Mechanism of Reactions in Organic Chemistry
Whitehead’s Process Model and the Hughes-Ingold Model in Organic Chemistry
Michael Akeroyd
Bradford College, BD7 1AY, UK
In the Lowell Lectures, 1925 (subsequently published in ‘Science in the Modern World’, 1926, reprinted CUP, 1953), Whitehead attacked deterministic models in physical science on p. 99 and pp. 133-4.
On p. 99 he wrote: ‘In this [my] theory, the molecules may blindly run in accordance with the general laws, but the molecules differ in their intrinsic characters according to the general organic plans of the situations in which they find themselves.’
One of the problems facing physical organic chemists from 1925-1952 was that, in solvolytic reactions involving alkyl halides, the ‘reactive’ hydroxide ion sometimes acted as a stronger attacking species than the water molecule and sometimes as a weaker species in apparently analogous circumstances. The then current deterministic model could offer no solution to this problem. A solution was offered from two chemists, E. D. Hughes and C. K. Ingold, utilizing a process methodology in line with Whiteheadean precepts. The role of the supposedly inert solvent (an 80:20 ethanol:water mixture) was far more subtle than previously supposed and offered a variety of situational ‘organic plans’ mentioned above.
Science in the Modern World
A N Whitehead 1926, Cambridge University Press 1953
‘I would term the doctrine of these lectures organic mechanism. In this theory, the molecules may blindly run in accordance with general laws, but the molecules differ in their intrinsic characters according to the general organic plans of the situations in which they find themselves. (Page 99)
‘The laws of physics are the laws declaring how the entities mutually react among themselves. For physics the laws are arbitrary, because science has abstracted from what the entities are in themselves. We have seen that the fact of what the entities are in themselves is liable to modification in their environments. Accordingly, the assumption that no modification of these laws is to be looked for in environments, which have any striking differences from the environments for which the laws have been observed to hold, is very unsafe.The physical entities may be modified in very essential ways, so far as these laws are concerned.’ (pp. 133-134)
Mechanism of reactions in Organic Chemistry
From 1840-1930 over 1 million organic reactions had been catalogued. The accepted theory was that all reactions proceeded by collision theory.
H3CH2C*X H3CH2C*O*H
HO*Na NaX
H3CH2C*X H3CH2C*O*H
HO*H HX
An important class of organic reactions was the solvolyses of alkyl halides (haloalkanes). However in 1927 the UK organic chemist Ward noted something odd:
When primary (CH3CH2X) halides and secondary (CH3)2CHX halides reacted in ethanol/water mixtures, addition of small amounts of NaOH increased the reaction rate (as one would expect since OH- ion is much more reactive), but when tertiary (CH3)3CX halides reacted, their much more rapid reaction rate was totally unaffected by the addition of NaOH.
It seems plausible to suggest that the presence of three bulky alkyl groups round the starred carbon atom stericallyhinders the approach of the reactive hydroxide ion from the back to form an activated complex but why then does the less reactive and more bulky water molecule prove a much more successful nucleophile?
In 1933 the UK chemists Hughes and Ingold (and in 1938 the US organic chemist Bartlett) used this paradox to support a radical new concept of organic mechanism.
The Hughes and Ingold paper was published in J Chem Soc 1935,244-255. It proposed the duality of mechanism in organic nucleophilic substitution reactions:
SN2 the classical deterministic model, in which ‘active’ substrate molecules are guided randomly by the thermal jostling of the inert solvent molecules until a fortuitous ‘high energy’ collision leads to the formation of an ‘activated complex’ and subsequent reaction
SN1 a novel mechanism in which the solvent molecules arrange themselves around one of the substrate molecules in such a way that it facilitates the heterolysis of that molecule into an stable solvated ion which takes no further part in the reaction and an unstable solvated ion which eventually reacts either with a solvent molecule (solvolysis) or the target molecule (substitution).
CH3 \
CH3 -C – X > (CH3)3C+ + X- + Y- > (CH3)3CY + X-
CH3 /
This mechanism requires a tendency of the organic moiety to form a stable carbocation and strongly ionizing solvent medium capable of temporarily stabilizing the carbocation once formed (the leaving group X- is permanently stabilized by the solvent molecules).
When using an 80 : 20 ethanol : water mixture as solvent, this model correctly retrodicted that CH3CH2Cl and (CH3)2CHCl would react slowly with the solvent and more rapidly if small amounts of NaOH were added. It predicted that (CH3)3CCl would react more rapidly with the solvent and that addition of small amounts of NaOH would make no difference to the reaction rate. In fact their experiments showed a slight but significant fall in the reaction rate on addition of NaOH.
What was going on?
In these solvolysis reactions the rate of reaction is most easily followed by “quenching” the reaction after various specific times and measuring the amount of chloride ion generated by precipitation with excess silver nitrate solution. This is a measure of the rate of destruction of the halo-alkane. If the reaction is following the SN2 mechanism the rate will vary with both the concentration of halo-alkane and sodium hydroxide: if however following the SN1 mechanism the rate should be independent of the concentration of sodium hydroxide. This is because the slow first ionization step is the rate determining step of the reaction.
