Articles and Publication Chemistry UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION DOES NOT EXIST!|
NUCLEOPHILIC SUBSTITUTION DOES NOT EXIST!
© Naum S.
Contact to the author:
VNIINeftekhim, 193148 St.Petersburg, Russia
At the modern stage of development of the
chemical science the unimolecular heterolytic reaction mechanisms become an
unjustified simplification for it is definitely established that a dissociation
into ions of a covalent bond can occur only forcibly, by the action of
electrophiles or nucleophiles.
In organic chemistry reactions R3C–Hlg
that currently are classed as unimolecular nucleophilic substitution at a carbon
atom proceeding by the dissociative mechanism SN1 are really
substitutions at Hlg occurring by a synchronous mechanism HlgSE.
Similarly in coordination chemistry reactions [L5M – Hlg]++
classified now as substitution at a metal atom by a dissociative mechanism are
actually electrophilic substitutions at Hlg by a synchronous mechanism.
It is suggested here to classify these and
analogous reactions according to their true mechanism. This classification
provides a better understanding of the reaction regularities and makes possible
adequate conclusions and permits the consideration of a large number of
versatile substitution reactions from a unique viewpoint.
The suggested approach to considering
reactions based on the true mechanisms provides easier and clearer
interpretations and can significantly facilitate
teaching chemistry and its understanding and mastering by students.
“Inadequacies of the SN1
Mechanism” and “Is the tert-Butyl Chloride Solvolysis the Most
Misunderstood Reaction in Organic Chemistry?…” are the titles of papers recently
published in JCE and JACS (1,2). The problem treated in these
papers and in this article has a 70-year history.
In the nineteen thirties at the early stage of
investigating reaction mechanisms in organic chemistry all reactions were
represented as occurring at carbon reaction center, like the antique astronomy
that regarded the Earth as the center 1) of the Universe (Ptolemaic system). For
instance, any replacement of one nucleophilic group by another was regarded as
nucleophilic substitution at a carbon atom (3). This was quite
natural since the data for more adequate classification were lacking. In keeping
with the fundamental works of the school of C.K. Ingold two generally
acknowledged mechanisms of nucleophilic substitution were formulated and found a
prominent place in modern textbooks:
- SN2, bimolecular, or synchronous, or
- SN1, unimolecular, or pre-dissociative
Therewith the mechanism (2) + (3) = (4) based
on the nucleophilic character of the HO- reagent in the overall
reaction (4) is classified as a nucleophilic substitution at the carbon atom
although the stage (2) of this reaction comprises dissociation, and stage (3) is
reaction of ions, and neither of these elementary stages represents a
nucleophilic substitution at a carbon.
It was initially assumed that for
the dissociation along equation (2) to occur the use of a solvent with a high
dielectric constant was quite sufficient. Even nowadays it is a popular belief,
although flawless data (3-7) have
demonstrated that spontaneous dissociation of a covalent bond into ions is
impossible 2) without a nucleophilic or an electrophilic attack on one of the atoms
constituting this bond. The solvents possessing a high dielectric constant only
facilitate the separation of the thus arising ion pair.
The nucleophilic or electrophilic attack is
performed by a reagent, a catalyst, or a solvent providing the latter possesses
these nucleophilic or electrophilic properties. For the pre-dissociative
mechanism (2) + (3) = (4) the dissociation along equation (2) is effected by
nucleophilic attack of water that may be described as follows 3)
There is a substantial literature on the
importance of nucleophilic solvent participation in the solvolysis of tert-butyl
chloride (8-10). Therewith finally was found a reason for classing
the pre-dissociative mechanism (2) + (3) = (4) as nucleophilic substitution at
The dissociation along equation (2) in the
pre-dissociative mechanism (2) + (3) = (4) is effected by the
electrophilic influence of acetic acid and may be written as
Already Hammett (11) concluded
that specific solvation of the halogen in the transition state by hydrogen bond
formation was the driving force of solvolytic reactions of alkyl halides. The
requirement of electrophilic assistance to stabilize the “departing” anion has
been repeatedly emphasized (5-7). Mixed, push-pull (3,5-7,12)
mechanisms with simultaneous involvement of nucleophilic and electrophilic
reagents were also suggested. An impression was created that all the above
versions were possible.
