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Crystalline Molecular Complexes and CompoundsStructures and Principles$

Frank H. Herbstein

Print publication date: 2005

Print ISBN-13: 9780198526605

Published to Oxford Scholarship Online: September 2007

DOI: 10.1093/acprof:oso/9780198526605.001.0001

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Historical outline

Historical outline

(p.15) Chapter 2 Historical outline
Crystalline Molecular Complexes and Compounds

Frank H. Herbstein

Oxford University Press

Abstract and Keywords

The history of our subject goes back to the beginning of the 19th century, although the compounds concerned remained curiosities outside the mainstream of the development of chemistry until the first structures were determined by X-ray diffraction in the 1940s. There is now an explosion of interest and application, ranging from condensed-matter physics to structural biology.

Keywords:   19th century, X-ray diffraction, chemistry, condensed-matter physics, structural biology

Fir'd at first sight with what the Muse imparts,

In fearless youth we tempt the heights of Arts,

While from the bounded level of our mind,

Short views we take, nor see the lengths behind;

But more advanc’d, behold with strange surprize

New distant scenes of endless science rise!

So pleas'd at first the tow'ring Alps we try,

Mount o'er the vales, and seem to tread the sky,

Th' eternal snows appear already past,

And the first clouds and mountains seem the last:

But, those attain'd, we tremble to survey

The growing labours of the lengthened way,

Th' increasing prospect tries our wand'ring eyes,

Hills peep o'er hills, and Alps on Alps arise.

Alexander Pope: An Essay on Criticism

Summary: The history of our subject goes back to the beginning of the nineteenth century, although the compounds concerned remained curiosities, outside the main stream of the development of chemistry, until the first structures were determined by X-ray diffraction in the 1940s. We are now immersed in an explosion of interest and application, ranging from condensed-matter physics to structural biology.

Having defined our terms in Chapter 1, we can now sketch out the historical background. The first molecular complexes to be reported had illustrious parentages. The hydrate of sulphur dioxide appears to have been prepared in 1777–1778 by Joseph Priestley, while chlorine hydrate was reported in the following terms by Sir Humphry Davy in 1811

‘it is generally stated in chemical books, that oxymuriatic gas [the original name of chlorine – F.H.H.] is capable of being condensed and crystallized at low temperature; I have found by several experiments that this is not the case. The solution of oxymuriatic gas in water freezes more readily than pure water, but the pure gas dried by muriate of lime undergoes no change whatever, at a temperature of 40 below 0° of FAHRENHEIT. The mistake seems to have arisen from exposure of the gas to cold in bottles containing moisture’ (Davy, 1811).

The complex was assigned the composition 10H2O·Cl2 by Michael Faraday (1823); the currently preferred formulation is about 6·6H2O·Cl2, the exact composition depending on conditions of preparation (see Chapter 7).

(p.16) The first molecular compound to be reported was quinhydrone (hydroquinone: p-benzoquinone) by Wöhler (1844), who noted its unexpected colour. Continuation of these studies led Wöhler (1848) to the preparation of the first clathrates, with quinol (hydroquinone) as host and H2S as guest; the reported compositions of 4(quinol)·H2S and 3(quinol)·H2S are close to modern values. The SO2 clathrate was reported 10 years later (Clemm, 1859); Mylius (1886), who prepared the CO, HCN and formic acid clathrates somewhat later, suggested possible enclosure of guests by quinol without chemical combination. The picrates of benzene, naphthalene and anthracene were also prepared in the middle of the nineteenth century (Fritzsche, 1858), at a time when the atomic weight of carbon was still taken as 6. The first tunnel (channel) inclusion complex was perhaps the 2(thiourea)·diethyl oxalate complex reported by Nencki (1874), although this would appear to require checking. There followed many disparate observations, unrelated to main currents of contemporary organic chemistry and perplexing from a structural point of view. The classical period of development culminated with the publication of the second edition of Paul Pfeiffer's Organische Molekülverbindungen (1927, First Edition 1921), which remains a mine of useful factual information although some of the structural ideas are fanciful in terms of current knowledge (Fig. 2.1).

The modern period was inaugurated by the application of X-ray diffraction methods to the determination of key crystal structures. The first of these appears to have been

                      Historical outline

Fig. 2.1. Pfeiffer's representation of Posner's (1904) suggestion for the structures of phenoquinone and quinhydrone. From the short quotation attached, it is clear that Pfeiffer was not an enthusiastic supporter of the proposal. The diagram has been copied from p. 276 of Pfeiffer's book (1927).

