\def\refinput#1{}
\def\back#1{}
\def\0{\phantom{0}}
\def\ubreak{\break}
\def\bPhi{\boldsymbol{\Phi}}
\def\tabnote#1{\vskip4pt\parbox{.78\linewidth}{#1}}
\newenvironment{inftab}{}{}
\usepackage{multirow} 
\def\nrow#1{\@tempcnta #1\relax%
\advance\@tempcnta by 1\relax%
\xdef\lenrow{\the\@tempcnta}}
\def\morerows#1#2{\nrow{#1}\multirow{\lenrow}{*}{#2}}
\DOI{10.5802/crchim.441}
\datereceived{2025-12-08}
\daterevised{2026-01-13}
\dateaccepted{2026-01-15}
\ItHasTeXPublished
\makeatletter
\g@addto@macro{\UrlBreaks}{\UrlOrds}
\gappto{\UrlBreaks}{\UrlOrds}
\makeatother
}
{\documentclass[crchim]{article}
\def\CDRdoi{10.5802/crchim.441}
\let\refinput\input
\makeatletter
\def\CDRsupplementaryTwotypes#1#2{}
}
\makeatother

\usepackage{upgreek}

\dateposted{2026-03-06}
\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{clarification}

\title{The discovery and development of self-assembling and
self-organizable dendrons, dendrimers, and dendronized polymers}

\alttitle{D\'{e}couverte et d\'{e}veloppement de dendrons, de
dendrim\`{e}res et de polym\`{e}res dendronis\'{e}s auto-assembl\'{e}s
et auto-organisables}

\author{\firstname{Virgil} \lastname{Percec}\CDRorcid{0000-0001-5926-0489}\IsCorresp}
\address{Roy and Diana Vagelos Laboratories, Department of Chemistry,
University of Pennsylvania, Philadelphia, PA 19104-6323, USA}
\email[V. Percec]{percec@sas.upenn.edu}

\author{\firstname{Dipankar} \lastname{Sahoo}\CDRorcid{0000-0002-7646-6419}}
\addressSameAs{1}{Roy and Diana Vagelos Laboratories, Department of
Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA}

\author{\firstname{Devendra Surendrakumar} \lastname{Maurya}\CDRorcid{0000-0002-4488-9927}}
\addressSameAs{1}{Roy and Diana Vagelos Laboratories, Department of
Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA}

\shortrunauthors

\keywords{\kwd{Self-organizable dendrons}\kwd{Self-organizable
dendrimers}\kwd{Self-organizable dendronized
polymers}\kwd{Half-disc}\kwd{Biaxial nematic}\kwd{Helical columnar
dendrimers}\kwd{Supramolecular spherical helices}}

\altkeywords{\kwd{Dendrons auto-organisables}\kwd{Dendrim\`{e}res
auto-organisables}\kwd{Polym\`{e}res dendronis\'{e}s
auto-organisables}\kwd{Demi-disque}\kwd{N\'{e}matique
biaxial}\kwd{Dendrim\`{e}res colonnaires
h\'{e}lico\"{i}daux}\kwd{H\'{e}lices sph\'{e}riques
supramol\'{e}culaires}}

\editornote{Article submitted by invitation}
\alteditornote{Article soumis sur invitation}

\thanks{National Science Foundation (grants DMR-2104554, DMR-1720530,
DMR-1807127), Leonard Case Jr. Chair at Case Western Reserve
University, P. Roy Vagelos Chair at the University of Pennsylvania,
Alexander von Humboldt Foundation Awards}

\begin{abstract}
\looseness=-1
This account discusses the accidental discovery of self-assembling and
self-organizable dendrons, dendrimers, and dendronized polymers. Our
laboratory never intended to make this discovery. At the time of this
finding, our laboratory was interested in developing a methodology to
mimic the self-assembly of helical rod-like and icosahedral or
spherical viruses. An attempt to transform a monotropic biaxial nematic
(N\textsubscript{\textit{b}}) phase of a compound constructed from a combination of a half-disc
and a rod into an enantiotropic phase by attaching this building block
as a side group to a polymer led to a polymer coated with a helical
dendritic jacket appearing as a primitive rod-like virus. Investigation
of more and less complex variants of the half-disc and rod compound
led to the discovery of self-organizable dendrons, dendrimers, and
dendronized polymers assembling into both helical rod-like and spherical
helices supramolecular dendrimers. The combination of a disc-like and a
rod-like compound that never exhibits the N\textsubscript{\textit{b}}
phase was developed in
France and published in this journal. Our discovery provided an example
in which an incorrect assignment of a phase led to a finding
that facilitated the development of several new unrelated research
fields, all pioneered by self-assembling and self-organizable dendrons,
dendrimers, and dendronized polymers. We would like to use this
opportunity to thank the scientists who elucidated the structure and
the mechanism of self-assembly of viruses,  the laboratory that
developed the combination of disc-like and rod-like molecules, and  
the scientists who asked us to investigate this molecule for providing
the inspiration for this discovery.
\end{abstract}

