B American Society for Mass Spectrometry, 2013
J. Am. Soc. Mass Spectrom. (2014) 25:10Y17 DOI: 10.1007/s13361-013-0758-y
RESEARCH ARTICLE
Nucleophilic Aromatic Substitution with Dianions: Reactions Driven by the Release of Coulomb Repulsion Allison D. Eanes, Diogo O. Noin, Maheteme K. Kebede, Scott Gronert Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, USA
Abstract. The reactions of a nucleophilic dianion with a series of activated aryl bromides were studied in the gas phase. Nucleophilic aromatic substitution (SNAr) as well as proton transfer reactions were observed. Rate constants and branching ratios were determined for all the reactions and the experimental data are supported by ab initio calculations. Reactions with bis-trifluoromethylbromobenzenes give only SNAr reactions and the rate constants follow the expected pattern, with substituents at the ortho and para positions having the greatest impact. Reactions of polyfluorobromobenzenes give a mix of proton transfer (when possible) and SNAr, with both bromide and fluoride acting as leaving groups. The latter is much less thermodynamically favorable but is the dominant pathway in each case. The selectivity of the reactions indicate that the products are determined early on the potential energy surface, before there is significant cleavage of the bond to the leaving group—the reaction is potentially directed by the initial formation of a hydrogen bond with the arene. The computational data also suggest that hydrogen bonding in the product ion–ion complexes can stabilize the system until there is sufficient charge separation to use the internal Coulomb repulsion to drive the reactions to products. Overall, the results highlight (1) the ability of multiply-charged systems to efficiently funnel their Coulomb repulsion into reaction processes that are intrinsically unfavorable, and (2) the high degree of selectivity that can be attained even in systems with multiple, lowbarrier pathways. Key words: Ion-ion, Dianion, Gas-phase reaction, Nucleophilic aromatic substitution Received: 28 June 2013/Revised: 4 September 2013/Accepted: 6 September 2013/Published online: 18 October 2013
Introduction
N
ucleophilic aromatic substitution (SNAr) provides a powerful means of altering substituents in aromatic systems bearing moderate to strong electron-withdrawing groups [1–4] (Scheme 1). Depending on the basicity of the nucleophile and the nature of the substituents, proton transfer, elimination (benzyne formation), and SN2 reactions can compete. There have been many studies of nucleophilic aromatic substitution in the gas phase, and these studies have provided a good understanding of the potential energy surfaces of the reactions as well as the importance of ion– dipole complexes in the processes [5–11]. Over a number of years, we have used dianion nucleophiles to probe aliphatic SN2 reactions and analyze the competition with E2 elimination processes [12–15]. The advantage of the dianion methodology is that it leads to two ionic products that can
be detected by mass spectrometry, one of which is characteristic of the reaction mechanism—singly-charged, anionic nucleophiles generally give the leaving group as the product ion, which could result from either an SN2 or E2 process. In this contribution, we apply this methodology to a set of SNAr reactions. Along with exploring the intrinsic selectivity in model systems, we have examined how the internal electrostatic repulsion in the dianion can be used to fuel processes that would be significantly endothermic in singly-charged systems. A key question is how the electrostatic repulsion, which is released along an exceptionally long reaction coordinate, can be applied to the transition states, which typically would occur early on such a reaction coordinate [16]. This provides general insight into processes involving multiply-charged ions.
Methods Electronic supplementary material The online version of this article (doi:10.1007/s13361-013-0758-y) contains supplementary material, which is available to authorized users. Correspondence to: Scott Gronert; e-mail: [email protected]
Mass Spectrometry All experiments were performed in a previously-described quadrupole ion trap mass spectrometer (modified ThermoFinnigan LCQ DECA) equipped with electrospray
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
11
ionization (ESI) [15, 17]. In a typical experiment, the dianion precursor was dissolved in methanol (10–4 M) and injected through the electrospray interface at flow rates ranging from 3 to 5 μL/min. The neutral reagents were mixed into the buffer gas by injecting a constant flow of reagent (20–400 μL/h) into a measured flow of helium (1000–1500 mL/min). Reactions were monitored as a function of time at various flow rates (pressures) of the reagent and branching ratios were determined. Time delays and reagent flows were adjusted to obtain plots that covered two to three half-lives of the reactant ion. Reported rate constants were measured at three different reagent flow rates and at least nine kinetic runs were collected on 2 or more days (918 runs). In the past, we have shown that the ion trap gives reactivity at near ambient temperature [18]. All the arene reagents were obtained from commercial sources.