(p.17) {{[(CH3)3AsPdBr2]2}-[dioxane]} (Wells, 1938), which is a tunnel inclusion complex. However, the real breakthrough came during and soon after the end of the Second World War when H. M. Powell and coworkers at Oxford reported the structures of p-iodoaniline┅1,3,5-trinitrobenzene (Powell, Huse and Cooke, 1943), and {{3(quinol)}-[CH3OH]} (Palin and Powell, 1945; cf. Davies, 1998), representative of charge transfer molecular compounds and clathrate complexes respectively. Other important structural elucidations of about the same time were those of gas hydrates (Stackelberg, 1949a,b; Pauling and Marsh, 1952), urea and thiourea tunnel inclusion complexes (Smith, 1950; Hermann and Lenne, 1952), and n−σ* (localized) charge transfer compounds of halogens with donors containing oxygen or nitrogen (Hassel and Rømming, 1962). The important theoretical studies of charge transfer compounds by Mulliken (1952a,b) were complemented by thermodynamic and statistical-mechanical studies of clathrates (van der Waals and Plateeuw, 1959).

The current period is distinguished by a number of themes. Firstly, there is extensive activity in the area of crystal structure analysis, which isthe major experimental tool. The adducts range in size and complexity from the combination of small organic molecules found in hyperol (urea:hydrogen peroxide) (Lu, Hughes and Giguere, 1941) to complexes of large biomolecules, with the complex of lysozyme and tri(N-acetylglucosamine) (Phillips, 1966) as an early example now far surpassed in complexity. Secondly, there is considerable study of interactions between components using a wide range of spectroscopic techniques. Thirdly, there has been renewed interest in physical properties, especially electrical conductivity, and in theoretical explanations for the various types of physical behaviour that have been found. A major gap in current knowledge, in regard to both theory and experimental data, relates to the energetics and thermodynamics of the interactions between the components.

One must also note that an important new direction of investigation has developed with the explosive growth of the branch of host-guest chemistry which we have called “moieties within molecules,” the moieties being ions as well as molecules. As we noted in Chapter 1, the importance of these substances rests on their occurrence in solution as well as in the crystalline state. Perhaps the first examples to be studied structurally as well as chemically were the cyclodextrin inclusion complexes (Cramer, 1954), which can enclose many different types of moiety within the hydrophobic interior of the doughnut-shaped molecule. The antibiotics such as enniatin constitute a somewhat similar group. These two sorts of host compound are natural in origin; the first purely synthetic examples, the macrocyclic “crown” ethers, were reported by Pedersen (1967) and since then this has become one of the most rapidly growing areas in the general field of inclusion complexes. The crown ethers were followed by the cryptands and many other variations on this theme and there seem to be few limits to the ingenuity of the organic chemist in the tailoring of particular hosts for the inclusion of specific guests. There have been many applications in analytical chemistry, synthetic organic chemistry and in biochemistry. The analogies to the behaviour of many biomolecules is striking and the phrases “molecular recognition” and “supramolecular chemistry” have become established in the literature (Lehn, 1995; Desiraju, 1995; Nangia and Desiraju, 1998). An important potential contribution of a study of crystalline supramolecular systems (“binary adducts,” in a more old-fashioned language) is to provide detailed structural information, both static and dynamic, leading to an understanding of the interactions which are fundamental to molecular recognition, and (p.18) thus hopefully, to the enhancement of our capabilities as molecular engineers, designing desired structures from first principles.

The ability to form binary adducts is not limited to small molecules and considerable progress has been made in preparing adducts of large biomolecules, an early example of which has already been mentioned (Phillips, 1966). An important application is in the area of design of drugs that have a capability of recognising receptors in proteins and DNA. Both small-molecule model compounds and biomolecule complexes are subjects of active study. Biomolecule complexes of various kinds are hardly mentioned in this book – their variety and importance demand a book in its own right. However, there is no reason to believe that the interactions involved are fundamentally different from those described here.

Highlights in the historical development of the scientific study of binary adducts are summarized in Table 2.1 (references are given in the body of the text). The task of this book is to weave these varied themes into whole cloth in as coherent and cohesive a manner as possible.