\begin{altabstract}
Ce compte rendu discute de la d\'{e}couverte accidentelle de dendrons,
dendrim\`{e}res et polym\`{e}res dendronis\'{e}s auto-assemblants et
auto-organisables. Notre laboratoire n'avait jamais eu l'intention de
faire cette d\'{e}couverte. Au moment de cette trouvaille, notre
laboratoire s'int\'{e}ressait au d\'{e}veloppement d'une
m\'{e}thodologie visant \`{a} imiter l'auto-assemblage des virus
h\'{e}lico\"{i}daux en forme de b\^{a}tonnet et des virus
icosa\'{e}driques ou sph\'{e}riques. Une tentative de transformer une
phase n\'{e}matique biaxiale monotropique (N\textsubscript{\textit{b}}) d'un compos\'{e}
construit \`{a} partir d'une combinaison de demi-disque et de
b\^{a}tonnet en une phase \'{e}nantiotropique, en attachant ce motif de
construction comme groupe lat\'{e}ral \`{a} un polym\`{e}re, a conduit
\`{a} un polym\`{e}re recouvert d'une enveloppe dendritique
h\'{e}lico\"{i}dale ressemblant \`{a} un virus primitif en forme de
b\^{a}tonnet. L'\'{e}tude de variantes plus ou moins complexes du
compos\'{e} demi-disque/b\^{a}tonnet a men\'{e} \`{a} la d\'{e}couverte
de dendrons, dendrim\`{e}res et polym\`{e}res dendronis\'{e}s
auto-organisables, s'assemblant en dendrim\`{e}res
supramol\'{e}culaires h\'{e}lico\"{i}daux en b\^{a}tonnet et en
h\'{e}lices sph\'{e}riques. La combinaison du compos\'{e} disco\"{i}de
et b\^{a}tonnet, qui n'avait jamais pr\'{e}sent\'{e} la phase N\textsubscript{\textit{b}}, a
\'{e}t\'{e} d\'{e}velopp\'{e}e en France et publi\'{e}e dans cette
revue. Notre d\'{e}couverte a fourni un exemple o\`{u} une attribution
incorrecte d'une phase a conduit \`{a} cette r\'{e}v\'{e}lation,
facilitant le d\'{e}veloppement de plusieurs nouveaux domaines de
recherche ind\'{e}pendants, tous initi\'{e}s par les dendrons,
dendrim\`{e}res et polym\`{e}res dendronis\'{e}s auto-assemblants et
auto-organisables. Nous souhaitons profiter de cette occasion pour
remercier les scientifiques qui ont \'{e}lucid\'{e} la structure et le
m\'{e}canisme d'auto-assemblage des virus, le laboratoire qui a
d\'{e}velopp\'{e} la combinaison de mol\'{e}cule disco\"{i}de et
b\^{a}tonnet, ainsi que les chercheurs qui nous ont demand\'{e}
d'\'{e}tudier cette mol\'{e}cule, pour avoir fourni l'inspiration de
cette d\'{e}couverte.
\end{altabstract}

%\input{CR-pagedemetas}

\maketitle

\twocolumngrid

\end{noXML}

\section{Introduction} \label{sec1}

This account discusses the discovery and the development of
self-assembling and self-organizable \mbox{dendrons}, dendrimers, and
dendronized polymers. It also briefly illustrates similarities and
differences between covalent dendrimers and supramolecular dendrimers
by stressing the advantages and disadvantages exhibited by each of them.
This article provides a personal view of the corresponding author (VP) on
this discovery. As the main author (VP), I would like to state that our
laboratory never intended to make this discovery. Therefore, brief
stories that provided this accidental discovery are \mbox{presented}
here. We were happy when the corresponding author received the
invitation from Anne-Marie Caminade to write an account on dendrimers
in this special issue, and we decided to tell the story of this discovery.
Two reasons led to this decision: (a)~the French scientific community
played a very important role in this discovery; 
(b)~the most important paper that led to this finding was also
published in this journal. Finally, I would like to make a few comments
about the rules I (VP) employed in writing this report. Searching by
current electronic systems is very efficient. However, this search
could generate misleading results if authors did not use the same
words in their title and abstract that were employed during the
electronic search. Therefore, we used the rules of the late Professor
Herbert Morawetz when he wrote the most accurate and influential
history of polymers in his book \textit{Polymers. The Origins and
Growth of a Science}~\cite{1}. In the Preface to his book, Herbert
Morawetz made the following important statement:
\vspace*{1pt}

\begin{quote}
\fontsize{8.65}{10.2}\selectfont
I found out quite quickly that there is no substitute for reading
every reference cited---second-hand citations are incredibly
unreliable. Unfortunately, the insistence on citing only publications I
had read has led undoubtedly to some neglect of the Russian and
Japanese contributions; for this I apologize but it was a price I had
to pay if I was to cite only what I knew in detail.\vspace*{1pt}
\end{quote}

\noindent
He also listened to recollections of many polymer scientists from
different areas of research. One example was Herman Mark. On talking
about Mark, Herbert Morawetz stated the following:

\vspace*{1pt}

\begin{quote}
\fontsize{8.65}{10.2}\selectfont
Throughout our association of more than thirty years I had never seen
so much of him. Listening to his recollections was frequently a
revelation; his memory of events lying back sixty years or more never
ceased to amaze me.\vspace*{1pt}
\end{quote}

{\advance\baselineskip by -.2pt

\noindent
In addition to the two statements made by Herbert Morawetz, I would like
to add that an electronic search of the literature can be not only  extremely
efficient but also incredibly unreliable if different names are used
for a certain structure. For example, in the case of the discovery of
covalent dendrimers, on which I have written a brief article
recently~\cite{2}, different names in addition to the name dendrimer
were used by the four laboratories that pioneered
this field. Therefore, an electronic search of the literature would
have failed to find three of the four discoverers of covalent dendrimers. Only
a careful and complete reading of the literature enables documenting
discovery events. Covalent dendrimers were discovered by
synthetic organic chemists who published their work in chemistry
journals and in patents. However, credit was given to all of them
regardless of the different names they used. Supramolecular dendrimers
were discovered at the interface among several different disciplines
including molecular biology, synthetic biology, chemistry, physics,
crystallography, and liquid crystals. Most of the scientists working on
covalent dendrimers are not involved in these fields. Therefore, the
literature on liquid crystals was not of interest to scientists working
on covalent dendrimers. Incidentally, our laboratory was and is active
in a large number of research fields including liquid crystals.
Therefore, this account tries to bridge  all disciplines
that influenced the discovery process reported here.

\begin{figure*}
\vspace*{5pt}
\includegraphics{fig01}
\vspace*{5pt}
\caption{\label{fig1}Rosalind Franklin (left), TMV model (center), and
Aaron Klug~(right). {\textcopyright}~Elliott \& Fry and the National
Portrait Gallery. {\textcopyright}~MRC Laboratory of Molecular
Biology.}
\vspace*{5pt}
\end{figure*}