Calculations were done using the GAUSSIAN03 quantum mechanical package [19]. Optimizations were completed at the MP2/6-31+G(d) level. Energies were computed at the MP2/6-31+G(d,p)//MP2/6-31+G(d) level and corrected for the zero-point vibrational energies at the HF/6-31+G(d) level (ZPE, scaled by 0.9135 [20]). In the calculations of reaction surfaces, one variable was held fixed in the optimizations. Energies for the potential energy surface calculations were computed at the MP2/6-31 + G(d,p)//HF/6-31+G(d) level.
In this study, two general types of aryl bromide systems were investigated. In the first, trifluoromethyl substituents were used as electron-withdrawing groups. In the second system, multiple fluorines were used as the electronwithdrawing groups. In all cases, we employed a dianion with a 2-naphthoxide as the nucleophilic site (Scheme 2). Isolated 2-naphthoxide has a proton affinity (PA) of 344 kcal/mol [21], but it is enhanced to 376 kcal/mol (computed at MP2/6-31+G(d,p)//MP2/6-31+G(p) level) in this dianion due to internal electrostatic repulsion. Although eliminations to give benzyne products can compete with SNAr reactions, the dianion is not sufficiently basic to make this process thermodynamically viable.
Trifluoromethyl Systems For the three model systems, the orientation of the trifluoromethyl groups, relative to the bromine, are meta/
–X
Y Y
Z X
Br
364
CF3
368
Br
369
364
Br
365
366 F3C
I
II
CF3
F
F
F
Br
F
F
F
F
IV
356 F
F
F
358
F
Br
V
F
Br
367
III
CF3
F
F Br
360
360
363
F
Br
F
F
F
VI
VII
VIII O–
–O S(CH ) O 3 2 3
naphthoxide dianion
Results and Discussion
Z
F3C
361
Computational
CF3
361
Z
X
Scheme 1. Nucleophilic aromatic substitution
Y
Scheme 2. Reaction systems. The computed ΔHacid values (MP2/6-31+G(d,p)//MP2/6-31+G(d) level) for various sites are shown (kcal/mol)
meta (I), ortho/meta (II), and ortho/para (III). Each of the doubly-substituted trifluoromethyl systems led exclusively to nucleophilic aromatic substitution with the loss of bromide. The computed ΔHacid values for I, II, and III are 361 (deprotonate C-2), 364 (deprotonate C-6), and 365 (deprotonate C-3) kcal/mol, respectively, and are well above the proton affinity of 2-naphthoxide (singly-charged analog of the dianion nucleophile). The naphthoxide dianion is basic enough to deprotonate the substrates (PA = 376 kcal/ mol), but apparently the release of electrostatic repulsion does not occur early enough on the reaction coordinate to allow proton transfer to compete with the facile substitution process. There is also no evidence of substitution leading to the loss of trifluoromethide. This process is likely to be endothermic by a few kcal/mol given the relative proton affinities of the dianion and trifluoromethide—the loss of bromide should be favored by more than 50 kcal/mol in these systems. The rate constants of the substitution reactions vary by over a factor of 6 in the order III 9 II 9 I. For III, the rate is near the collision-controlled limit. The
12
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
collision rates of these systems are problematic to characterize by standard approaches. The dianions have two widely-spaced charge sites and the application of ADO theory with a charge of 2 is not a realistic representation of the situation. Using ADO as a general guide, these reactions give predicted collision rates in the range of 2–4 × 10–9 cm3 molecule–1 s–1 [22]. The order of reactivity, ortho/para fastest and meta/meta slowest, is not surprising and follows typical patterns seen in aromatic substitution where resonance effects give activating groups the greatest impact in the ortho or para position [2].
Pentafluorophenyl Bromide (IV) and 2,3,4,5Tetrafluorophenyl Bromide (V) In the pentafluoro system, substitution is the only viable pathway and the loss of bromide is the only observed pathway (Table 1). The rate constant for IV is near the expected collision-controlled limit. With an acidic proton available in V, the reaction shifts completely to a proton transfer pathway. The rate constant drops by a small amount relative to IV. One expects an increase in the substitution barrier with one fewer activating group, but the dramatic shift in the observed products is likely related to the proton transfer having a large entropic advantage over the SNAr processes, which require the formation of more highly constrained transition states. Despite the high rate constant, V is computed to have a ΔHacid value, 350 kcal/mol, which is 6 kcal/ mol above the proton affinity of 2-naphthoxide. As a result, the reaction must be driven by the release of Coulomb repulsion in the dianion. Using a simple electrostatic model with a dielectric constant of unity [16], this requires a 3 Å increase in the charge separation in the doubly charged system to generate the energy needed to counterbalance the inadequate basicity of the 2naphthoxide base. This is a modest increase in charge separation and would occur in the part of the reaction coordinate where the developing carbanion is stabilized by hydrogen bonding to the departing 2-naphthol unit. As a result, it is not surprising that the effective basicity of the dianion would be sufficient to produce an efficient proton transfer process in this system.