However recently a preference was
given to the predominant occurrence of reactions of the type (2) + (3) = (4)
through electrophilic attack of the kind represented in (6). The decisive
arguments were obtained by quantitative multiparameter solvent effect factor
analysis utilizing the KOMPH2 equation (2). It turned out that
there is no evidence for significant nucleophilic participation of the solvent
in the SN1 reaction of any tert-alkyl chloride in
any solvent. Remarkably, this statement is valid even for
non-hydroxylic basic solvents. And vice versa
excellent correlations were obtained of energies of the tert-butyl
chloride solvolysis transition state with the hydrogen bond donor parameter of
The situation is paradoxical: The reaction
described in the modern textbooks as nucleophilic substitution at
carbon by the SN1 mechanism actually occurs as electrophilic
attack on the adjacent heteroatom! And this atom which really is the
reaction center is called a “departing”, “leaving” group. This strange picture
is a result of the common practice of fitting disagreeing facts into a generally
adopted pattern by means of additional assumptions. Therewith the majority of
chemists in discussions agree that terms and concepts are contrary to fact but
the tradition is conserved.
Now a need is generated of essential changes
in description of these reaction mechanisms (13,14). Similarly to
transition made by astronomy in XVI century from Ptolemaic system where the
Earth has been the center of the Universe to Copernicus system where the Earth
is only one among planets it seems appropriate in XXI century for organic
chemistry to take into consideration in classification of reaction mechanisms
not only the substitution at carbon but also substitution at heteroatoms on the
other end of the bond. In other words, the case in point is replacing the formal
classification of reaction mechanisms according the reagents in the overall
reaction [for instance, in reaction (4)] by the classification in keeping with
actual mechanisms of the elementary stages [for reaction (4) by stage (6)].
The most efficient way to improving the
concepts on reaction mechanisms is the introduction of the corresponding changes
into the teaching the reaction mechanisms to the students.
Not SN1 at carbon but SE
It is readily seen (13,14) that
stage (6) is a synchronous reaction similar to (1). The likeness becomes
especially clear considering the modification of the reaction (2) + (3) = (4)
catalyzed by electrophilic reagents (3,6,7)
The fundamental difference between reaction
(1) on the one hand and stages (6), (7) on the other hand is the site of attack
and the character of the acting reagent. In the first case the attack is
directed at the carbon, in the second case to the heteroatom at the other end of
the bond; in the former case the attacking species is a nucleophile, in the
latter it is electrophile. Therefore the first reaction (1) should reasonably be
called nucleophilic substitution at carbon and designated as CSN
(instead of SN2). The reasonable symbol for reaction (2) + (3)
= (4) in keeping with the limiting stage (6) or (7) is electrophilic
substitution at chlorine with the corresponding designation ClSE
(instead of SN1). The reactions of type (5) should be classified as
CSN together with reaction (1).
Therewith the molecularity of a reaction need
not be defined, especially since fundamental alternative versions exist: Ingold
insisted (3) on his initial definition of molecularity as “the
number of molecules necessarily undergoing covalency change” 4) , many authors
define the molecularity as the kinetic order of the reaction. Besides, “Also,
the unimolecularity has never been demonstrated, but is an assumption only.”(1).
If formerly the molecularity has been almost
the main characteristic (SN1 or SN2 ?), now it is not so
important compared to the site of attack and character of the attacking reagent
(Cl SE or CSN ?).
Not dissociative substitution at metal, but
synchronous one at ligand
The study of reaction mechanisms in
inorganic chemistry started later than in organics, and it was based on concepts
developed in the organic chemistry (15). In inorganic chemistry
the reaction center is as a rule placed on the centrally located element,
usually a metal.
In reactions classified as following a
dissociative mechanism many of relations are valid as described above for the SN1
reactions. The majority of the above-considered conflicts between the
classification and real mechanisms also exists. For instance, in aquation of
octahedral complexes (16)
(M = Co3+, Rh3+, Cr3+;
X = Hal-, NCS-, CN-) reactions (10) are
classified as following the dissociative mechanism (8) + (9). They are catalyzed
with ions Ag+, Hg++, Cd++ and Tl3+
along equations of the type
Even at the first glance the great resemblance
between reactions (2) and (8), (7) and (11) is obvious (13,17).