\vspace*{-4pt}
\section{The inspiration} \label{sec2}
\vspace*{-2pt}

During the fall of 1982, my colleagues from the Department of Physics
at Case Western Reserve University in Cleveland, Ohio, invited me to
attend a lecture given by Professor Aaron Klug of the Laboratory of
Molecular Biology from Cambridge University~\cite{3,4}. His lecture was
followed by a French dinner, which I was also invited to attend.
Professor Aaron Klug had obtained his PhD in physics at Cambridge
University in the UK. After his PhD, he started to work with Rosalind
Franklin in the Department of Physics led by J.~D.~Bernal at Birkbeck
College, University of London, on the structure of viruses
(Figure~\ref{fig1}) \cite{5}. Rosalind Franklin had made important
contributions to the determination of the double helix of DNA and to
the elucidation of the structure of viruses~\cite{5,6,7,8,9,10}.
Originally, I was hesitant to attend a lecture given by an expert in
physics rather than chemistry. However, the invitation to the French
dinner together with the lecturer convinced me to attend his
presentation. A few days after this event, Professor Aaron Klug received
the Nobel Prize for Chemistry for\vspace*{.1pc}

}

\begin{quote}
\fontsize{8.65}{10.2}\selectfont
his investigations of the three-dimensional structure of viruses and
other particles that are combinations of nucleic acids with proteins
and for the development of the crystallographic method of electron
microscopy.~\cite{4}
\end{quote}

\looseness=-1
``{We aim to understand the functioning of molecules through
their structure}'', stated Aaron Klug while explaining his
work~\cite{3}. The fact that Aaron Klug was a physicist and received
the Nobel Prize in Chemistry was quite intriguing to me, so I decided
to read his Nobel lecture~\cite{4,11}. Almost immediately, I became
inspired by the self-assembly and self-organization of viruses.  I
decided to develop synthetic systems that could, at least in a
primitive way, mimic the structure(s) and the self-assembly of viruses.
I saw this as a fascinating new avenue for research in my laboratory.
However, for several years, I struggled to find a viable approach to
tackle this challenge, which involved synthesizing unknown
non-biological molecules that behaved like biological molecules and
therefore self-assemble and self-organize into helical rod-like and
globular virus-like supramolecular architectures. Natural viruses were
fascinating to us since they were known to form various liquid crystal
lyotropic phases~\cite{12,13,14,15,16}. Helical rod-like viruses were
known to self-organize into columnar hexagonal lyotropic liquid crystalline
phases while globular viruses generate cubic periodic arrays.
\textbf{Crick and Watson stated that it is a striking fact that all
viruses are either rods or spheres}~\cite{17}. The structural characterization of 
crystalline and liquid crystalline periodic arrays of viruses was provided
by X-ray and by other diffraction\break methods.

\section{The scientific failure leading to the{\hfill\break} discovery}
\label{sec3}

During the early fall of 1987, Professor Alfred Saupe from Kent State
University visited my office on the recommendation of our mutual friend
Professor Helmut Ringsdorf from the University of Mainz. Professor
Ringsdorf had suggested that Saupe reach out to me for assistance in
solving a synthetic scientific problem. Saupe presented to me a paper
by Jacques Malth\^{e}te and his collaborators~\cite{18} from College de
France who had reported a molecule constructed from combining a
half-disc with a rod (Scheme~\ref{sch1}, right). Malth\^{e}te {et
al.} had claimed that this molecule exhibits a monotropic
biaxial nematic (N$_b$) liquid crystal phase. Malth\^{e}te's structure was
inspired by a concept advanced by the theoretical physicist
Chandrasekhar (Scheme~\ref{sch1}, left)~\cite{19,20}. A monotropic phase
refers to a phase that is metastable and is observed only during
cooling. Saupe discovered the first N$_b$ liquid crystal phase that was
lyotropic and difficult to investigate~\cite{21}. Normal nematic (N)
molecules undergo translational and rotational motions while N$_b$
molecules are expected to display a more complex combination of
motions. Saupe was keen to transform the monotropic phase of the
Malth\^{e}te {et~al.}\ molecule into an enantiotropic state in order to
be able to explore and elucidate its physical properties including its
motions.

\begin{scheme*}
{\vspace*{-.15pc}}
\includegraphics{sc01}
{\vspace*{.6pc}}
\caption{\label{sch1}The thermotropic biaxial nematic liquid crystal is
composed of a half-disc and rod-like entities as proposed and
demonstrated by Chandrasekhar (see structure on left side). The
structure from Malth\^{e}te {et~al.}\  is on the right
side~\cite{18,20}.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc02}
{\vspace*{.6pc}}
\caption{\label{sch2}Synthesis of
poly(4-11-methacryloylundecan-1-yloxy)-4'-[3,4,5-tri-(\textit{p},\textit{n}-dodecan-1-yloxbenzyloxy)benzoate]bi\-phenyl)
(top); synthesis of
4-(11-undecan-1-yloxy)-4$'$\{3,4,5-tri[\textit{p}-(\textit{n}-dodecan-1-yloxy)-benzyloxy]benzoate\}biphenyl
side groups (middle); hydrogen-bonded structure of
3,4,5-tri-(\textit{p}-\textit{n}-dodecan-1-yloxybenzyloxy)benzoic acid
(bottom).}
{\vspace*{-.75pc}}
\end{scheme*}

We were just about to publish together with Professor Andrew Keller
from Bristol University in the UK some phase diagrams that explained
the correlation between the molecular structure of liquid crystals and
the transformation of monotropic and even virtual liquid crystal phases into
the enantiotropic phase~\cite{22}. Based on this concept, I asked my junior
graduate student Jim Heck to attach a methacrylate group at the end of
the rod side of Malth\^{e}te's molecule expecting that the resulting
polymethacrylate, or any other polymer backbone, will accomplish the
monotropic to enantiotropic transformation of Malth\^{e}te's N$_b$
phase (Scheme~\ref{sch2}). 