Trifluorophenyl Bromides (VI – VIII) In the reactions of the dianion with the trifluorophenyl bromides, a richer chemical reactivity is observed because there is a better balance between the barriers of the competing reaction pathways. In all cases, proton transfer is evident and varies from 100 % to 10 % of the observed reaction products. The range of proton transfer reactivity is broader when cast in terms of rates. The proton transfer partial rate constant peaks in 2,4,5-trifluorophenyl bromide, VI, at 1.7 × 10–9 cm3 molecule– 1 –1 s and is smallest in 2,4,6-trifluorophenyl bromide, VIII, at 1.1 × 10–11 cm3 molecule–1 s–1. The sensitivity of the proton transfer rate to the ΔHacid of the arene is surprising. The computed ΔHacid values vary only from 358 kcal/mol for VI to 360 kcal/mol for VIII. Given that the proton transfer rate for VI is very close to the collision-controlled limit and VIII is 100 times slower, the data suggest that the dianion has an effective proton affinity somewhere between them (~359 kcal/mol). The proton affinity of 2-naphthoxide is 344 kcal/mol and the dianion has a computed PA of 376 kcal/mol, so about one-half of the estimated Coulomb repulsion (15 out of 32 kcal/mol) must be available to drive the proton transfer process. This is much larger than the computed impact of Coulomb repulsion on the transition states of SN2 reactions with similar amounts of electrostatic repulsion in the starting dianion [23]. The situation is more complicated than an SN2 process because as the proton transfer progresses, the system is stabilized by hydrogen bonding between the newly-formed anionic site and the conjugate acid of the base—an interaction that is stabilizing over a reasonable distance. As a result, the full endothermicity of a proton transfer is not realized until later on the reaction coordinate than in an SN2 process. A potential energy surface is shown in Figure 1. The intrinsic endothermic nature of the
Table 1. Measured Rate Constants and Branching Ratios in Reactions of 2Naphthoxide Dianion with I -VIII ka
Substrate
I II III IV V VI VII VIII a
–10
PTb
4.2 ± 0.1 7.4 ± 0.1 27 ± 1 28 ± 3 22 ± 1 17 ± 1 0.85 ± 0.05 1.1 ± 0.1 3
–1
–1
0 0 0 0 100 100 50 10
Branching ratio (%) SNAr(Br)c
SNAr(F)c
100 100 100 100 0 0 20 0
0 0 0 0 0 0 30 90
10 cm molecule s . Uncertainties are measure of experimental precision. Absolute accuracy estimated as ±15 % b Proton transfer fraction c Aromatic substitution fraction. Leaving group given parenthetically
Figure 1. Potential energy surface for proton transfer from VIII to naphthoxide dianion. Reaction coordinate is the distance between the transferring proton and C-3 of VIII. Surface based on single path at MP2/6-31+G(d,p)//HF/631+G(d) level
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
proton transfer from VIII to 2-naphthoxide is only partially realized because hydrogen bonding along the reaction coordinate stabilizes the system while Coulomb repulsion is released, pushing the transition state to a C–H distance of about 6 Å and leading to only a small barrier on the surface at this level of theory (2 kcal/mol versus the 15 kcal/mol expected for singlycharged naphthoxide). VI only gives proton transfer but VII and VIII also give substitution products. Surprisingly, the major substitution product in each case involves the loss of fluoride (PA = 371 kcal/mol) instead of bromide (PA = 323 kcal/mol) [21]. Spectra are shown in Figure 2. In VII, fluoride loss represents about 30 % of the product yield and bromide loss represents about 20 %. In VIII, fluoride loss represents about 90 % of the total product yield and there is no evidence of bromide loss. Given the difference in proton affinities of these leaving groups, one expects that bromide loss is thermodynamically more favorable by nearly 50 kcal/ mol! In these systems, we are unable to ascertain which fluoride is lost in the reaction (see below). The fluoride-loss process would not be thermodynamically viable with singlycharged 2-naphthoxide (PA = 344 kcal/mol) and the system must take advantage of a large portion of the internal Coulomb repulsion in the naphthoxide dianion (computed PA = 376 kcal/mol) to proceed. It is true that condensedphase nucleophilic aromatic substitutions are known to have reactivity patterns that run counter to expectations based on thermodynamics. This has been called the “element effect” and can lead to attack and substitution at the carbon bearing the most electronegative group rather than the best leaving group [24]. We recently presented calculations that indicated that the “element effect” could be manifested in the gas phase for nitro-substituted arenes [25]. The competition between fluoride and bromide loss in these systems provides an experimental example of the “element effect” in the gas phase. In comparison to solution, however, the energetics are
