Bimolecular Nucleophilic Displacement Reactions
John 0. Edwards Brown University Providence, Rhode Island 02912
T h e bimolecular nucleophilic displacement reaction is important and should be included in any detailed discussion of kinetics and mechanism a t an early undergraduate level. This type of mechanism is common to many of the elements in the periodic chart. Because of its essential simplicity in comparison to most other mechanisms, it can be taught without difficulty and it is fairly easily understood by undergraduates. Also, it provides good illustrative data on chemical reactivities, and reactivity is a matter of considerable importance in our quantitative studies of chemical dynamics. The reaction may be written schematically as follows X+R-Y-X-R+Y (1) where X is the nucleophile, Y is the leaving group, and R-Y is the substrate. Both X and Y are electron pair donors and one may consider R to be an electron acceptor (Lewis acid). Thus the reaction may be classed as an acid-base type of reaction in either the Lewis (1) or the Pearson (2) definitions of acid-base reactions. It is not our intent to cover all mechanisms by which reaction ( I ) can take place; we shall focus our attention only on those mechanisms which lead to rate laws in which the orders in nucleophile and in substrate concentration are both one and in which the rate constant is significantly dependent on the nature of the nucleophile. General Characteristics
It is possible to list the phenomenological characteristics of this type of mechanism. These characteristics appear to be generally independent of the particular substrate; nevertheless, details depend on the specific chemical nature of the reactants. An important characteristic is a rate law with orders of unity for both nucleophile and substrate, which we may write as Rate = k[Xl [R-Yl On occasion, some other species-perhaps an acid catal y s t m a y appear in the rate law; for example, the oxidation of aryl sulfides Ar2S by monosubstituted peroxides (HOOM) ArS
+ HOOM
-
AGO
+ HOM
often follows the rate law (3) Rate = k[Ar2Sl[HO--OM][Htl I n this case wherein ArZSis X and HO-OM is R-Y. the proton facilitates the reaction by changing the leaving group from OM- to the less basic and therefore more easily displaced HOM. Basic catalysis is also possible when a nucleophile such as ArSH can be changed to its conjugate basic form ArS- which is a more powerful nucleophile. 386 /
Journd of Chemical Education
The second characteristic is that the rate constant k depends on the nature of the nucleophile X. The substrate discriminates significantly between the various nucleophiles with which it reacts. The fact that discrimination is a characteristic of these reactions does not mean, however, that the orders of nucleophilic character observed with the several substrates are similar. Indeed, there is a variability among nucleophilic orders; this variability is important for it gives information on the nature of the interaction in the activated complex. As will be seen in the following sections, some predictions can be made concerning nucleophilic orders. A related characteristic is that the rate constant d e pends on the nature of the leaving group Y. As the strength of the R-Y bond increases, the rate with constant nucleophile X decreases. The influence of leaving group Y on reactivity has not been studied as carefully as the influence of nucleophile X, nevertheless discnssions of nucleophile reactivity can he related to leaving group reactivity. It is a third characteristic of these reactions that they do not exhibit any of the properties typical of radical reactions. No strong influences of sensitizers (such as azomethane or benzoyl peroxide), of inhibitors (such as oxygen or nitrobenzenes), or of other factors (such as wall-effects, light, or nitric oxide) are observed with the bimolecular nucleophilic displacement reactions. These reactions are best classed as group transfer reactions with the transferred group of the substrate being a Lewis acid such as OH+, CH,+ or PtCla-. (At no point on the reaction coordinate diagram does s u ~ ha group act as a free particle. Nevertheless, other cases of replacement reactions do proceed through a mechanism involving a free Lewis acid.) The mechanism has implications relevant to the activation parameters which are obtained from the rate data. It is a fourth general characteristic of these reactions that the values of entropy of activation AS: are quite negative, usually in the range -10 to -25 cal mole-' deg-'; even values such as -35 are observed. The values of A V f (activation volume) also are expected to be negative, although there is not enough evidence to allow definition of magnitudes at the present time. The negative values of ASz and A V f both result from the fact that two independent particles are brought into a single, structured activated complex. The values for enthalpy of activation AHt are often lower than those obtained with radical reactions or with unirnolecular scission reactions, however it is hard to predict values for A H f for all types of substrates. Typical values for any one class of substrates may be obtained from the literature; for example, values of AH$ for most displacements on peroxide oxygen are in the
Table 1. X
Br-
RR'Sc HSO OH-
1-
NOt-
H%O
*SCN-
NCS*CrH&H,O
Representative Data far Nucleophilic Displacement Reactions R-Y
I
cwLoo~
Rf'OOHd CIIICI NHGL IPt(dien)C1liO bans-(Pt(PEta)&I,I HaP06 C6H~CHnSCN CaHiCHlSCN (CsI1sS)a (1) HOCl
Solvent
HZO
CHIOH
HSO EL0 Hz0 H10 Hz0
CHGN
CIIrCN
CHnOH H10
&Hi
13.1 13.5 28.5 21 14
20 l5
20.1 24.4 15.2 20.8 6.5
NO%H20 a sarin ( i ~ p r o p o r y m e t h y phosphoryi l fluoride). a Nitmphenyl &oetate. c ðyl oydohexyl sulfide. d t-nutyl I8ydroperonde.