Similarly to the above discussed reactions of
synchronous substitution at the heteroatom (not at carbon) in organic chemistry,
reactions (8) + (9) = (10) in inorganic chemistry proceed as synchronous
substitution at the ligand (not at the metal). Therefore the correct
classification (13,17) should be a synchronous substitution at the
ligand, and not a formal one, as dissociative substitution at the metal.
Most reactions proceed along mixed (intermediate)
It is very important to make
students understand that the considered versions of mechanisms for reaction (1)
involving a transition state I and for reaction (6) with a transition state II
are the limiting cases.
In the first limiting case, in the “pure”
nucleophilic substitution at carbon the nucleophile HO- in the
transition state I (Table 1) is maximally close to the carbon whereas the
electrophile HOC2H5 is outside of the transition state. In
going downstairs along Table 1 the electrophile (HOC2H5,
Å, HOOCCH3) approaches the chlorine whereas the nucleophile (HO-,
Nu, H2O) moves away from the carbon. In the limiting case II the
electrophile is maximally close to the chlorine, and the nucleophile is outside
of the transition state: we has come to the “pure” electrophilic substitution at
The frontier between nucleophilic
substitution at carbon and electrophilic substitution at chlorine is set by line
III (Table 1) where both interactions are equal. It is shown in Table 1 that
every version of the transition state gradually and regularly transforms into
the neighboring ones similarly to changes of colors in the spectrum of sunlight
or in a rainbow. Therewith the majority of the reaction mechanisms are situated
between the limits I and II (Table 1), in these intermediate cases are revealed
both the features characteristic for the main and partially for the assisting
Table 1. Substitution mechanisms range (spectrum)
from nucleophilic to electrophilic.
“Push-pull” transition states of III type were
described long ago (12) and are widely believed (3,7).
They were also suggested as generalized transition state SN for SN2
and “SN1” mechanisms (1,3,7). A novel concept in Table
1 consists in a statement of the fact that below the frontier line III occurs
an electrophilic substitution at
It should be specifically emphasized that the
designation SN1 (XSE) applies to all the
mechanisms occurring below the line III and not only the “pure” electrophilic
substitution at halogen characterized by the transition state II. To the latter
case corresponds formation of a free carbocation and consequently racemization (inversion
by 50%). Whereas in electrophilic substitution at chlorine with nucleophilic
assistance at carbon with the transition state IV the attack by nucleophile Nu
contributes to the reaction and the resulting inversion is over 50%.
Strong arguments were advanced (1)
against the possibility of carbocation formation in reactions (2), (6), and
(7), i.e. against the limiting case II in Table 1. Presumably carbocation
formation occurs not so frequently as it is assumed nowadays, but a complete
denial of its existence (even in a solvated form) is hardly justified. It would
have signified complete rejection of transition state II in favor of IV, but it
has already been indicated that there is no evidence for significant
nucleophilic participation of the solvent in the SN1 reaction of
any tert-alkyl chloride in any solvent (2).
Now a generalized approach becomes possible
In a more general form the limiting
electrophilic synchronous stages (6), (7), and (11) can be expressed by an
In the case illustrated in (6) the
electrophilic attack on X forms a hydrogen bond, and in cases (7) and (11) it is
a covalent bond. This is no reason for contrasting these mechanisms: The modern
quantum-chemical concepts (18) regard the hydrogen bond as a kind
of ordinary chemical bond for it forms with reconstruction of electron orbitals,
collectivization, and transfer of electrons. At the same time such
characteristics as bond length and its energy do not define the bond type
(18). Besides the small energy gain at hydrogen bond formation is
supplemented with energy solvation of ions which in this case were generated
from an uncharged species.
Actually the thorough investigation of
stereochemistry observed in spontaneous (12, caused by solvent E = H2O,
hydrogen bond) and induced (12, caused by reagent E = Hg++, covalent
bond) reactions of a series of complexes A – X of a general formula (+)-cis-[CoEn2LX]n+
established that no fundamental difference exist between these processes
(19). In other words, the solvent in the spontaneous reaction (H2O)
acts in the same way as the reagent (Hg++) in the induced one. Thus
the assumption that the hydrogen bond formation (12, E = H2O) is not
a chemical reaction but a “simple solvation” is outdated. By the way, just this
assumption is the reason of survivability of the error concerning the
nucleophilic unimolecular substitution at carbon or at metal in reactions of (4)
and (10) type, for manipulations with solvation make possible overlooking of the
electrophilic character inherent to the hydrogen bond formation with the halogen.