(a)
13
much different in the gas phase. Fluoride is more basic than bromide by 48 kcal/mol in the gas phase [21], which is equivalent to about 38 pKa units at 300 K. In the condensed phase, the pKa difference is less than 15 pKa units. How can the fluoride compete in the gas phase against such a large thermodynamic bias? There are two issues to deal with in these systems. The first is the ability of fluoride loss to compete with bromide loss and the second is the exclusive nature of fluoride loss in VIII. Both of these outcomes require that the productdetermining point in the reaction process occurs early, before the disadvantage of a poor leaving group (i.e., fluoride) is manifested. In other words, the product pathway is fixed at a point when the fluoride loss process has some advantage. The key, then, is to identify a factor that would direct attack at a fluorine-bearing carbon early on the reaction coordinate. The fact that VII gives a mix of bromide and fluoride loss whereas VIII gives exclusively fluoride loss suggests that both pathways are mechanistically competitive in the trifluorophenyl bromides, but that some unique feature of VIII tips the balance completely to the fluoride loss channel. Computational data provide some insight. Transition states were computed using simpler model systems, the reaction of phenoxide with VII and VIII (the full system is too large for efficient calculations at an acceptable level). Sample transition states are given in Figure 3 and the barriers are listed in Table 2. All of the transition states are well below the entrance channel and there is a modest variation from site to site. In VII, the lowest energy transition state is for substitution at C-3 and involves the loss of fluoride. It is pictured in Figure 3a and exhibits a well-developed O–C bond and a slightly weakened C–F bond. Both are relatively close to normal lengths and the structure is similar to what would be expected for a Meisenheimer complex. In fact, the transition state leads to a stable complex that is slightly more stable. The barrier for
(b) F2Br
OH
O3S(CH2)3O
O
O3S(CH2)3O
F
F2Br
F
OH
F O
O
O3S(CH2)3O O3S(CH2)3O
O3S(CH2)3O
Figure 2. Reaction of dianion with (a) VII and (b) VIII. PT represents proton transfer and leads to two ionic products—protonated dianion (m/z 281) and deprotonated arene (m/z 209/211). Secondary product results from reaction of deprotonated arene with arene and is a fluoride complex of the arene. Structures are shown for m/z 281, 410, 471/473. For the SNAr(F) product, the regiochemistry is unknown and the product is given generically
14
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
(a)
(b) F
F
F
PhO
PhO
Br
F F
Br
F
1.688 Å
1.533 Å 2.059 Å 1.460 Å
Figure 3. Transition states for the reaction of phenoxide at (a) C-3 and (b) C-1 of VII. Carbon is green, fluorine is blue, oxygen is red, bromine is yellow, and hydrogen is white
loss of fluoride from the complex occurs late on the potential energy surface and is created by the competing effects of bond cleavage and Coulomb-repulsion release (see below). Attack at C-2 or C-5 offers similar potential energy surfaces, but the transition states are less favorable. Figure 3b is the corresponding transition state for bromide loss. It occurs earlier on the reaction coordinate and exhibits a relatively long C–O distance. This transition state is 3.5 kcal/mol less stable than the one for reaction at C-3 and is part of a concerted bromide loss process; a stable Meisenheimer intermediate could not be located. The higher barrier for bromide loss is somewhat deceptive because the surface is dropping off quickly on the addition path and the transition state is merely a shoulder on the surface; the shoulder occurs earlier on this path and, therefore, is higher in energy. In VIII, all of the transition states are about as favorable as those for VII. Again, attack at a fluorine-bearing carbon is preferred with C-2 being most favorable. Given the low barriers, the calculations are unable to give definitive guidance as to which fluoride is lost in these SNAr reactions. The computational results suggest that addition at a fluorinated carbon could compete favorably with addition at a brominated carbon, but they are not consistent with the experimental data in other ways. For example, why do the reactions have modest efficiencies? In VII, attack at C-1 to give bromide loss has a concerted transition state that is