nSt
Reference
-17 -33
(so)
-12e
(10) (20) (61) (21)
-61
-23
-30 -27 -14 -16
-9 -27
-36
(3)
(693)
(23) (63)
(gal (64)
(66)
the stereochemical data for substitution in octahedral systems are very complicated (7,8). Another consequence of the stereochemistry of attack on carbon is that steric effects are predictable. Attack by hydroxide ion on alkyl bromides follows the order (4) CHsBr > CIHsBr > i-CsH7Br > (CHdrCBr The variation in rates for these compounds depends largely on the fact that replacement of a hydrogen atom by a methyl group partially blocks the backside of the carbon atom being attacked by the nucleophile. A highly-hindered compound such as neopentyl bromide or triphenylmethyl chloride will react only very slowly if a t all with a nucleophile in an SN2mechanism. Similar steric problems arise in displacements on sulfur (9) and phosphorus (10). Nucleophiles
(1s).
e ~ntropy value ooriected to standard state for Ha0 = 1 M I E n t m p y value oorreeted to standard state for Ha0 = 1 M (M).
o 1-(N,N-Dimetliyloarl~zmoyl) pyridium chloride: ASf corrected to atandard state for H20 = 1 M.
range 10-18 kcal mole-' (3). Some representative data including activation parameters are given in Table 1. Certain stereochemical consequences of the mechanism are known, particularly with saturated carbon compounds as substrates (4). For example, in the reaction of isotopically labeled iodide ion with 2-iodopropane, the two iodine atoms must be placed in identical positions relative to the balance of the atoms in the activated complex. We may, therefore, picture the activated complex as
in this one-step reaction going by an SN2 mechanism (4a) A consequence of this structure is that inversion of optical activity (which when the nucleophile equals the leaving group will appear as a racemization) will occur when the carbon compound has an asymmetric center at the reaction site (4e) Also it seems reasonable to assume that the three atoms undergoing covalent change (iodine-carbon-iodine) form a straight line. Bimolecular nucleophilic displacement reactions of saturated carbon substrates where X and Y are not identical presumably go through the same type of activated complex since isotope exchange reactions follow normal patterns of nucleophilic reactivity. We have, therefore, much evidence for the well-known Walden inversion mechanism both for isotope exchange and for simple displacement reactions. The stereochemical consequences of nucleophilic attack on other substrates have not been as thoroughly studied as with saturated carbon substrates. The data for some optically active tetrahedral silicon substrates suggest a backside attack of the Walden inversion type; for example, asymmetric compounds R3SiOCOR1 undergo reaction with inversion when the nucleophile is CHaOH, L i l H a , ICOH, or R3SiOIC (5). Similar results are expected when optically active phosphorus compounds react with nucleophiles (6). By way of comparison to the above cases of tetrahedral substrates,
The nucleophile X is a particle which can form a covalent bond by electron pair donation to a Lewis acid. The former can be strongly basic to protons as are hydroxide ion and dimethyl amine, or it can be a large, polarizable particle such as iodide ion and thiourea (11). The order and magnitude of reactivity for nucleophiles depends on the chemical nature of the suhstrate with which it interacts in the activated complex and of the solvent (Ifd). Table 2.
D
b
Nucleophiles and Their Relative Reactivities
pK. for eonjugate acid of nualeoohile (3). Relative resotivity t o methyl bromide (11s).
c Oxidative dimerir+m sohlo (11). d Reactivity to p-n~trophenylacetstq on this male
reactivity of 11.6 (1601. c see ref. (21).