Apart from the already discussed cases, a lot
of existing reactions possess limiting electrophilic synchronous stages (12).
Some well studied examples are listed in Table 2
(13, 14, 17).
Table 2 illustrates the wide opportunities
provided by the approach under consideration. Within the framework of a
classical SN1 mechanism it is hardly expected to see many common
points in substitution reactions at carbon [Table 2, ¹ 1–3, A = (C6H5)3C]
and at transition metals [Table 2, ¹ 4, 5, A = (NH3)5M3+].
In contrast, mechanism (12) treats both reactions as occurring at the X atom;
providing it is the same in both cases, the rules governing these reactions
should be similar. Actually, when X is a halogen the reactivity of both R3C
- Hlg, and [(NH3)5M - Hlg]++ for all E’s
considered here, excluding H+, changes in the same order: F < Cl < Br
< I. For E = H+ also in both case the series is reversed
Table 2. Examples of limiting synchronous
reaction types are similarly catalyzed by Brønsted and Lewis acids (14),
in particular with metal ions (Table 2, ¹ 2-5, 7, 8). Moreover, for R3C
– Hlg and [L5M – Hlg]++ the dependence of the hydrolysis
rate induced by cations (including H+) on the stability constants of
the respective EX is described by the same equation (20,21).
Therewith the stability constants change in the range from 1 to 1010.
Finally, the catalytic effect of cations
similar to types (7) and (11) is not limited by solvolysis of C – Hlg and M –
Hlg bonds but is also characteristic of B – F, P - F, As – F and even Xe – F
(20). In particular, the hydrolysis of the difluoride of the noble
gas, xenon, is accelerated with Al3+, Be++ and Ti4+
similar to the acceleration observed with the same cations in the
hydrolysis of (CH3)3CF (organic compound), Co(NH3)5F++
(coordination compound), and BF4- (inorganic anion).
All the data compiled are understandable only
from the viewpoint of electrophilic substitution at the halogen in all cases
Thus the suggested approach provides a
possibility to treat large series of reactions belonging to organic,
organometallic, and coordination chemistry from a single viewpoint as a
substitution at the same common atoms for all these series X.
Interpretations become simple and compelling
A number of essential regular trends
characteristic of the reactions in question may be explained more
convincingly based on the suggested concept of the decisive role of the
electrophilic attack on X in (12) stages:
· It is known (3) that a
modification of X strongly affects the rates of these reactions [compared
with synchronous processes of type (1)]; now it looks natural in
reactions for type (12) with just X as the reaction center;
· The acceleration of reactions (12)
when A contains electron-donor groups (a strange phenomenon for a true
nucleophilic substitution) is readily understood because of growing
electron density on X facilitating the electrophilic attack thereto;
· Bulky substituents at A do not
hamper reactions as the attack is directed to X;
· Abnormally strong (considering the
increase in the dielectric constant of the medium) reaction acceleration
on addition of small amounts of polar compounds is easily explained by
the fact that these substances play the role of reagents or catalysts E;
· Applied directly a very strong
sensitivity of the reactions to the solvent follows from the fact that
it can really function as a reagent (E).
The concepts described here on the decisive
role of the electrophilic impact on the heteroatom (ligand) in reactions (4) and
(10) provides a possibility to formulate some regularities.
Upon initial consideration of the mechanism,
it is useful to remember that the attack treated here on the peripheral
atoms is more probable than the attack on the carbon atom shielded by four
substituents or on the metal surrounded by six ligands:
Simple calculations revealed that the carbon
in the first structure and the metal in the second are nearly completely
“closed” and chlorine is “opened” to 60-80% (14).
The stereochemistry of electrophilic
synchronous substitution may essentially differ from that of nucleophilic
synchronous substitution. Since the Pauli principle excludes the presence of
more than two electrons in the same orbital a nucleophile carrying its electron
pair in reaction (1) can approach only from the side opposite to the group to be
substituted and along the straight line extending the bond to be broken. As a
result the synchronous nucleophilic substitution occurs with reverse of
configuration, and the size of substituents at the reaction center strongly
affects the reaction rate.
