CHAPTER 2 SOLVENT EFFECTS ON ORGANIC RATES AND EQUILIBRIA

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1 HAPTER 2 SLVENT EFFETS N RGANI RATES AND EQUILIBRIA References 1. arey and Sundberg, 5 th ed section arroll, p L & R pp ; Isaacs hapter 5 5. E. Buncel and H. Wilson, J. hem. Ed., 57, 629(1980). Importance a) hanges in solvent can produce changes in reaction rate of up to or more. Some understanding of solvent effects is therefore useful in minimizing reaction times, or maximizing yields where two or more products are formed by competing pathways b) Solvent effects on reaction rate can yield information about the reaction mechanism (specifically, information about the TS structure). I SLVENTS AND SLVATIN assification of solvents: a) polar dielectric constant (ε) greater than about 15 nonpolar ε < about 15 b) protic contain a proton attached to N or that is usually rapidlyexchangeable in D 2 and that can form a hydrogen bond with an aprotic electron pair donor. no rapidlyexchangeable proton RGANI REATIVITY HEM*4720 URSE NTES W

2 Some common solvents are classified in this way in the Table. assification of Solvents Dipolar Protic ε Nonpolar Protic ε H H 6.2 H 2 H 58.5 ( ) 3 H 12.5 H 32.7 cyclohexanol 15.0 H 2 H 24.6 phenol 9.8 H()NH Dipolar Aprotic Nonpolar Aprotic acetone H()N( ) 2 (DMF) 36.7 pyridine 2.4 S() 46.7 nhexane 1.9 N 37.5 cyclohexane 2.0 N ethyl ether 4.3 [( ) 2 N] 3 P (HMPA) 30 dioxane 2.2 H 2 H 2 (DME) 7.2 benzene 2.3 THF 7.6 Solvation involves the same forces as are involved in all intermolecular interactions, namely dispersion (London), dipoledipole, and iondipole forces. In general, solutes and solvents in which the intermolecular forces are of the same kind and similar in magnitude are mutuallymiscible (i.e., "like dissolves like"). RGANI REATIVITY HEM*4720 URSE NTES W

3 Two generalizations: a) Uncharged solutes are usually more soluble in organic solvents than in water, while ionic solutes are usually more soluble in water. b) Salts (at least at lower concentrations) tend to make ionic solutes more soluble and uncharged solutes less soluble. Ions are solvated by iondipole interactions. onsider, for example, a solvent such as methanol or water: M X R H Solvation of ions is stronger the more concentrated the charge. Ionic or dipolar solutes are stabilized by iondipole or dipoledipole attractions in dipolar solvents. With anions, particularly small anions, hydrogen bonding is particularly important. The hydrogen bond is a dipoledipole attraction but is stronger than other dipoledipole attractions because the positive end of the bond dipole (the proton) is very exposed and permits very close approach. Dipolar aprotic solvents such as dimethyl sulfoxide (DMS) are not nearly as effective at solvating anions because the positive end of the dipole is less exposed. S δ δ RGANI REATIVITY HEM*4720 URSE NTES W

4 II QUALITATIVE ELETRSTATI MDEL F SLVENT EFFETS N RATES (Hughes & Ingold) The largest solvent effects are seen where reactant and transition state differ greatly in polarity, i.e., when charges are developed or neutralized in going from reactants to the transition state. Hughes and Ingold reasoned that reactions leading to increased charge separation in the transition state should be increased in rate by increased "solvent polarity" (increased ionsolvating ability) while those leading to decreased charge separation should respond in the opposite way. These ideas were developed for nucleophilic substitution reactions and are summarized in the Table. Solvent Effects in Nucleophilic Substitutions (Hughes & Ingold) Reactants T.S. change in charge distribution R X δ R X δ increased charge separation effect of increased solvent polarity (ion solvating ability) large increase R X δ R X δ charge dispersal small decrease Y R X δ δ charge dispersal small decrease Y R X δ Y R X Y R X δ Y R X Y R X δ δ increased charge separation decreased charge separation large increase large decrease Y δ δ charge dispersal small decrease Y These rules very often lead to a correct qualitative prediction of a change in solvent polarity on the rate. The reason they work is that they usually correctly predict the solvent effect on the difference G G reactants (ΔG ) even though both may increase RGANI REATIVITY HEM*4720 URSE NTES W