OOH- has a relative
I n Table 2, some nucleophiles along with their relative reactivities to various substrates are presented. The numbers are logarithms of reactivity with respect to water as a standard. The reactions from which the numbers are obtained are as follows: X+HCSHX+ X + C&Br XCIT8++ Br2X s X2'+ 2e-
-
0
+
0
It is obvious from the data of Table 2 that the orders of nucleophilic strength vary widely. Some reasons for this variability will be discussed below. Substrates
The substrates R-Y
can be either an organic com-
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387
sulfoxide. Change of solvent from water to acetone can even change the usual order I-
> Br- > Cl- > F -
for attack on saturated carbon to the reverse order F- > C1- > Br- > I-
( a ) INGOLD,C. K., "Structure and Mechanism in Organic Chemistry," Cornell University Press, Ithaca, New York, 1953, pp. 306408. ( b ) Goum, E. S., "Mechanism and Structure in Organic Chemistry," H. Halt and Co., New York, 1959, pp. 250313, (c) STREITWIESER, A,, JR., "Solvolytic Displacement Reactions," McGraw-Hill Book Co., New York, 1962. ( d ) HINE, J., "Physical Organic Chemistrv" f8nd ed.) MeGraw-Hill Bwk Co.. New York. ~~ 1962. (bj HUGAES,E. D., JOLIUSB&ER, F., MASTEL MAN, S., TOPLEY,B., AND WEISS,J., 3. C h a . SW., 1525 (1935). (5) SOMMER, L. H., "Stereochemistry, Mechanism and Silicon," McGraw-Hill Book Co., New York, 1965. R. F., "Structure and Mechanism in Organa( 6 ) ( a ) HUDSON, Phosphorus Chemistry," Academic Press, New York, 1965, pp. 90-130. ( 6 ) GREEN,M., AND HUDSON, R. F., 3. Cham. Soc., 540 (1963). ( 7 ) LANGFORD, C. H., AND G ~ Y H., , "Ligand Substitution Processes," W. A. Benjamin Co., New York, 1965. F., AND PEARSON, R. G., "Mechanisms of Inorganic ( 8 ) BASOLO, Reactions," John Wiley & Sons, Inc., New York, (8nd ed.), 1967. ( 9 ) ( a ) FAVA,A,, AND ILICETO, A,, 3. Am. C h . Soc., 80, 3478 E., (1958). (b) FAVA,A., ILICETO,A., AND CAMERA, 3. Am. Cham. Sac., 79, 883 (1957). (c) PRYOR,W . A., "Mechanisms of Sulfur Reactions," MoGraw-Hill Book Co., Inc., 1962, pp. 62-64. 0. B., Cham. Reus., 64, 314(10) Cox, J. R., JR., AND RAMSEY, 352 (1964);seep. 323. (11) ( a ) SWAIN,C. G., AND S c m , C. B., 3. Am. Cham. Soc., 75, 141 (1953). ( b ) Enwaxus, J . O., 3. Am. Cham. Soc., 76, J. O., 3. Am. Cham. Soc., 78, 1540 (1954). ( e ) EDWARDS, J. O., AND PEARSON, R. G., 1819 (1956). ( d ) EDWARDS, J. Am. Chem. Soc., 84, 16 (1962). ( e ) DAVIS,R. E., in "Survey of Progress in Chemistry," Vol. 2, (Editor: Scott, A,) Academic Press, New York, 1964, pages 189-238. ( j ) see also reference (4). (12) BUNNETT, J. F., Ann. Reu. Phys. C h . , 14, 271 (1963). (13) (a) HUDSON,R. F., Chimia, 16, 173 (1962). ( b ) see also reference (6a). A. J., Qua~t.Reus. (London), 16, 163 (1962). (14) (~)PARXER, (b) PARKER,A. J., J. Cham. Soc., 1328 (1961). J., 3. Am. Cham. Soc., (15) ( a ) JENCKS,W. P., AND CARRIUOLO, W . P., in "Enayme Models 82, 1778 (1960). (b)JENCKS, and Enzyme Structure," Brookhaven Symposia in Biology No. 15, 1962, p. 134. (c) JENCKS,W. P., in Vol. 2 of Progress in Physical Organic Chemistry (Editors: S. G. COEEN,A. STREITWIESER, JR., AND R. W. TAFT), Interscience (a division of John Wiley & Sons, Inc.), New York, 1964, p. 104. R. D., 3. Am. Chem. Soc.,. 