9.5 kcal/mol below the entrance channel and leads to a process that is favorable by over 30 kcal/mol, but it has an efficiency in the 5 % range. In addition, why would VIII be 100 % selective for fluoride loss given that attack at a brominated carbon gives a transition state that is also well below the entrance channel? Both of these outcomes can be explained by assuming that the reaction system does not give statistical behavior and that the reactions are, to some extent, dictated by nature of an initially formed complex. The electrostatic maps for the trifuorobromobenzenes indicate that the C–H bonds are the sites of the most favorable interaction with an anion. An example for 2,4,6trifluorobromobenzene is shown in Figure 4a. Here, there is a large attractive potential at the hydrogen that suggest a strong hydrogen-bonding interaction, whereas the π-system is only slightly electron-poor. For comparison, the electrostatic potential for pentafluorobromobenzene is shown in Figure 4b and, in this case, the π-system is clearly electronpoor and direct attack on the π-system would be much more
(a)
(b)
Table 2. Computed Transition State Energies for Reaction of Phenoxide with VII and VIII at the MP2/6-31+G(d,p)//MP2/6-31+G(d) level (kcal/ mol) Substrate VII
VIII
a
Transition state
F
at at at at at at at
C-1 C-2 C-3 C-5 C-1 C-2 C-4
F
Energya F
SNAr SNAr SNAr SNAr SNAr SNAr SNAr
F
-11.3 -11.6 -13.0 -9.5 -9.3 -13.5 -11.5
See Methods section for details. C-1 is the carbon bearing the bromide
Br
F
F
Br
F
F
Figure 4. Electrostatic potential maps for (a) VIII and (b) IV. Map based on MP2/6-31+G(d) calculations. Blue areas are electronpoor and red areas are electron-rich, with yellow-green representing neutral surfaces. Both surfaces use the same scaling
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
favorable. It is important to note that the lowest point on the potential energy surface in Figure 1 is a hydrogen-bonded complex of the naphthoxide and a C–H bond of the trifluorobromobenzene. In the higher-level calculations on the reaction of phenoxide with VIII, the hydrogen-bonded complex is calculated to be about 10 kcal/mol below the transition states in Table 2 (it also exhibits a π-stacking interaction). These observations suggest that there is a driving force to push the system initially to an interaction between the naphthoxide and one of the C–H bonds. The next assumption is that the formation of this complex localizes the SNAr reactions to the adjacent carbons. In VIII, this would be C-2 (or C-6) and C-4, but not C-1. Because the C–H bonds are flanked only by C–F bonds in VIII, fluoride loss would be the exclusive product if the hydrogen-bonded complex directed the substitution process. In VII, the potential sites for hydrogen-bonding are flanked by C–F and C–Br bonds and, therefore, attack a fluorinated or brominated carbon would be possible. In addition, a cursory study with 3,4,5-trifluorobromobenzene and 2,3,4trifluorobromobenzene (substrates where the C–H bonds are flanked by C–F and C–Br bonds) also indicates that both fluoride and bromide loss occur, with a preference for the former. Previous gas-phase work on hydrogen/deuterium exchange with halogenated benzenes indicates that anions can become localized on the potential energy surfaces of these systems [26]. The assumption that a hydrogen-bonded intermediate directs reactivity requires non-statistical behavior and removes the constraints of the Curtin-Hammett principle. Localization in the hydrogen-bonded complex also provides an explanation for the low reaction efficiencies because proton transfer reactions for VII and VIII are expected to have barriers (see above); the system could be locked onto the proton transfer pathway and rarely explore the favorable SNAr pathways before the complex dissociates. Although it is a large system for non-statistical behavior, the rigidity can contribute to the system’s inability to fully explore the potential energy surface [27, 28]. Taken together, these rationalizations provide an explanation for the low efficiencies as well as the exclusive attack at a fluorinated carbon in VIII. The last question is how the loss of fluoride from the Meisenheimer complex can occur with a barrier that is small enough to compete with the very facile bromide loss when both pathways are possible from a hydrogen-bonded complex. In Figure 5, the potential energy surface for fluoride loss from VIII is presented. The pathway was generated by simply extending the C–F distance stepwise from the Meisenheimer complex. The pathway is surprisingly complicated and involves a number of species that could be potential intermediates (the surface is too coarse to identify transition states between these possible intermediates). The departing fluoride forms a series of hydrogen-bonded complexes with the substitution product before separation occurs. Three structures are shown in Figure 6 and each involves the fluoride forming a hydrogen bond to an aryl