5 or decrease. For example, in the solvolysis of benzyl chloride in methanolwater mixtures, the rate increases by a factor of 200 in going from 100% methanol to 100% water. Increasing the % H 2 actually increases both γ R and γ T.S., but γ T.S. is increased less than γ R. More examples of kinetic solvent effects follow. Me 3 S H MeH Me 2 S (Et) 3 N EtI (Et) 4 N I % EtH (v/v) in H 2 /EtH system rel. rate (100 ) solvent ε rel. rate (100 ) hexane X 10 benzene X X 10 2 acetone X x 10 4 nitrobenzene X 10 3 Acetyl Peroxide Decomposition nbui *I nbui* I medium rel. rate (85 ) solvent ε rel. rate (25 ) gas 1.0 methanol cyclohexane 0.57 ethanol isooctane 0.67 nbutanol benzene 0.72 nhexanol acetic acid 0.58 ndodecanol propionic acid 0.74 carbon tetrachloride 0.54 RGANI REATIVITY HEM*4720 URSE NTES W

6 tbu tbus H (solvolysis in SH) SH rel. rate (25 ) MeI Me I solvent rel. rate (25 ) EtH 1 methanol 1.0 MeH 9.3 formamide 1.6 X 10 EtH/H 2 = 80/20 (v/v) 1.08 x 10 2 Nmethyl formamide EtH/H 2 = 60/40 (v/v) 1.43 x 10 3 N,Ndimethyl formamide EtH/H 2 = 40/60 (v/v) 2.02 x 10 4 N,Ndimethyl acetamide 4.5 X X X 10 6 H x 10 5 Nmethylpyrrolidine 7.9 X 10 6 acetonitrile 4.0 x 10 4 acetone 1.6 X 10 6 nitromethane 1.6 X 10 4 The qualitative rules do not correctly predict the large differences between aprotic and protic solvents in reaction involving anions (see I example). The term "solvent polarity" is not precisely defined. Several solvent properties, particularly the ability of the solvent to solvate anions and cations, must be considered. The origin of the dramatic increase in reactivity of anions in changing from a protic to an aprotic solvent is the poor solvation of anions in aprotic solvents. The qualitative rules can also lead to an incorrect prediction for reactions of ionic nucleophiles Y unless the reactions compared actually involve free Y. In very poorly ionsolvating media the nucleophile may be present entirely as ion pairs, M Y, or higher aggregates. In such situations reaction of Y with a substrate RX can be strongly RGANI REATIVITY HEM*4720 URSE NTES W

7 increased in rate by an increase in solvent ionsolvating ability by increasing the concentration of much more reactive Y ions. III EMPIRIAL SALES F INSLVATING ABILITY The solvent dielectric constant is in general a very poor indicator of ionsolvating ability unless the solvents are very similar in structure. H Br H S SH HBr H Br δ via this T.S.: δ SH = H 2, EtH, 2 H, etc. Nitrobenzene (ε = 35) added to ethanol (ε = 25) decreases the rate. Acetic acid (ε = 6.1) solvent reacts faster than ethanol (ε = 25). The reason for these seemingly anomalous observations is that solvation of the anion and cation are both important. Ethanol (protic solvent) solvates the incipient better than nitrobenzene, while acetic acid is a better anionsolvating solvent than ethanol. There are several quantitative scales of ionsolvating ability based on model reactions or physical processes (analogous to σ values for substituent effects). These ionsolvating power or "polarity" scales can be used to develop linear free energy relationships for solvent effects. RGANI REATIVITY HEM*4720 URSE NTES W

8 A GRUNWALDWINSTEIN Y VALUES model reaction: H 3 H H 3 SH 3 H 3 δ δ H 3 25 H 3 H 3 H 3 T.S. S H Y = log (k/k o ) tbu, 25 where k = rate constant in the solvent whose Y value is to be measured. k o = rate constant in the standard solvent, 80% aqueous ethanol, i.e., 80/20 (v/v) ethanol/water. Y = 0 (by definition) for 80% ethanolwater, positive for solvents of greater ionizing power, and negative for solvents of lower ionizing power. The Y scale is limited to solvolyzing (i.e., protic) solvents. It therefore cannot be used to correlate or predict rate constants in aprotic solvents. Y values for some common solvents are listed in the table on p B KSWR Z VALUES Me Me N I N I H 2 Nethyl4carbomethoxypyridinium iodide H 2 chargetransfer complex RGANI REATIVITY HEM*4720 URSE NTES W