In the electrophilic attack no additional
electrons are involved, and the electrophile may also approach sideways
(3,17). Therefore if instead of chlorine in reactions (6), (7) or of X
in reactions (12) operate relatively complex groups, the reversal of
configuration in these groups (14) would not be obligatory (15), and
steric deceleration would not always be great (15).
The consideration goes now to the heart of
It should be noted that the approach suggested
in this article does not formally regard terminology and does not simply propose
to replace one name by another. Here we intend
· to find the classification of a true
mechanism of reaction
· to move the principal attention to the true
reaction center (heteroatom, ligand) and not to regard it as “departing”,
· to attract attention to the key
importance of bond formation between X and E along equation (12):
The energy of the new bond and that of ion solvation making up for
the energy loss at the rupture of the A – X bond, and that the
reaction is impossible without it
· to make evident that “pure
dissociative” reactions of nucleophilic substitution of the type (2)
+ (3) = (4) or (8) + (9) = (10) under common conditions as a rule do
not exist: they proceed through synchronous mechanisms (6), (7) or
· to emphasize that the practice
of dividing reactions of substitution into nucleophilic synchronous
(SN2) and nucleophilic dissociative (SN1) in
organic and inorganic chemistry creates erroneous notions
In connection to the
above discussed doubts on the existence of real reactions of unimolecular nucleophilic substitution a question arises: Are there any true unimolecular
mechanisms? Against the possibility of a unimolecular electrophilic
substitution the same argument is valid as has been advanced in this paper
against the nucleophilic substitution: The dissociation of a covalent bond into
ions cannot occur without reaction with a nucleophile or an electrophile (3,4,6,7). Therefore the substitution in a Y–Z molecule classified now as
electrophilic unimolecular substitution at Y atom proceeds actually as
synchronous nucleophilic substitution at the Z atom.
However the homolytic cleavage of a
is more energetically feasible than
heterolytic one (14), and unimolecular radical reactions occur
relatively often with organic compounds.
Similarly in organometallic chemistry neutral
ligands are easily eliminated: a characteristic example that may be cited is the
dissociation of metal carbonyls with liberation of carbon monoxide:
At the same time the attack on the peripheral
atoms (ligands) remains very probable for steric reasons described above (13).
The suggested approach to classification of
reactions is intended to facilitate significantly the teaching of chemistry and
mastering of this subject by students regarded as “difficult and forbidding”
At the modern
stage of development of the chemical science the unimolecular heterolytic
reaction mechanisms become an unjustified simplification for it is definitely
established that a dissociation into ions of a covalent bond can occur only
forcibly, by the action of electrophiles or nucleophiles.
In organic chemistry reactions R3C–Hlg
that currently are classified as unimolecular nucleophilic substitution at a
carbon atom proceeding by dissociative mechanism SN1 are really
electrophilic substitutions at Hlg occurring by synchronous mechanism HlgSE.
Similarly in coordination chemistry reactions [L5M – Hlg]++
classified now as substitution at a metal atom along a dissociative mechanism
are actually electrophilic substitutions at Hlg by synchronous mechanism. The
role of attacking Hlg electrophiles in both cases play solvents or catalysts.
It is suggested here to
classify these and analogous reactions according to their true mechanism.
This classification provides better
understanding of the reaction regularities and makes possible adequate
The assumed classification permits the
consideration of a large number of versatile substitution reactions from a
unique viewpoint. In particular, in substitution at halogen the
reaction rates both of hydrolysis of organic compounds and of aquation of
coordination compounds are described by the same equation and catalyzed by the
same reagents. The hydrolysis of the difluoride of the noble gas, xenon, is
accelerated with Al3+, Be++ and Ti4+ similar to
the acceleration with the same cations of the hydrolysis of (CH3)3CF
(organic compound), Co(NH3)5F++ (coordination
compound), and BF4- (inorganic anion), for all these
reactions actually àre electrophilic substitutions at fluorine atom.