\begin{scheme*}
{\vspace*{.1pc}}
\includegraphics{sc03}
{\vspace*{.6pc}}
\caption{\label{sch3}Polysiloxanes containing Malth\^{e}te's side group
and variants of a Malth\^{e}te-like side group.}
{\vspace*{-.6pc}}
\end{scheme*}

As seen from the top part of Scheme~\ref{sch2}, we have shown the half-disc part
of Malth\^{e}te's molecule to be a first-generation
self-assembling dendron or as we will discuss later a ``mini-dendron'',
which by H-bonding self-organizes a supramolecular disc-like structure
forming a column~\cite{23,24}. Supramolecular columns form a
hexagonal periodic array. A combination of differential scanning
calorimetry (DSC), thermal optical polarized microscopy, and X-ray
diffraction  was employed to demonstrate that by H-bonding, this self-assembling
dendron forms a disc-like structure assembling a
supramolecular columnar dendrimer, which self-organizes a columnar
hexagonal liquid crystalline periodic array. This will be discussed
later.\ The~\mbox{experiments} shown in Scheme~\ref{sch2} along with numerous
studies on libraries of closely related molecules to Malth\^{e}te's
compound and their polymers did not yield the expected transformation
from monotropic N$_b$ to enantiotropic N$_b$
(Schemes~\ref{sch2}~and~\ref{sch3}). All these compounds self-organized to form
columnar hexagonal periodic arrays. In fact, the N$_b$ phase was shown
by Saupe and others from the Liquid Crystal Institute at Kent
University to be a monotropic smectic phase. Since we do not publish
negative results about other laboratories, we did not publish this
information. However, two different laboratories made this
correction~\cite{25,26}. A reinspection of the first two lab notebooks
of Jim Heck was made during the writing of this article. This
inspection indicated that from January 1, 1988 to February 28, 1989 he
investigated numerous libraries of Malth\^{e}te-like,
Malth\^{e}te-related, and fragments of Malth\^{e}te's molecules
(Schemes~\ref{sch2}--\ref{sch5}). The combination of methodologies
mentioned previously revealed that libraries of Malth\^{e}te-like molecules
formed a supramolecular coat around the polymer backbone, assembling into a
helical column or a supramolecular column if no polymer backbone was
attached to the building\break block. 

\begin{scheme*}
\includegraphics{sc04}
{\vspace*{.6pc}}
\caption{\label{sch4}Representative examples of self-organizable
molecules based on the modified disc-like part of Malth\^{e}te's
molecule.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc05}
{\vspace*{.6pc}}
\caption{\label{sch5}Synthesis of 2-vinyloxyethyl
3,4,5-tris[4-(\textit{n}-dodecanyloxy)benzyloxy]benzoate based
corresponding polymer.}
{\vspace*{-.5pc}}
\end{scheme*}

Scheme~\ref{sch3} illustrates that kinked or bent-rod-like moieties
attached to the half-disc of Malth\^{e}te's structure or even
two simplified half-discs assembled on their own (not shown) or when
attached to polymer backbones self-organize into columnar hexagonal liquid
crystalline periodic arrays. Surprisingly, removing the rod-like moiety
of Malth\^{e}te's molecule and replacing it with monoethylene glycol,
diethylene glycol, triethylene glycol, and tetraethylene glycol
containing an OH or methoxy groups at their end generate by
complexation with metal triflates or without the same self-organized
columnar hexagonal periodic array. 
The presence of a single H-bond
mediates this self-organization process. Replacing Malth\^{e}te's
half-disc with a simplified half-disc without benzyl ether groups
provided the same periodic arrays. Replacing the oligooxyethylene
fragments from Malth\^{e}te's half-disc or from the simplified
half-disc with crown ethers benzo-15-crown-5 and 15-crown-5 produced
the same periodic arrays after complexation with metal triflates.
\mbox{Representative} \mbox{results} with triethylene glycol and with crown ethers
are summarized in Scheme~\ref{sch4}. 

The structures from Scheme~\ref{sch4} are in fact the first examples of
self-assembling amphiphilic dendrons~\cite{27,28,29,30,31,32,33,34,35}.
Jim Heck was highly disappointed by these results but I (VP) became
enthusiastic, as the resulting polymers exhibited a three-dimensional
structure resembling the helical rod-like structure of the tobacco
mosaic virus (TMV) (Figure~\ref{fig1}). These were the first results on
self-organizable dendrons and dendronized polymers. At that time,
covalent dendrimers were thought to have a spherical shape. A different shape was
reported in our
communication from the 1989 ACS meeting at Miami Beach,
Florida~\cite{23}, in five additional ACS
presentations~\cite{27,36,37,38,39} up to 1992, and five publications
between 1990 and 1991~\cite{24,40,41,42,43}. In all these
presentations and publications, we referred to these groups as
tapered-shaped moieties, tapered side groups, tapered side chains, or
hemiphasmidic mesogens rather than tapered self-assembling or
self-organizable dendrons. In 1991~\cite{43} and  1992, powder X-ray
diffraction experiments allowed us to name the supramolecular columns
generated in the absence of the rod-like part of the dendronized
polymer with Malth\^{e}te's molecule, TMV-like
assembly periodic arrays. These periodic arrays were the first to be
generated by living cationic polymerization of vinyl ethers containing
Malth\^{e}te's half-disc group (Scheme~\ref{sch5}) \cite{44,45}.

\begin{scheme*}
{\vspace*{-.05pc}}
\includegraphics{sc06}
{\vspace*{.3pc}}
\caption{\label{sch6}Divergent and convergent synthesis of covalent
dendrimers~\cite{82,83,84,85,86,87,88}.}
{\vspace*{-.65pc}}
\end{scheme*}