9 The spectrum of Nethyl4carbomethoxypyridinium iodide (and also some other quaternary pyridinium and related halides) shows a strong maximum in the UVvisible which is very sensitive to solvent (examples: λ max = 342 nm in methanol, 450 nm in H 3 ). The new maximum is absent in the chloride or bromide and the absorbance does not follow Beer's law. The absorption corresponds to a chargetransfer transition corresponding approximately to Py I hν Py. I. Excited State Py I. Py. I. minor major hν (charge transfer Ground State Py I. Py. I. major minor Since the ground state is stabilized by solvation of ions, the energy of the transition increases with increasing ionsolvating ability. Z = ΔE = Nhν = Nhc λ in kcal/mol hν ct hν ct H 3 MeH Some values are listed in the Table on p (reference: E.M. Kosowor, J. Am. hem. Soc. 80, 3253(1958).) RGANI REATIVITY HEM*4720 URSE NTES W

10 DIMRTH E T VALUES reference:. Reichardt, Angew. hem. Intl. Ed. Engl., 4, 29(1965) (a review of solvent "polarity" scales) Ph Ph N Ph Ph Ph Again, the long wavelength maximum is very sensitive to solvent because there is less charge separation in the excited state than in the ground state. E T is the transition energy in kcal mol 1 (as with Z values). For reactions of unknown mechanism a plot of log k vs Y, Z, or E T gives some idea of the sensitivity of reaction rate to ionsolvating ability and therefore some indication of the difference in charge separation between the reactant(s) and transition state. Interpretation of the slopes of such plots requires a comparison with slopes for reactions of "established" mechanisms or wellcharacterized transition states. The slopes are analogous to ρ values, which measure sensitivity to substituent effects. Again, we are comparing the reaction to some model reaction or model process. If the correlation is good, the model is a good one. The original Dimroth solvent parameters are called E T (30) values in more recent papers. Several new betaine dyes having different substituents on the pyridinium and phenoxide rings (compared to the structure noted above) have been synthesized and the new compounds have permitted considerable extension of the original scale. Reichardt & HarbuschGörnet Liebigs (Ann., 721 (1983)) have defined a scale called E N T values based on all of these compounds. In the E N T scale, tetramethylsilane is assigned a value of 0.00 and water a value of 1.00, so that all other values fall between 0 and 1.0. E N T values for 243 solvents are listed. RGANI REATIVITY HEM*4720 URSE NTES W

11 Selected Solvent Polarity Parameters Solvent E T Z Y water formic acid 2.05 trifluoroacetic acid 1.84 trifluoroethanol /20 (v/v) EtH/H methanol ethanol acetic acid propanol nitromethane acetonitrile DMS DMF acetone chloroform ethyl acetate THF ethyl ether 34.6 benzene carbon tetrachloride 32.5 nhexane 30.9 Y values: Fainberg & Winstein, JAS 78, 2770(1956) E T values: Reichardt Angew. hem. Int. Ed. Engl. 4, 29(1965) Z values: Kosower JAS 78, 3253(1956) RGANI REATIVITY HEM*4720 URSE NTES W

12 IV PHASE TRANSFER ATALYSIS references: W.P. Weber and G.W. Gokel, Phase Transfer atalysis in rganic Synthesis, SpringerVerlag, Berlin, M. Starks and. Liotta, Phase Transfer atalysis, Principles and Techniques, Academic Press, N.Y Phase transfer catalysis is a way of carrying out reactions between an organic compound, soluble in an organic solvent, and an ionic compound not appreciably soluble in the organic solvent. The reaction is carried out in a twophase organic/aqueous system using a large quaternary ammonium or related salt (phase transfer catalyst) which carries the ionic reactant into the organic phase as an ion pair. Using this method it is possible to carry out reactions ordinarily requiring a scrupulously anhydrous medium. example: aqueous phase organic phase Na H in H 2 PhH 2 N I in H 2 2 No reaction occurs until PhH 2 N Et 3 is added. After addition of the phase transfer catalyst the reaction is over in a few minutes. product: Ph H( )N Procedure: Add aqueous Na H R 4 N H to a solution of PhH 2 N I in General Mechanism: H 2 2 and stir. aqueous phase organic phase Q H [Q H ] Q PhHN H 2 Q PhHN H3 I [Q H ] PhH 2 N PhHN [Q I ] RGANI REATIVITY HEM*4720 URSE NTES W

13 The method depends on the fact that R 4 N H is much more soluble in organic solvents than Na H. another example: aqueous phase Na H, PhH 2 N Et 3, in H 2 organic phase in H 3 rown ethers and cryptands can also be used a phase transfer catalysts: Na H crown [crown. Na ] H (soluble in organic phase V SLVENT EFFETS N PRDUT MPSITIN The solvent can have a large effect on the product composition in reactions where two or more products are produced by competing pathways that respond differently to changes in solvent. ne familiar example is competition between concerted nucleophilic substitution (S N 2) and nucleophilic substitution by a stepwise ionization (S N 1) mechanism. Depending on the substrate and nucleophile, the solvent can effect the % rearrangement or % racemization, both of which require a carbocation intermediate. Two other examples are shown: (i) oncerted vs Ionic ycloaddition RGANI REATIVITY HEM*4720 URSE NTES W