87,. 3387 (16) . . HINE,J.. AND WEIMAR, (1965j. (17) EPSTEIN,J., et d.,3. Am. C h . Sac., 86,3075,4959 (1964). L., Suensk K a i s k Tidskrift, 70, 405 (1958). (18) LARSSON, E. R., "Solvolysis Mechanisms," Ronald Press, (19) THORNTON, New York, 1964, p. 185. (20) ANRAR,M., AND YAGIL,G., J. Am. C h a . Soc., 84, 1790 (1962). (21) BASOLO,F., in "Mechanisms of Inorganic Reactions," Advances in Chemistry Series, no. 49,American Chemical Society, Washington, D.C., 1965, p. 95. C. J., AND EDWARDS, J. O., Inwg. C h a . , 4,552 (22) BATTAGLIA, ~~
in some cases. All the anions are more reactive in the non-protonic solvent, but the effect is much stronger for the smaller anions. One must remember, however, that the influence of solvation on the transition state must be considered too. It is to be expected that the strength of the bond being formed should influence the stability of the transition state. Thus the bond strength in product will influence nucleophilic reactivity. It is hardly surprising then that fluoride ion is a good nucleophile to tetrahedral phosphorus substrates, and that olefins react rapidly with platinum(I1) compounds. The aspect of bond strength in product has been stressed by Jencks (16) and by Hine (16). It is expected that the charges on the nucleophile and substrate should influence orders of reactivity. Indeed, Epstein (17) in his studies of phenolate anions attacking Sarin (see Table 1) has shown that the resulting rate constants do not form a good Br6nsted plot when the phenolate ion has a quaternary ammonium group attached to the benzene ring. A neutral phosphorus substrate and a proton react with a different rate ratio to a negative ion than they do to a neutral molecule. In aqueous solution, this Coulomb effect influences rates by one or two powers of ten. A rather unexpected contributor to the nucleophilic character of donors is the "alpha-effect." Donors in which the nucleophilic site is attached to an electronegative atom with one or more non-bonded electron pairs are very reactive (11d). Some examples are hydwzine, hydroxylamine, hypochlorite ion, hydroperoxide ion, oximate anions, and hydroxamate ions. The basis for this exceptional reactivity lies apparently in the electronic nature of these molecules, but the raison d'etre is not understood. Literature Cited
( 1 ) ( a ) LEWIS,G. N., "Valence and the Structure of Atoms and Molecules," Chemical Co., New York, 1923. (b) LEWIS, G. N., J. Franklin Inst., 226, 293 (1938). (c) LUDER, W. F., AND ZUFFANTI,S., T h e Electronic Theory of Acids and Bases," John Wiley & Sons, Inc., New York, 1946. R. G., 3. Am. Chem. Soc., 85, 3533 (1963). ( 2 ) ( a ) PEARSON, R. G., Science, 151, 172 (1966). ( b ) PEARSON, J . O., in "Peroxide Reaction Mechanisms" ( 3 ) ( a ) EDWARDS, (Editm: J. 0. EDWARDS), Interscience (a division of John Wiley & Sons, Inc.), New York, 1962. ( b ) BEHRMAN,E. J., AND EDWARDS, J. O., in "Progress in Physical Organic Chemistry" (Editors: S. COHEN,A. STREITWIESER,JR., AND R. W. TAPT),Interscience (a division of John Wiley & Sons, Inc.), New York, 1966, Val. 3.
,
~
.
(25) LISTER,M. W., 1645 (1961).
AND
.