Living cationic polymerization of vinyl ethers~\cite{46,47,48} and
other living polymerizations~\cite{49,50,51,52,53,54} were routinely
employed in our laboratory to elucidate molecular-structure
phase-transition properties in other complex systems including in
liquid crystal polymers. Moreover in 1992, we introduced the name liquid
crystalline dendrimeric polymer for a library of higher generation
self-organizable dendrimers~\cite{55}, demonstrating that with proper
molecular architecture, dendrimers can adopt a variety of conformations
including columnar and willow-like rather than only the commonly
expected spherical shape~\cite{56,57}. Branched \mbox{columnar} \mbox{architectures}
were also elaborated at the same time~\cite{58}. These experiments
demonstrated that simple self-organizable dendrimers of first and other
lower generations can form complex molecular architectures that are
not achievable by  conventional covalent dendrimers. In 1992, Jim
Heck defended his Master of Science thesis titled ``Supramolecular
Polymers''~\cite{59}. Most probably, this was the first thesis with
this title in the entire world. Few years later in January 1995, Jim
Heck defended his PhD thesis titled ``Self-Assembly of Tubular
Supramolecular Architectures via a Combination of Endo- and
Exo-Recognition Processes''~\cite{60}. In his PhD thesis, he employed
self-assembling dendrons to self-organize into functional columnar
assemblies. During the early 1990s, the corresponding author of this
paper was invited to give numerous invited and plenary lectures around
the world. The first four brief review articles on this topic
including the first on TMV-like assemblies were published in
1994~\cite{29,61,62,63}. Seven more brief reviews were published in the
next two years, and in some of them, the name dendrimer is part of their
title~\cite{28,64,65,66,67,68,69}. The only proof that covalent
dendrimers such as PAMAM may also exhibit a rod-like shape was provided
in a landmark publication by Naylor, Goddard, Kiefer, and Tomalia, which
suggested, by molecular mechanics simulations, an ovoidal highly
asymmetric shape in generations 1--4 followed by a transition to a
nearly spherical shape in generations 5--7~\cite{70}. Definitive
proof for ``helical'' columns was provided by oriented-fiber X-ray
diffraction experiments conducted with my colleague John Blackwell and
his postdoc Sergei N.~Chvalun, which were reported in 12 publications
starting in 1994~\cite{67,71,72,73,74,75,76,77,78,79,80,81}. These
studies showed that the half-disc of Malth\^{e}te's molecule was not
a half-disc but rather one-eighth of the cross-section of a 
supramolecular helical column regardless of whether it was attached to a
polymer backbone or~not.\looseness=1

\begin{figure*}
{\vspace*{-2pt}}
\includegraphics{fig02}
{\vspace*{-3pt}}  
\caption{\label{fig2}Supramolecular helical columns from
self-assembling dendrimers (top) and from self-organizable dendronized
polymers (bottom).}
{\vspace*{-3pt}}
\end{figure*}

The experiments demonstrated that these first-generation dendrons,
synthesized through a convergent rather than divergent approach 
(Scheme~\ref{sch6}, top) even before the name convergent synthesis 
(Scheme~\ref{sch6}, bottom) was coined~\cite{2}, self-assemble into helical
columns, which in turn self-organize just like TMV into helical
columnar hexagonal periodic arrays (Figure~\ref{fig2}). The helical
pitch of the \mbox{supramolecular} columns self-assembled from both
dendronized polymers and from tapered dendrons was also discussed in
these publications.\looseness=1

The libraries of self-organizable dendrons and dendronized polymers
from Schemes~\ref{sch4} and~\ref{sch5} and from references associated
with them concluded that helical columns induce a helical
conformation in an atactic polymer backbone, resembling the case of mRNA
in TMV (Figure~\ref{fig2}).

\looseness=-1
These publications encouraged both our laboratory and the broader
scientific community to recognize that supramolecular dendrimers can
adopt a variety of shapes or conformations in addition to the widely
accepted spherical shape. The name ``TMV-like'' was included in
publications and in review titles~\cite{29,44}. A microsegregation of
the aliphatic part from the aromatic fragment of self-assembling
dendrons was demonstrated to be responsible for the mechanism of
self-assembly and self-organization (Figure~\ref{fig3})~\cite{89}.

\begin{figure*}
\includegraphics{fig03}
\caption{\label{fig3}(a)~Structures of
1,2-bis\{3,4,5-tris[S(-)-2-methylbutan-lyloxy]benzamido)ethane and
l,2-bis[3,4,5-tris(\textit{n}-dodecan-l-yloxy)benzoyloxy]ethane (top);
(b)~schematic representation of the columns in the $\bPhi_{\mathbf{h}}$
phase (top view), where the inner core is composed of fixed width by
aromatic groups and linkers and an outer sheath is composed of molten
alkyl chains of uniform density (bottom left); (c)~linear dependence of
the column diameter ($D_{\mathrm{Col}}$) or hexagonal lattice parameter
($a_n^2$, $D_{\mathrm{Col}} = a$) on $n$ ($n = 1$--18); (d,
e)~schematic views of the columns of two different models forming a tilted
angle. Each parallelepiped represents one DA-$n$ molecule, and the
connecting vertical lines represent the hydrogen bonds.}
{\vspace*{-.1pc}}
\end{figure*}

This demonstration provided access to systematic developments of
self-organizable dendrons, dendrimers, and dendronized polymers. Moreover,
different functionalities were incorporated at the apex of
self-assembling dendrons, which led to the development of functional
supramolecular columns and their self-organizable periodic arrays. This
was the time when electronic literature searches began to be used.
Unfortunately, the absence of terms such as self-assembling,
self-organizable dendron, dendrimer, and dendronized polymer in the
titles of our very early publications may have made it difficult for
laboratories to find our and other laboratories' work in
specialized literature by electronic searches except for
those specifically interested in the liquid crystallinity of covalent
or supramolecular dendrimers. Nevertheless, we believe that the words
taper, tapered, tapered molecule, tapered building block, and half-disc
clearly indicate the structure of a dendron. Therefore
scientific curiosity should have provided access to the chemical
structure investigated just like in the case of covalent
dendrimers. What else could a tapered shape be generated from other than
a dendron~\cite{90,91,92}?