14 N N N in: benzene 50% 9% 38% acetonitrile 26% 2% 64% N Adduct 1 is produced by a thermallyallowed π 2 s π 2 s π 2 s cycloaddition, while 2 and 3 are presumed to arise from the accompanying zwitterionic intermediate. N (ii) Reactions of Ambident Anions Ambident anions have two or more nucleophilic sites and can react with alkyl halides, acyl halides, etc. at two or more positions. examples: N N etc. R R H enolate anions R H R etc. General rule: the more free the anion the greater the tendency to react at the most electronegative atom RGANI REATIVITY HEM*4720 URSE NTES W

15 For enolate anions, protic solvents strongly solvate the oxygen site favouring alkylation. Polar aprotic solvents, by leaving the anion relatively unsolvated, favour alkylation. Examples: Ph Ph Ph I Ph Ph Ph Ph Ph Ph in tbuh 96% 4% DME/DMS 50% 50% H 2 Ph H 2 Ph H PhH 2 Br in: DMF 97% 0% methanol 57% 24% F 3 H 2 H 7% 85% RGANI REATIVITY HEM*4720 URSE NTES W

16 PRATIE PRBLEMS 3 1. Predict the effect on the rate accompanying a change to a more polar solvent. Is the rate change considered to be large or small? a) b) c) Et 3 S Br Et 2 S EtBr H Et 4 N H 2 H 2 H 2 Et 3 N H 2 H 2 Br 2 BrH 2 H 2 Br via rate determining bromonium ion formation 2. Account for the trends in K eq for the following equilibrium. H K eq solvent K eq % enol nhexane ,4dioxane methanol onsider the accompanying substitution reaction, which follows the additionelimination mechanism introduced in HEM*3750. Br Br N 3 N 3 Na N 3 Na Br N 2 N 2 N 2 When the reaction is done in DMF, the rate of disappearance of the starting material is rapid. If increasing incremental amounts of water are added to the mixture, the reaction slows down. Please explain. 4. Rank the following compounds for their propensity to solvolyze under the conditions indicated (fastest to slowest). Give reasons for your rankings. The temperature is the same in each instance. RGANI REATIVITY HEM*4720 URSE NTES W

17 Situation A Situation B Situation Situation D Situation E H3 H3 H3 H3 H3 H3 80% EtH/20% H 2 80% EtH/20% H 2 50% EtH/50% H 2 80% EtH/20% H 2 90% iprh/10% H 2 5. For the following reaction that proceeds by way of a dipolar (or zwitterionic) intermediate, a) Match the relative rate with the appropriate solvent. S 2 S 2 H2 N H 3 N H 2 H3 measured relative rates reaction solvents 1, 31, 5000 diethyl ether, nhexane, nitrobenzene a) Draw the structure of the probable intermediate. 6. You have been introduced to the HughesIngold model for predicting solvent polarity effects on reaction rates. onsider the following reaction: Et 3 N EtI Et 4 N I which is for the 2 nd table of page 25 of the course notes. Draw a potential energy level diagram (as on course notes p. 310 at the top) demonstrating the reaction path when this reaction proceeds in benzene vs. nitrobenzene. Place both curves on one diagram and be sure to label each curve. RGANI REATIVITY HEM*4720 URSE NTES W

18 7. Although it was only briefly mentioned in class, the solvent susceptibility parameter m can assume a negative value, as shown in the two similar reactions below. Me 3 S Et 3 S H MeH Me 2 S m = 0.78 H EtH Et 2 S m = 0.84 a) Briefly explain, in general, what kinds of chemical reactions give a positive m value and hence the kinds of chemical reactions that give provide a negative m value. b) Briefly justify the negative m value in the particular instance of the reactions above. 8. As indicated by the symbolic drawing below, benzyltrimethyl ammonium chloride is complexed by a crown ether (18crown6) and the equilibrium constant (K) for the complexation is solvent dependent (298 K). The interaction of the ether oxygens with the ammonium ion is through hydrogen bonding. The table showing the data also shows the entropy change for the reaction, ΔS r, which is presented as TΔS; that is, the temperature component has been incorporated. K PhH 2 NH 3 H 3 N H 2 Ph solvent log K TΔS (kj/mol) H iprh DMS You are required to: a) Explain why the entropy for the complexation equilibrium is negative. b) Explain why the log K for iprh is much larger than that for water. RGANI REATIVITY HEM*4720 URSE NTES W