15
Figure 5. Potential energy surface for nucleophilic aromatic substitution of the naphthoxide dianion at C-4 of VIII. Reaction coordinate is the distance between the fluoride leaving group and C-4 of VIII. Surface based on single path at MP2/6-31+G(d,p)//HF/6-31+G(d) level
hydrogen. In essence, the fluoride is hopping along the edge of the arene until the force from the internal Coulomb repulsion overwhelms the forces associated with hydrogen bonding. The structure with an 8 Å C–F separation in Figure 6 represents the point where the hydrogen bonding with the arene begins to break down. This pathway leads to a counterintuitive situation in that the distance between the charge centers (fluoride and sulfonate) in the ion–ion complex decreases initially before rapidly increasing once the hydrogen bonding interaction severs. The key feature of the surface is that like the proton transfer, the reaction path does not face the intrinsic endothermicity of the process immediately because interactions such as hydrogen bonding can mitigate the disadvantage of fluoride expulsion until the release of Coulomb repulsion is sufficient to drive the process forward. The path in Figures 5 and 6 is only a single example of many possible paths. The complexity, and likely variability, of the pathways for fluoride departure suggest that the transition state opens into an expansive phase space, which would make the process effectively irreversible once the C–F bond is cleaved. The absence of any opportunity for hydrogen bonding to the arene in pentafluorophenyl bromide, IV, might explain the absence of a fluoride loss channel with this substrate. Together, these assumptions lead to a situation where product determination occurs early on the surface, well before the enthalpic disadvantage of a fluoride leaving group can be fully realized. The strong hydrogen bonding that is observed on the surfaces for fluoride loss would not be likely with other leaving groups, and the fluorinated systems may be exceptional cases.
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A. D. Eanes et al.: Nucleophilic Aromatic Substitution
1.80 Å
2.8 Å
3. The “element effect” is an intrinsic feature of SNAr reactions and is manifested in the gas phase. It is a powerful driving force and can outweigh the large thermodynamic disadvantage of fluoride versus bromide loss, which is many orders of magnitude more significant in the gas phase. 4. Doubly-charged systems present complicated surfaces where stabilizing interactions, such as hydrogen bonding, can mitigate the disadvantages of intrinsically endothermic processes until the combined advantages of Coulomb repulsion release and expanded phase space can drive the system to enthalpically-favorable, singly-charged products.
References 1.85 Å
2.15 Å
6.0 Å
8.0 Å
Figure 6. Selected structures on the nucleophilic aromatic substitution pathway of the naphthoxide dianion attacking C4 of VIII. Carbon is green, fluorine is blue, oxygen is red, bromine is yellow, sulfur is black, and hydrogen is white
Conclusions The reactions of a dianion nucleophile with activated aryl bromides point to a number of interesting aspects of nucleophilic aromatic substitution as well as unusual features of the reactions of doubly-charged ions. 1. In systems that are limited to SNAr reactions at a single center (i.e., the bis-trifluoromethylbromobenzenes), the reactivity follows the expected trends for activated processes. The electron-withdrawing trifluoromethyl groups are most effective in activating the SNAr reaction when they are in the ortho or para position. 2. When a sufficiently acidic proton is available, proton transfer easily out-competes an SNAr reaction. This is presumably an entropic effect. The release of Coulomb energy is efficient in proton transfer processes and the dianion has an effective proton affinity that implies up to a 50 % release of Coulomb energy at the rate-determining transition state for proton transfer.
