SEPTEMBER 18, 1913] 
NA1 URE 
79 
tuted in the molecule,*? whereas in meta-substitution 
it arises by union of the addendum with this radical,** 
transformation to the respective disubstitution deriva- 
tives being effected possibly in step-by-step progres- 
sion, as conjectured by Lapworth.*® Holleman, who 
also adopts the additive hypothesis, is of the opinion 
that the radical already present in the molecule may 
promote or retard the association of the addendum 
with the pair of carbon atoms, to one of which it is 
itself attached. By the operation of the first of the 
alternatives an ortho- and by conjugation a para- 
derivative will arise; from the second a meta-deriva- 
tive will result, when scission of the additive com- 
pound ensues. Holleman’s is the only hypothesis 
which has been submitted to the test of quantitative 
investigation, and although, as already mentioned, the 
results do not suggest that finality has been reached, 
it marks an advance in the study of this obscure 
problem.*° 
No discussion of substitution in the benzene series 
would be adequate without reference te the remark- 
able behaviour of amines and phenols. Unlike other 
mono-substitution derivatives, which do not differ 
markedly from benzene in reactivity, these furnish 
mono-, di-, and tri-derivatives very readily. With 
aniline or acetanilide, substitution occurs first of all 
in the side chain, being followed under appropriate 
conditions by removal of the substituent from the 
amino-group and entry into positions relatively ortho-, 
para-, or both ortho- and para- to it. The earliest of 
these changes to be studied was the transformation 
of methylaniline into para-toluidine; many of them 
have been discovered by Chattaway and his collabora- 
tors, and until a critical study of the chlorination of 
acetanilide was undertaken by Orton and Jones,*? it 
was held that the changes, which occur only in the 
presence of hydrochloric acid, were of the type :— 
NHAc CINHAc NClAc NHAc 
\ 
ace | | 
AX Hae 
ee | | 
ny wes tes 
From the dynamics of the reaction, it is now known 
that intra-molecular transformation from the side 
chain to the ring does not occur, the agent promoting 
the substitution being chlorine arising from the fol- 
lowing series of reactions :— 
—HCl 
-> 
NClAc NHAc NHAc 
ee Are oN 
| ) +HCl = | | + Cl,——> | | + HCl 
ara eA Se 
Cl 
As bromination has been shown to follow the same 
course, it is evident that no secure foundation now 
exists for the view, formerly widely held, that the 
reactivity of amines is intimately connected with the 
variable valency of nitrogen leading to initial sub- 
stitution in the side chain. 
47 Kinetic studies of the chlorination and bromination of toluene, 
CgH5'CHs, however, gave no indication of the production of an intermediate 
additive compound of ihe hydrocarbon and addendum (cf Holleman, Polak, 
van der Laan, and Euwes, Rec, trav. chim., 1908, xxvii, 435; Bruner and 
Dluska,_ Bull. Acad. Sci., Cracow, 1907, 693; Bancroft, J. Physical Chem., 
1908, xii, 417 3 Cohen, Dawson, Blockey, and Woodmansey, Trans. Chem. 
Soc., 1910, xcvii, 1623. 
H. E. Armstrong, Trans. Chem. Soc., 1887, li, 258. 
4 A. Lapworth, Trans. Chem. Soc., 1898, Ixxiii, 454 } 1901. Ixxix, 1265. 
50 It should be mentioned that other views, based on the loosening or 
strengthening of the affinity of the hydrogen atoms situated in ortho- para- 
or in mefa- positions, brought about by the disturbing influence of the 
radical already present in the molecule on the valency of the carbon atom to 
skates is srmched, ae neaetne al that of the other five carbon atoms. 
ave been advanced by Fliirscheim (J. prakt. Chem., 1902 [ii]. Ixvi, 321), 
‘Tschitschibabin (ibid., 1912 [ii], lxxxvi, be and others. oe a 
fl K. J. P. Orton and W. J. Jones, British Association Report, ‘1910, p. 
96; Trans. Chem. Soc., 1g09, Xcv, 1456. 
NO. 2290, VOL. 92] 
Even were this view, now discredited, still applic- 
able to the amines, it could not be extended with the 
same certainty to the phenols. Hence, in explanation 
of the rigid adherence to the ortho-para-law observed 
among the mono-substitution derivatives of these two 
groups of compounds, it is noteworthy that Thiele,® 
for the phenols, suggests that the reactivity may be 
due to these substances being stable enolic forms of 
ketodihydrobenzenes, and that Orton,** for the 
amines, conjectures that it may arise from the forma- 
tion of dynamic isomerides of quinonoid structure :— 
O NAc 
OH “s NHAc . 
(ee a (\:3 
P= = = ig oe 
\F \4 Vi 
How far these suggestions may open up a new 
field of inquiry into the “mechanism” of substitution 
remains to be seen; it is at least interesting that their 
extension to the naphthalene series shows that not 
only does the reactivity of the naphthols and of 
a-naphthylamine recall that of pheno! and aniline, but 
the orientation of their mono-substitution derivatives ** 
in almost every case is the same as that of one or 
other of the six naphthaquinones, the existence of 
which has been predicted by Willstatter.°° 
Symmetric and Asymmetric Syntheses. 
It must not be supposed that the ‘‘mechanism”’ of 
substitution can be explained by reference only to the 
examples of this type of reaction which have been 
mentioned, or that the summary attempted in the 
restricted field of the replacement of hydrogen by 
halogen is a complete picture of all the different views 
advanced to account for this chemical change. Rather, 
the effort has been made to indicate in broad outline 
the difficulties that beset any exploration of that debat- 
able region which lies between the two sides of a 
chemical equation. But, as the wonderful story of 
carbon chemistry shows, the failure to comprehend 
the processes operative in substitution does not impede 
rapid progress in other directions. The study of the 
mobility of radicals, desmotropy being only one of 
many examples of this phenomenon, continues to 
present fresh problems, of which that raised by 
Thorpe*® in connection with the mobile hydrogen 
atom of glutaconic and aconitic acids may be men- 
tioned, as it revives a question of old standing: Do 
free units of valency exist in carbon compounds? 
The syntheses of caffeine and certain alkaloids, of 
sugars and peptone-like polypeptides, of natural ter- 
penes and camphor, of indigo and rubber, are well- 
known achievements, while natural processes, in 
which enzyme action plays a part, are yielding their 
closely guarded secrets to the persistent inquiry of 
Armstrong and his collaborators, who are probing the 
relationship between enzyme and substrate which Emil 
Fischer pictured as that of lock and key. Further, 
there is that large field of work which includes not 
only the Walden inversion but new problems of asym- 
metry, with which the names of Frankland, Pope, 
Werner, and others are associated; while Barlow and 
Pope’s conception of the relation of valency to atomic 
volume, by correlating crystalline structure with the 
composition, constitution, and configuration of carbon 
compounds, has given a new interest to the study of 
crystallography. 
Nor is progress less rapid in that other important 
branch of chemistry—the unravelling of the structure 
52 J. Thiele, Ansalen, 1890, cccvi, 129. 
58 British Association Report, 1910, p. 96. 
54 Cf W.P. Wynne, art. ‘' Naphthalene,” Thorpe’s “ Dictionary of 
Applied Chemistry,” second edition, vol. 3 (Longmans, 1912). 
© R, Willstatter and J. Parnas, Se7., 1907, xl, 1406. ' 
56 N. Bland and J. F. Thorpe, Trans. Chem. Soc., ror2, ci, 871, 1490. 