This anomaly caused the American physical organic chemist Paul Bartlett to question the “SN2 fits all” paradigm followed by all other US physical organic chemists of that time and after some experimental work of his own on “caged molecules” he threw his lot with Hughes and Ingold. As he remarked : “If sodium hydroxide is a stronger reagent in some reactions and water in others how can the fundamental mechanism be the same?”
Hughes and Ingold would be aware of an important paper authored by J D Bernal and R H Fowler, in the Journal Chem. Physics 1, 515-548, (1933). In it the structure of water is described as “Ice-like” < 4oC and “quartz-like” >4oC, with “4-coordination” due to presence of TWO positive sites and one negative site.
+H
O =
+H
Simple disordered close packing of molecules of RMM 18 and covalent radius 1.4 Ao would predict a density of 1.84 rather than the observed 1.0. This illustrates how much space and order exists in the liquid state of water. Because methanol and ethanol possess only ONE positive site and one LESS negative site, their structures must involve rings and chains:
CH3 CH3 CH3 CH3 CH3 CH3
OH --- OH -- OH -- OH -- OH -- OH
When alcohol molecules and water molecules are mixed in roughly equal proportions there is a complete breakdown of the “quartz-like structure” of the water component and the consequent well-known shrinkage in volume of water-alcohol mixtures.
The solvent used by organic chemists at the time for nucleophilic solvolyses was an 80:20 ethanol-water mixture (volume:volume). Because pure water contains 55.5 moles per litre and ethanol only 17.1 moles per litre, an 80:20 volume mixture contains roughly 1:1 mixture of MOLECULES.
For a typical 0.1 M haloalkane solvolysis, the molecular proportions are: 1 : 111 : 137
Substrate : water : ethanol
So there are plenty of solvent molecules around to form both a “solvent cage” round each substrate molecule as well as an “inert medium” to facilitate mixing. According to the classical theory, an “attacking” species like an azide ion (N3-) has to jostle its way through the medium in its solvent cage propelled by random collisions with solvent molecules until by CHANCE it collides with sufficient energy in the correct geometric alignment with a halo-alkane molecule to generate an irreversible reaction.
N3- + (CH3)3CCl > (CH3)3CN3 + Cl-
In the case of solvolytic reactions, the classical theory suggests that an energetic “free” water molecule must possess sufficient energy to disrupt the “alcoholic” solvent cage surrounding the hydrocarbon “end” of the haloalkane in order to initiate a reaction (analogous to the azide reaction). Classical theory would expect that the addition of 0.1M sodium hydroxide
(i.e. molecular ratios 1:1:110:137) would significantly raise the reaction rate because (a) OH- ion is more reactive than H2O molecule and (b) the ion does not have to “struggle” through the solvent medium in order to collide with the target but can move rapidly via rapid proton exchange. Ward found in 1927 this is exactly what happens when the target molecule is a primary (RCH2X) or secondary (R1R2CHX) haloalkane but not with a tertiary (R1R2R3CX) haloalkane. Ward found that the reaction rates were identical for hydroxide and water: later, more accurate experiments by Hughes and Ingold showed that there was a small but significant DECLINE in the reaction rate with OH- . What was going on?
Hughes and Ingold explained Ward’s original results as follows: for tertiary haloalkanes there was a different mechanism (the SN1 mechanism).
Hughes and Ingold in 1935 reported on but did not comment on the slight reduction of reaction velocity when 0.1 M NaOH was introduced into the reaction mix. However it was commented on by Paul Bartlett in 1938 (J Amer Chem Soc ) as a further justification for the SN1/SN2 concept. In 1952, Hughes, Ingold and their research student T. Benfey investigated the phenomenon more closely with other tertiary substrates and concluded “that the attacking lyate ions (OH- or OEt- ions) were waylaid by the exterior protons of the solvent cage of the target molecule” ( J Chem Soc, 1952, 2494 )
All this shows that the effect of a mixed solvent which allows differential solvation on the target molecule generates the possibility of duality of mechanism: a classical deterministic collision with the “attacking” species OR an indirect mechanism where the solvent initiates heterolysis into two ionic fragments in a slow, rate determining step followed by a rapid classical attack by the “attacking species” on the positive fragment.
The fact that the presence of OH- ions and their rapid proton exchange chains hinders the attack of “free” water molecules on the solvated carbenium ions while in turn they are “waylaid” by the exterior protons of the solvent cage shows that the reaction mix is behaving as a SYSTEM in which PROCESSES occur, and the supposedly inert solvent can exert a subtle directive effect. These results in 1927 encouraged Hughes and Ingold to move away from the narrow deterministic model popular at the time towards a more process oriented model on Whiteheadean lines.