1. Bunnett, J.F., Zahler, R.E.: Aromatic nucleophilic substitution reactions. Chem. Rev. 49, 273–412 (1951) 2. Miller, J.: Aromatic Nucleophilic Substitution. Elsevier, Amsterdam. 1– 26 (1968) 3. Bernasconi, C.F.: Kinetic-behavior of short-lived anionic sigmacomplexes. Acc. Chem. Res. 11, 147–152 (1978) 4. Buncel, E., Dust, J.M., Terrier, F.: Rationalizing the regioselectivity in polynitroarene anionic sigma-adduct formation—relevance to nucleophilic aromatic-substitution. Chem. Rev. 95, 2261–2280 (1995) 5. Briscese, S.M., Riveros, J.M.: Gas-phase nucleophilic reactions of aromatic systems. J. Am. Chem. Soc. 97, 230–231 (1975) 6. Giroldo, T., Xavier, L.A., Riveros, J.M.: An unusually fast nucleophilic aromatic displacement reaction: the gas-phase reaction of fluoride ions with nitrobenzene. Angew. Chem. Int. Ed. 43, 3588–3590 (2004) 7. Ingemann, S., Nibbering, N.M.M.: Gas-phase reactions of anions with 2-fluoroanisole, 3-fluoroanisole, and 4-fluoroanisole. J. Org. Chem. 48, 183–191 (1983) 8. Ingemann, S., Nibbering, N.M.M.: Gas-phase reactions between anions and alkyl pentafluorophenyl ethers. Nouv. J. Chim. 8, 299–304 (1984) 9. Ingemann, S., Nibbering, N.M.M., Sullivan, S.A., Depuy, C.H.: Nucleophilic aromatic-substitution in the gas-phase—the importance of F-ion molecule complexes formed in gas-phase reactions between nucleophiles and some alkyl pentafluorophenyl ethers. J. Am. Chem. Soc. 104, 6520–6527 (1982) 10. Laerdahl, J.K., Uggerud, E.: Gas phase nucleophilic substitution. Int. J. Mass Spectrom. 214, 277–314 (2002) 11. Linnert, H.V., Riveros, J.M.: Benzyne-related mechanisms in the gas-phase ion–molecule reactions of haloarenes. Int. J. Mass Spectrom. Ion Process. 140, 163–176 (1994) 12. Gronert, S., Fagin, A.E., Wong, L.: Direct measurements of deuterium kinetic isotope effects in anionic, gas-phase substitution and elimination reactions. J. Am. Chem. Soc. 129, 5330–5331 (2007) 13. Gronert, S., Fagin, A.E., Okamoto, K., Mogali, S., Pratt, L.M.: Leaving group effects in gas-phase substitutions and eliminations. J. Am. Chem. Soc. 126, 12977–12983 (2004) 14. Gronert, S.: Gas phase studies of the competition between substitution and elimination reactions. Acc. Chem. Res. 36, 848–857 (2003) 15. Nettey, S., Swift, C.A., Joviliano, R., Noin, D.O., Gronert, S.: The impact of substituents on the transition states of S(N)2 and E2 reactions in aliphatic and vinylic systems: remarkably facile vinylic eliminations. J. Am. Chem. Soc. 134, 9303–9310 (2012) 16. Gronert, S.: Coulomb repulsion in multiply charged ions: a computational study of the effective dielectric constants of organic spacer groups. Int. J. Mass Spectrom. 185, 351–357 (1999) 17. Gronert, S.: Quadrupole ion trap studies of fundamental organic reactions. Mass Spectrom. Rev. 24, 100–120 (2005) 18. Gronert, S.: Estimation of effective ion temperatures in a quadrupole ion trap. J. Am. Soc. Mass Spectrom. 9, 845–848 (1998) 19. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery Jr., J.A., Vreven, T., Kudin, K.N., Burant, J.C., Millam, J.M., Iyengar, S.S., Tomasi, J., Barone, V., Mennucci, B., Cossi, M., Scalmani, G., Rega, N., Petersson, G.A., Nakatsuji, H., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa,
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J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Klene, M., Li, X., Knox, J.E., Hratchian, H.P., Cross, J.B., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Ayala, P.Y., Morokuma, K., Voth, G.A., Salvador, P., Dannenberg, J.J., Zakrzewski, V.G., Dapprich, S., Daniels, A.D., Strain, M.C., Farkas, O., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Ortiz, J.V., Cui, Q., Baboul, A.G., Clifford, S., Cioslowski, J., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Gonzalez, C., Pople, J.A.: Gaussian 03 Revision B04. Gaussian Inc, Pittsburgh (2003) 20. Pople, J.A., Scott, A.P., Wong, M.W., Radom, L.: Scaling factors for obtaining fundamental vibrational frequencies and zero-point energies from HF/6-31G* and MP2/6-31G* harmonic frequencies. Isr. J. Chem. 33, 345–350 (1993) 21. Bartmess, J.E.: In: Nist Standard Reference Database Number 69; Mallard, W.G., Linstrom, P.J., Eds. National Institute of Standards and Technology (available at: http://webbook.nist.gov): Gaithersburg, MD (2013). Accessed 1 June 2013 22. Su, T., Bowers, M.T.: In: Bowers, M.T. (ed.) Gas Phase Ion Chemistry, Vol. 1, pp. 83–118. Academic Press, New York (1979)