~
ROWNBLUM, P., Can. J. Chem., 39,
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/
389
pound such as methyl bromide, or p-nitrophenyl-acetate, or an inorganic compound such as hydrogen peroxide, tetrachloroplatinate(I1) anion or tris(phenanthr0line)iron(II) cation. The specific atom upon which substitution occurs can be in almost any molecular (i.e., nuclear) configuration. However, the electronic configuration around this atom appears to be a major factor in determining the type of nucleophile which reacts preferentially with the substrate (11). Those substrate atoms such as carbon or oxygen (in an alkyl halide or in a peroxide, respectively) which are electronically saturated (i.e., have no low-energy unfilled orbitals) react preferentially with polarizable nucleophiles. The reaction coordinate diagram for this case is uncomplicated and is characterized by a single maximum as may be seen in Figure 1. The activation
does not necessarily indicate that an isolatahle intermediate is formed. In terms of the notation and concepts of Langford and Gray (7), the mechanisms of type A (where a true intermediate is formed) merge with type Ia (where both the entering group and leaving group are strongly bonded to the central atom). The data for nucleophilic displacements on octahedral transition metal complexes have not been discussed here. The bonding between incoming nucleophile and central atom of the substrate is not as strong in these complexes as it is in the other cases. Because of this difference and because of the mechanistic complexity of replacements in transition metal compounds, the reader is referred to recent thorough treatments (798). Nucleophilic Reactivity
Figure 2. Roastion coordinate diagram for the rose whom on unstoble intermediate is formed. Case A where k* ka, and Coso B where ks kg.
Figure 1. Reaction coordinate diagram for the rare of a oneltep displmcoment mechanirm.
energy for the process is largely related to the Van der Waals repulsion on bringing the nucleophile with its electrons up to the electronically saturated substrate. Some other substrate centers such as carbonyl carbon have an orbital which can be used for bonding to the incoming nucleophile. In such cases, an intermediate in which the substrate atom is bonded simultaneously to nucleophile and leaving group may be formed. This type of mechanism has a reaction coordinate diagram as shown in Figure 2, and the mechanism can be written as X
+ R-Y
X-R-Y
k,
kr
k,
X-R-Y X-R
+Y
Interpretation of the reactivity is more difficult in this case since there are three rate constants that must he considered. In a few cases, as in displacements on tetrahedral phosphorus, there is an empty orbital available on the substrate (a 3d orbital in this example) so that bonding simultaneously to the incoming nucleophile and to the leaving group is possible. As the depth of the potential well that denotes the intermediate becomes more shallow ( e k T ) , the distinction between the single-step and the intermediate complex mechanism vanishes. A firm distinction between the two mechanisms does not appear to be presently possible in displacements on tetrahedral phosphorus, yet the nucleophilic order suggests interaction of nucleophile and open d orbital in this reaction. Stabilization of a transition state by d orbitals 388
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Journal of Chemical Education
Learning about chemical reactivity is an important part of rate and mechanism studies, and nucleophiiic character has been the subject of many quantitative investigations. The chemical nature of the electron pair donor which bonds to a central atom in the transition state is worthy of detailed inspection, since the quantitative data on reactivity (derived from relative rates) tell quite a bit about the interactions between nucleophile, substrate and solvent. The number of things that must be considered in assessment of reactivity is large, as may he seen in the list reported by Bunnett (18) and in the reviews by Hudson (13). In this paper, we will consider only six of the most important factors which influence nucleophilic reactivity; it is important to note that these six are by no means completely independent of each other and that other interactions have been left out. To the extent that the electrophilic center on the substrate is similar to a proton, the reactivity of the nucleophile will follow its B~$nsted basicity. The characteristics of a proton are a high positive charge density and an absence of outer electrons. A similar condition will obtain when Lhe substrate atom being attacked by the nucleophile has an available open orbital; i.e., in trigonal carbon and trigonal boron with an open p orbital, and in tetrahedral phosphorus, sulfur, and silicon with an open d orbital. Such an orbital presents a site of positive potential with which the electron pair on the nucleophile can favorably interact thus stabilizing the activated complex. In those substrates wherein the central atom is electronegative (often negatively charged in the ground state) and has a number of outer-orbital non-bonded electrons, the polarizability of the nucleophile seems to be an important factor (11). The activation energy in such substrates would be very high since uon-bonded electron interactions (Van der Waals repulsions) should be serious. Only those nucleophiles with available unfilled orbitals (those which are "polarizable") allow a transition state to be reached without a large energy expenditure; the electrons on the substrate can interact favorably with these open orbitals to form a partial bond, thereby lowering the activation energy. It is known that the nature of the solvent can markedly influence nucleophilic reactivity (14). A small, negative particle (such as OH- or F-) will be strongly solvated by a protonic solvent. Thus, anions will be more reactive in a non-protonic solvent like dimethyl