It is pointed out that students must come to
understand that the mechanism versions under consideration, XSE
(SN1) and CSN (SN2), are limiting
cases. The majority of mechanisms are situated between these extremes. The
alternative mechanisms gradually and regularly pass from one to another in the
following sequence (spectrum):
· nucleophilic substitution at
· nucleophilic substitution at
carbon (metal) with electrophilic assistance at heteroatom (ligand),
· electrophilic substitution at
heteroatom (ligand) with nucleophilic assistance at carbon (metal),
· electrophilic substitution at
The suggested approach to consider reactions
basing on the true mechanisms provides easier and clearer interpretation
and can significantly facilitate teaching chemistry and its
understanding and mastering by students.
It should be noted that «centric» (geocentric, anthropocentric) treatment is a
characteristic simplification for a branch of science at the early stage of
development. Beside the mentioned examples from astronomy and parts of chemistry
considering reaction mechanisms we can indicate anthropocentrism in philosophy,
absolute space and time in the classical physics.
Evidently the high-energy chemistry
(plasma chemistry, photochemistry, radiation chemistry) is an exception
For the sake of simplicity here and hereinafter is omitted the formation of ion
pairs (internal or intimate, and external or solvent-separated).
the way, according to Ingold reaction (7) same as (1) is bimolecular showing
once more the inadequacy of the classical (SN2 and SN1)
Dale, Johannes. J. Chem. Educ. 1998
Gajewski, Josef J. J. Am. Chem. Soc.
2001 123 10877-10883.
Ingold, Christopher K. Structure and
Mechanism in Organic Chemistry; 2nd ed.; Cornel Univ. Press: Ithaca –
London, 1969 242-246, 427,453,459,475-483, 519.
Groutas William C.
Organic Reaction Mechanisms. Selected Problems and Solution;
Wiley: New York, 2000 265 pp.
Harris, Joe Milton; Wamser, Carl C. Fundamentals of
Organic Reaction Mechanisms; John Wiley & Sons: New York, 1976
Reichardt Christian. Solvents and solvent
Effects in Organic Chemistry; 3rd, updated and enl. ed.; Wiley-VCH: Weinheim,
2003 629 pp.
Streitwieser, Andrew. Solvolytic Displacement
Reactions; McGraw-Hill Book Company, Inc: New York – San Francisco –
Toronto – London, 1962 39, 43, 49, 50, 62-65, 167-171.
Takeuchi, Ken'ichi; Takasuka, Masaaki;
Shiba, Eiji; Kinoshita, Tomomi; Okazaki, Takao; Abboud, Jose-Luis M.;
Notario, Rafael; Castano, Obis. J. Am. Chem. Soc. 2000 122
Bentley, T.William.; Llewellyn, Gareth. In Progress in Physical Organic Chemistry; Taft, R.W., Ed.; John Wiley &
Sons: New York, 1990 17 121-158.
Lowry, Thomas H.; Richardson, Kathleen S.
Mechanism and Theory in Organic Chemistry;
3rd ed.; Harper Collins Publishers: New York, 1987 335-340.
Hammett, Louis P. Physical Organic Chemistry;
McGraw-Hill: New York, London, 1940
Swain, C. Gardner. J. Am. Chem. Soc.
1948 70 1119-1128.
Imyanitov, Naum S. J. Gen. Chem. USSR (Engl.
Transl.). 1990 60 417-419.
Imyanitov, Naum S. J. Gen. Chem. USSR (Engl.
Transl.). 1991 61 1-7.
Langford, Cooper H.; Gray, Harry B. Ligand Substitution Processes; W.A.Benjamin, Inc: New York, Amsterdam,
Linkoln, Stephen F.; Merbach, Andre E. Adv. Inorg. Chem.
1995 42 6-9, 43-47.
Imyanitov, Naum S. Koord. Khimiya. 1983
Bersuker, Isaak B. Electronic Structure
and Properties of Transition Metal Compaunds: Introduction to the Theory;
Wiley: New York, 1996 668pp.
Jackson, W. G.; Sargesson, A. M. Inorg.
Chem. 1978 17 1348-1362.
Rudakov, E.S.; Kozhevnikov, I.V.;
Zamashchikov, V.V. Usp. Khim. 1974 43 707-726.
Kozhevnikov, I.V.; Rudakov, E.S. Inorg.
Nucl. Chem. Lett. 1972 8 571-576.
Pagni, Richard. J. Chem. Educ.
2001 78 33
Publishing date: November 19, 2008