Table 2.1. Some highlights in the study of binary adducts. The dates are only approximate and have generally been chosen to indicate publication of a particularly significant paper or book, or to mark some special event. Usually the contributions of the authors cited (and their coworkers) extend over many years

Approximate date




Joseph Priestley

First observation of a gas hydrate (of SO2).


Humphry Davy

Observation of the gas hydrate of Cl2.


Michael Faraday

Analysis of the gas hydrate of Cl2.


C. Schafthäult

Preparation of graphite intercalates.


F. Wöhler

Preparation of quinol clathrate of H2S.


J. von Fritzsche

Preparation of first mixed-stack donor–acceptor compounds (benzene, naphthalene and anthracene with picric acid).


A. Villiers

Preparation of cyclodextrin inclusion complexes.


H. W. Pickering

Preparation of alkylamine hydrates.


A. W. Hofmann

Preparation of nickel ammonium cyanide inclusion complex of benzene.


H. Wieland and H. Sorge

Preparation of choleic acid inclusion complexes.


J. Martinet and L. Bornand

Qualitative donor–acceptor theory of π–π* molecular compounds.


P. Pfeiffer

Second edition of Organische Molekülverbindungen.


E. Hertel

Early crystallographic studies of molecular compounds.


A. F. Wells

Crystal structure of {{[(CH3)3AsPdBr2]2} [dioxane]} tunnel inclusion complex.


M. F. Bengen

Preparation of urea-hydrocarbon tunnel inclusion complexes.


H. M. Powell

Crystal structure of p-iodoaniline┅1,3,5-trinitrobenzene.


H. M. Powell

Crystal structure of quinol clathrate of CH3OH.


G. Briegleb

Spectroscopic studies of binary adducts.


A. E. Smith; C. Herrman and H.-U. Lenne

Crystal structures of urea-hydrocarbon tunnel inclusion complexes.


M. von Stackelberg;

Crystal structures of gas hydrates.

L. Pauling and R. E. Marsh; W. F. Claussen.

G. A. Jeffery, Yu. A. Dyadin, and their schools

Further development of crystal chemistry of gas hydrates and related complexes.


J. D. Watson and F. H. C. Crick

Structure of DNA (purine/pyrimidine hydrogen-bonded molecular compound).


F. Cramer W. Saenger; K. Harata

Publication of Einschlussverbindungen. Crystallography of cyclodextrin complexes.


J. H. van der Waals and J. C. Plateeuw

Statistical mechanics of clathrates.


L. Mandelcorn (editor)

Publication of Non-Stoichiometric Compounds.


R. S. Mulliken

Nobel Prize in Chemistry (inter alia theory of charge transfer interactions).


D. C. Phillips

Crystallography of lysozyme complexes.


O. Hassel

Nobel Prize in Chemistry (crystal structures of localized donor–acceptor molecular compounds).


J. L. Atwood and J. E. D. Davies (editors)

First issue of J. Inclus. Phenom.


D. J. Cram, J.-M. Lehn, C. J. Pedersen.

Nobel Prize in Chemistry (development of supramolecular chemistry).


J.-M. Lehn (chair, editorial board)

Publication of Comprehensive Supramolecular Chemistry in 11 volumes.


Bibliography references:

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Cramer, F. (1954). Einschlussverbindungen. Springer, Heidelberg.

Davies, J. E. D. (1998). J. Incl. Phenom. and Mol. Recogn. Chem., 32, 499–504.

Davy, H. (1811). Phil. Trans. Roy. Soc., 101, 1–35, (see p. 30).

Desiraju. G. R. (1995). Angew. Chem. Int. Ed. Engl., 34, 2311–2327.

Faraday, M. (1823). Quart. J. Sci. Lit. and Arts, 15, 71–74.

Fritzsche, J. von, (1858). J. prakt. Chem., 73, 282–292.

(p.20) Hassel, O. and Rømming, C. (1962). Quart. Rev., 16, 1–18.

Hermann, C. and Lenne, H.-U. (1952). Naturwiss., 39, 234–235.

Lehn, J.-M. (1995). Supramolecular ChemistryConcepts and Perspectives, VCH, Weinheim.

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Nangia, A. and Desiraju, G. R. (1998). Acta Cryst., A54, 934–944.

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Palin, D. E. and Powell, H. M. (1945). Nature, 156, 334–335.

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