\begin{figure*}
\vspace*{2pt}
\includegraphics{fig04}
\vspace*{2pt}
\caption{\label{fig4}(a)~Synthetic supramolecular system with
cylindrical and spherical shapes; (b)~supramolecular shape change
during radical polymerization of conical dendronized monomers,
illustrating the quasiequivalence concept; the SFM images of 
(c)~spherical and (d)~cylindrical assemblies. Adapted
from Ref.~\cite{95}. Copyright {\textcopyright}~1998,
Macmillan Magazines Ltd.}
\vspace*{2pt}
\end{figure*}

\section{The discovery of self-organizable spherical supramolecular
dendrimers} \label{sec4}

In 1997, after many years of very complex and time-consuming structural
analysis~\cite{93,94,95}, spherical supramolecular dendrimers
having the perfection to self-organize into cubic periodic arrays, as
spherical viruses do~\cite{17} and as originally predicted by Jim Heck
only from DSC and optical microscopy, were reported. When Jim Heck
predicted many years in advance the spherical shape of the supramolecular dendrimers from
1997~\cite{93}, I showed the structure to
\mbox{Professor} Andrew Keller who was visiting our department. He
responded by saying, ``{{Fire this student, since when an
organic chemist can predict the crystal structure of organic
molecules?}}'' I did not fire Jim. Instead, together with Goran Ungar,
a former postdoc of Andrew Keller, we determined the structure of 
Jim's molecules and demonstrated the spherical shape of the
supramolecular dendrimers, which were self-organized from conical
dendrons just as Jim had predicted. This challenging structural
analysis used a combination of X-ray diffraction, electron density
maps, reconstruction of the experimental \mbox{X-ray} data with
molecular models, isomorphic replacement, transmission electron
microscopy, and scanning force microscopy. My colleague Steven Hudson
together with Sergei Sheiko, who was working in Martin Moeller's
laboratory at the University of Ulm (Germany) at the time, also
contributed to this pioneering work confirming Jim's original
prediction. This cubic periodic array shown in Figure~\ref{fig4}
corresponds to the Frank--Kasper A15 phase.
This phase was discovered in 1958
in metals by Sir Charles Frank~\cite{96,97}, the head of the  laboratory 
at Bristol University in the UK, with whom Professor
Andrew Keller worked. Shortly
thereafter, the tetragonal or Frank--Kasper ${\sigma}$~\cite{98} and
the soft quasicrystal known as liquid quasicrystal (LQC)~\cite{99,100}
phases were also discovered in our laboratory. These discoveries laid
the foundation for the field of soft quasicrystals and soft
Frank--Kasper phases in other forms of \mbox{self-organized} soft
matter~\cite{101} including in block copolymers~\cite{102}.

\textit{At the time we discovered the first Frank--Kasper A15 phase in
supramolecular dendrimers, we had a joint grant on dendrimers with
several other scientists including W.~A.~Goddard from Caltech.
Ref.}~\cite{93} \textit{appeared in the 1997 JACS issue no.~7}~\cite{93}, 
\textit{which is published every Wednesday prior to our
meeting on Mondays. Each of us comes in
the morning of the meeting and starts our presentations at 9:00~am. Bill
Goddard from Caltech was the first speaker and I was second.
To~my shock, he gave a lecture on the work published in Ref.}~\cite{93}
\textit{explaining by computer simulation how and why the A15
Frank--Kasper phase would self-organize from our self-assembling
dendrons. I started my presentation by asking Bill Goddard how he could 
do this work so quickly since at that time JACS and all other ACS
journals were delivered as hard copies and this issue would not be at
Caltech on Wednesday but on Thursday or Friday. ``I put all my group to
work on this simulation from the minute we have seen the paper until I
boarded the plane on Sunday night to Washington'', he replied. I asked
him if he could predict what other primary self-organizable dendron
structures would generate new periodic arrays? His reply was very
simple: ``If somebody can say that he can predict the periodic array in
advance without having \mbox{X-ray} data on the structure, he is not
your friend!'' Since 1997, I kept asking Bill every couple of years
the same question. His answer was the same as in 1997: ``Progress is
being made but we are not yet there!!!'' It~\mbox{required} another 7 years to
\mbox{complete} the work of his Washington presentation, which was published in
JACS in the year 2004}~\cite{128}. In a review article on quasicrystals,
Tomonari Dotera~\cite{101} explains the discovery and the name in the
following\break manner:\vspace*{.3pc}
\begin{quote}
\fontsize{8.65}{10.2}\selectfont
In his speech at the conference banquet for the 9th International
Conference on Quasicrystals at Ames, Iowa, in 2005, notable polymer
chemist Virgil Percec coined the term soft quasicrystal, when two
decades had already passed since the revelation of
quasicrystals~\cite{103,104}.
{Until the advent of quasicrystals in a supramolecular dendrimer
system}~\cite{99} {followed by a star polymer
system}~\cite{105}, {quasicrystalline materials had been isolated
in one category of materials alone, namely, synthetic intermetallic
systems}~\cite{106}. 
\end{quote}
Following the discovery in dendrimers, soft
Frank--Kasper phases and quasicrystals have been discovered in block
copolymers~\cite{102,107,108,109}, giant
surfactants~\cite{110,111,112,113},
lipids~\cite{114,115,116,117,118,119,120},
surfactants \mbox{\cite{121,122,123,124}}, nanocrystals~\cite{125}, DNA
particles~\cite{126}, sugar--polyolefin block copolymers~\cite{127}, and in
many other soft materials~\cite{101}.\ Work on soft quasicrystals and
Frank--Kasper phases was accompanied by a substantial amount of
theoretical and simulation research~\cite{128,129,130,131,132}, creating
a new and independent field of research.\ ``{It is a striking
fact that almost all small viruses are either rods or
spheres}''~\cite{17}, \textbf{\textit{and it is even more striking that
almost all supramolecular dendrimers are either helical columns or
spherical helices.}} By drawing an analogy with the concept of
quasiequivalence from molecular biology~\cite{133,134,135}, we
demonstrated that conical dendrons can also be quasiequivalent, allowing
for a conformational change from conical to tapered under a wide range
of conditions~\cite{2}.\looseness=1