19 Explain why water and DMS have comparable equilibrium values despite being solvents of such different structure. SLUTINS T PRATIE PRBLEMS 3 1. a) Et 3 S Br Et 2 S EtBr an example of decreased charge separation large decrease in rate b) H Et 4 N H 2 H 2 H 2 Et 3 N another example of decreased charge separation large decrease in rate c) H 2 H 2 Br 2 BrH 2 H 2 Br via rate determining bromonium ion formation an example of increased charge separation large increase in rate 2. solvent K eq % enol nhexane H K eq 1,4dioxane methanol Much like one of the labs in HEM*3750, we see a dependence of internal Hbonding on solvent. With the least polar solvent, there in no opportunity for solvent participation through H Hbonding arrangemen bonding or dipole alignment, so the molecule satisfies itself somewhat by tautomerizing to the enol and doing the internal Hbonding. With 1,4dioxane, increased stabilization of H RGANI REATIVITY HEM*4720 URSE NTES W

20 the polar carbonyl form is possible through interaction with the solvent, (but not H bonding). With MeH there is good chance to Hbond to the carbonyl and to solvate it well through polar interaction. Hence selfstabilization by enol formation is reduced. 3. When sodium (or K ) azide is added to DMF, the sodium is solvated due to the direction of the dipole moment of the solvent. The azide is poorly solvated and readily does chemistry; hence the efficient addition elimination reaction. The addition of water creates a new solvent system that can assist in the stabilization of the positive sodium ion, but will probably have a greater effect on the azide which is poorly solvated in DMF alone. Water can perform Hbonding to the azide, which stabilizes it and reduces its reactivity. 4. Situation A Situation B Situation Situation D Situation E 80% EtH/20% H 2 80% EtH/20% H 2 50% EtH/50% H 2 80% EtH/20% H 2 90% iprh/10% H 2 ranks third, 2nd slowest slowest case, boring case, bears I bears I group and substituent and group and is in is in least ionizing common solvent common solvent system solvent system 2nd fastest case, is in common solvent system and bears R group for through resonance stabilization in the TS for loss fastest case, is in most ionizing solvent and bears R group for through resonance stabilization in the TS for loss H3 H3 H3 H3 H3 H3 5. a) A dipolar intermediate would suggest that more polar solvents would accelerate the reaction. The accompanying molecule is the proposed intermediate. Note that the tertiary carbon bears the cation while the collection of electronegative atoms bears the anion. Measured relative rates reaction solvents S 2 N H 2 H 3 H3 1 nhexane, 31 diethyl ether, 5000 nitrobenzene RGANI REATIVITY HEM*4720 URSE NTES W

21 6. Here is my thought. The important issues are that the starting materials should be close, the overall ΔG should be less for nitrobenzene and the ionic products in nitrobenzene should be of lower energy that in benzene. I also believe the energy difference between the products in the different solvents should be greater than the energy difference between the two transitions states in the different solvents 7. Me 3 S Et 3 S H MeH Me 2 S m = 0.78 H EtH Et 2 S m = 0.84 a) The concept of m arises from solvolysis reactions. ne can take the rate of solvolysis of a standard reaction, determine its rate in a number of solvents and then establish a solvent parameter, m. Since in a solvolysis, there is creation of charge, so more polar solvents create a large m and anything that creates charge will have a positive m based on how m was established in the first place. So when m is measured for a reaction that destroys charge, then m comes out to be negative. b) In the case of the reactions at hand, the negative m value is applicable since charged ion are reacting to create neutral compounds. RGANI REATIVITY HEM*4720 URSE NTES W

22 8. a) Two reasons: Two molecules come together to form one. The flexibility of the ring is lost when it closes to complex with the ammonium ion. b) iprh is not as good of an Hbonding solvent as water because of steric reasons, polarity and the number H bonds per molecule. Note that for the ammonium ion to bind with the crown ether, it must give up its interaction with the solvent. In water more so than iprh, that interaction is through Hbonding and hence it is more difficult to leave that Hbonding interaction behind in favour of the crown ether. The weaker interaction of the ion with iprh therefore will more readily concede the ammonium to the crown ether. Both water and DMS have oxygens capable of offering electron density towards cations. When that cation is something like an ammonium ion, then both can participate in Hbonding. Despite their structural differences, both can Hbond very well. RGANI REATIVITY HEM*4720 URSE NTES W