\section{The most important similarities and{\hfill\break} differences
between covalent and{\hfill\break} supramolecular dendrimers}
\label{sec5}

When comparing covalent with supramolecular dendrimers, we observe that
the multiplicity at the core of the spherical structure in
supramolecular dendrimers can be much larger than the maximum value of 4
possible for covalent dendrimers. The largest multiplicities observed
in our \mbox{laboratory} for hollow and non-hollow micellar or {vesicular}
spherical supramolecular dendrimers were 480 and less~\cite{136}, and
770~\cite{137}. The 770 multiplicity provides a supramolecular
dendrimer of ultrahigh molar mass equal to $1.78 \times 10^{6}$~g/mol,
which is in the molar mass range of ribosomes~\cite{137}. In
the case of supramolecular dendrimers, we define multiplicity as the
number of dendrons self-assembling a molecular object regardless of its
structure. The maximum multiplicity of conventional covalent dendrimers
like PAMAM is~4 although 6 was reported for covalent dendrimers
containing cyclotriphosphazene and cyclotriveratrylene cores and 8 for
covalent dendrimers containing phthalocyanine,
\mbox{cyclotetraveratrylene}, triphenylene, and other cores. At the same
time, the steric hindrance present on the surface of covalent
dendrimers is less pronounced in supramolecular dendrimers. These two
dissimilar features, larger conical multiplicity in the core and
reduced surface steric hindrance, determine the structures and physical
properties that differentiate many physical properties of covalent
dendrimers from supramolecular dendrimers. Regardless of the mechanism
of self-assembly, most supramolecular dendrimers adopt either columnar
or spherical shapes similar to viruses and thus exhibit helical
chirality (Figure~\ref{fig5}) \cite{137}. Covalent dendrimers do not
exhibit helical chirality. Self-organizable dendrimers can be
characterized in the same way as biological systems by a combination
of X-ray diffraction, electron density maps, and circular dichroism.
This combination is not feasible for covalent dendrimers that do not
self-organize.

\begin{figure*}
{\vspace*{6pt}}
\includegraphics{fig05}
{\vspace*{4pt}}
\caption{\label{fig5}Structural and retrostructural analyses of
libraries of supramolecular dendrimers and dendronized polymers. 
Adapted from Ref.~\cite{137}. Copyright
{\textcopyright}~2009, American Chemical Society.}
{\vspace*{4pt}}
\end{figure*}

\section{Discovery of the molecular design principles of supramolecular
dendrimers} \label{sec6}

The combination of methodologies available for the characterization of
self-organizable dendrimers endowed us with an accelerated
modular--orthogonal approach to the design and characterization of
libraries of supramolecular dendrimers. This allowed determination of the
molecular structure of self-organizable dendrons, dendrimers, and
dendronized polymers, which self-organize into helical columns or
spherical helices. The ovoidal shape of the covalent dendrimer PAMAM during
its first four generations indicated by computer simulation~\cite{70} was
demonstrated by our laboratory to be columnar in supramolecular
dendrimers. By analogy with the case of PAMAM, supramolecular
dendrimers become spherical at higher generations~\cite{138,139}. This
was demonstrated to be a general concept available in many libraries of
self-organizable dendrons and dendrimers~\cite{136,137,140,141,142,143,
144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,
162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,
179,180,181,182,183}. The primary structure of the self-organizable
dendron is responsible for the shape of the supramolecular dendrimer
and  dendronized polymer as a function of the degree of
polymerization. An example illustrating the principles of this concept
is shown in Figure~\ref{fig4}. 

Libraries obtained by increasing the generation number were named 
``generational'' while those produced by deconstruction were denoted
``deconstruction'' libraries. Both types of libraries were employed in
this process. Figure~\ref{fig5} summarizes the combined
structural and retrostructural analyses of these libraries,
which illustrates the conformation of the primary structure required to
generate periodic arrays constructed from hollow and non-hollow helical
columns and spherical helices. Since they are helical, it means that all
supramolecular assemblies are in fact chiral but racemic or by
spontaneous deracemization, homochiral, even if they are self-organized
from achiral building blocks. These results are not unexpected since
both helical rod-like and spherical viruses are also chiral although
they are generated from chiral building blocks~\cite{137}.

A nanoperiodic table of self-organizable dendrons was generated by
employing these principles~\cite{137}. Once a nanoperiodic table of
self-organizable dendrons, dendrimers, and dendronized polymers is
available (Figure~\ref{fig5}), the molecular design of a wide range
of functions becomes feasible.\ However, it should be noted that not
all self-assembling dendrons form supramolecular dendrimers that are
self-organizable into periodic or quasiperiodic arrays~\cite{91,184}.
It is important to state that unless supramolecular dendrimers
self-organize into periodic arrays, their structural analysis by X-ray
diffraction is not possible. More complex columnar structures
including bundles of columns were self-organized from what we called at
a certain time self-organizable mini-dendrons or
mini-monodendrons~\cite{185,186}. We explained in one of our
publications that self-assembling mini-dendrons have extraordinary
synthetic capabilities for the elaboration of new structural motifs
from larger generations of dendritic building blocks. The role of these
self-assembling mini-dendrons is analogous to that of simple peptides
used in the understanding of the molecular engineering involved in the
assembly of more complex and larger proteins or of maquettes used by
sculptors and architects to appreciate various aspects of full-size
objects~\cite{185,187}. Vesicular columns and vesicular spheres are now
achievable by employing mini-dendrons as maquettes\break (Figure~\ref{fig5}).

\section{From discovery to a brief discussion of the development and
impact on other research fields} \label{sec7}

We  mention only briefly the development of numerous functions and
applications generated by employing self-organizable dendrons,
dendrimers, and dendronized polymers.\ The first application was to
inspire artists to paint the supramolecular structure of dendrimers.\ An
example is shown in Figure~\ref{fig6}, which illustrates the structure
of an A15 supramolecular dendrimer discovered in our laboratory.\ 
Additional examples refer to ionic and
electronic {\cite{188,189,190}} conductors, mimics of the
transmembrane protein
aquaporin~\cite{191,192,193,194,195,196,197,198,199,200,201,202,203},
which {provided} an entirely new field of research for water
purification~\cite{204,205}, supramolecular orientational memory effect,
which predicts the structure of novel rod-like helical
assemblies~\cite{206,207,208,209,210,211}, mediating the reactivity of
functional groups including conjugated polymer chains by eliminating
their intramolecular electrocyclization followed by chain
cleavage~\cite{212,213,214,215,216,217,218,219,220,221,222,223},
molecular machines~\cite{224,225}, amphiphilic Janus dendrimers that
self-assemble into dendrimersomes, which are employed in the delivery of
drugs~{\cite{226,227,228,229,230,231,232,233}}, amphiphilic Janus
glycodendrimers that self-assemble into glycodendrimersomes mimicking the
glycans of biological membranes~{\cite{234,235,236,237,238,239,240,
241,242,243,244,245,246,247}}, deracemization in crystal
state~\cite{248}, the cogwheel mechanism of self-organization of
homochiral supramolecular systems~\cite{249,250,251,252,253,254}, and
last but not least, multifunctional sequence-defined ionizable
amphiphilic Janus dendrimers~{\cite{255,256,257,258,259,260,261,262,263,264,265}}, which
coassemble with mRNA into dendrimersome nanoparticles with predictable
dimensions. They enable targeted delivery of mRNA for therapeutics and
vaccines. \textit{It is also important to recognize that similar to
covalent dendrimers, the discovery of self-organizable dendronized
polymers, dendrons, and dendrimers was not accompanied immediately by
the name dendrimer.} Additionally, in parallel, self-organizable
dendronized biological macromolecules such as
peptides~\cite{192,266,267}, proteins, and RNA~\cite{255} were
elaborated~\cite{137,268}. Although the numerous functions mediated by
self-organizable dendrons, dendrimers, and dendronized polymers are not 
enumerated here in detail, it is essential to understand that the
mechanisms of self-organization in both biological and synthetic
systems are closely related or even identical.\looseness=1

\begin{figure}
\includegraphics{fig06}
\caption{\label{fig6}The painting of a spherical supramolecular
dendrimer self-organized from conical dendrons inspired by
Ref.~\cite{139}. Credit: Iektje Meijer Oosterbeek.}
{\vspace*{-.6pc}}
\end{figure}

\section{Conclusions} \label{sec8}

Accidental discoveries have permanently impacted numerous fields of
science including chemistry, and I (VP) am not sure if there is any
record about the significance and the outcome of accidental discoveries
versus rationally designed research in any field of science. I would
like to mention only a few examples referring to the discoveries of 
crown ethers, cryptands, molecular hosts and guests, molecular recognition,
and self-assembly~\cite{269,270,271}. This selection was made since
some of these concepts and building blocks were also employed in the
\mbox{discovery} that was discussed here.\ This account tells the
story of the accidental discovery of self-organizable dendrons,
dendrimers, and dendronized polymers.\ I would like to give credit to
J.-M.~Lehn for providing clarification when referring to self-assembly
and self-organization~\cite{272}. The main goal of this account is that
there is no failure in science since we never know if a correct or an
incorrect conclusion of a research and publication will have the
largest impact on future scientific developments. In this particular
case, the incorrect assignment of a \mbox{biaxial} nematic phase by
Malth\^{e}te's laboratory impacted in a positive way the discovery of
self-organizable dendrons, dendrimers, and dendronized polymers, which
by themselves led to the development of numerous additional research
fields. We want to thank again Malth\^{e}te's laboratory for being
incorrect in their assignment of this phase. In fact, the biaxial
nematic phase continues to be debated and it could be that we
discovered again by accident a biaxial nematic phase in macrocyclic
liquid crystals~\cite{273}. Our N$_b$ phase seems to be less debated but
it could be that it is also less known. However, Malth\^{e}te's
laboratory made numerous important contributions to the development of
supramolecular dendrimers almost at the same time as us, but they
received no recognition for their work since they, like us, did not use the
name dendrimer~\cite{274,275}. This~and other labs' work may become part
of a different story. I would like to apologize for not citing a lot of
additional work on supramolecular dendrimers including the spectacular
work of Didier Astruc~\cite{276}, Aida~\cite{277}, Majoral and
Caminade~\cite{278,279,280}, and many others, but the decision to write
a personal story of our discovery limited the scope of this account.

\vspace*{-3pt}

\section*{Acknowledgments}

\vspace*{-3pt}

The author VP thanks many generations of very gifted and hard-working students and
postdocs and many collaborators from the US and from around the world who
made this story possible. He also thanks  Donald A.~Tomalia who
recommended writing this story to him.\looseness=-1

\vspace*{-3pt}

\section*{Declaration of interests}

\vspace*{-3pt}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.

\vspace*{-3pt}

\section*{Funding} 

\vspace*{-3pt}

Financial support by the National Science Foundation (grants
DMR-2104554, DMR-1720530, DMR-1807127), the Leonard Case Jr. Chair at
Case Western Reserve University, the P.~Roy Vagelos Chair at the
University of Pennsylvania, and two Alexander von Humboldt Foundation
Awards is gratefully \mbox{acknowledged}.\looseness=-1

\CDRGrant[NSF]{DMR-2104554}
\CDRGrant[NSF]{DMR-1720530}
\CDRGrant[NSF]{DMR-1807127}

\back{}

\printbibliography
\refinput{crchim20250988-reference.tex}

\end{document}