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23. Gronert, S., Fong, L.M.: Gas phase reactions of dianions. 2. The effect of a second charge on S(N)2 potential energy surfaces: an ab initio study. Int. J. Mass Spectrom. 192, 185–190 (1999) 24. Bunnett, J.F., Garbisch, E.W., Pruitt, K.M.: The “Element Effect” as a criterion of mechanism in activated aromatic nucleophilic substitution reactions. J. Am. Chem. Soc. 78, 385–391 (1957) 25. Senger, N.A., Bo, B., Cheng, Q., Keeffe, J.R., Gronert, S., Wu, W.M.: The element effect revisited: factors determining leaving group ability in activated nucleophilic aromatic substitution reactions. J. Org. Chem. 77, 9535–9540 (2012) 26. Kato, S., DePuy, C.H., Gronert, S., Bierbaum, V.M.: Gas phase hydrogen/deuterium exchange reactions of fluorophenyl anions. J. Am. Soc. Mass Spectrom. 10, 840–847 (1999) 27. Manikandan, P., Zhang, J.X., Hase, W.L.: Chemical dynamics simulations of X– + CH3Y =9 XCH3 + Y– gas-phase S(N)2 nucleophilic substitution reactions. Nonstatistical dynamics and nontraditional reaction mechanisms. J. Phys. Chem. A 116, 3061– 3080 (2012) 28. Craig, S.L., Zhong, M.L., Brauman, J.I.: Translational energy dependence and potential energy surfaces of gas phase S(N)2 and addition-elimination reactions. J. Am. Chem. Soc. 121, 11790– 11797 (1999)
J. Am. Soc. Mass Spectrom. (2014) 25:10Y17 DOI: 10.1007/s13361-013-0758-y
RESEARCH ARTICLE
Nucleophilic Aromatic Substitution with Dianions: Reactions Driven by the Release of Coulomb Repulsion Allison D. Eanes, Diogo O. Noin, Maheteme K. Kebede, Scott Gronert Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, USA
Abstract. The reactions of a nucleophilic dianion with a series of activated aryl bromides were studied in the gas phase. Nucleophilic aromatic substitution (SNAr) as well as proton transfer reactions were observed. Rate constants and branching ratios were determined for all the reactions and the experimental data are supported by ab initio calculations. Reactions with bis-trifluoromethylbromobenzenes give only SNAr reactions and the rate constants follow the expected pattern, with substituents at the ortho and para positions having the greatest impact. Reactions of polyfluorobromobenzenes give a mix of proton transfer (when possible) and SNAr, with both bromide and fluoride acting as leaving groups. The latter is much less thermodynamically favorable but is the dominant pathway in each case. The selectivity of the reactions indicate that the products are determined early on the potential energy surface, before there is significant cleavage of the bond to the leaving group—the reaction is potentially directed by the initial formation of a hydrogen bond with the arene. The computational data also suggest that hydrogen bonding in the product ion–ion complexes can stabilize the system until there is sufficient charge separation to use the internal Coulomb repulsion to drive the reactions to products. Overall, the results highlight (1) the ability of multiply-charged systems to efficiently funnel their Coulomb repulsion into reaction processes that are intrinsically unfavorable, and (2) the high degree of selectivity that can be attained even in systems with multiple, lowbarrier pathways. Key words: Ion-ion, Dianion, Gas-phase reaction, Nucleophilic aromatic substitution Received: 28 June 2013/Revised: 4 September 2013/Accepted: 6 September 2013/Published online: 18 October 2013
Introduction
N
ucleophilic aromatic substitution (SNAr) provides a powerful means of altering substituents in aromatic systems bearing moderate to strong electron-withdrawing groups [1–4] (Scheme 1). Depending on the basicity of the nucleophile and the nature of the substituents, proton transfer, elimination (benzyne formation), and SN2 reactions can compete. There have been many studies of nucleophilic aromatic substitution in the gas phase, and these studies have provided a good understanding of the potential energy surfaces of the reactions as well as the importance of ion– dipole complexes in the processes [5–11]. Over a number of years, we have used dianion nucleophiles to probe aliphatic SN2 reactions and analyze the competition with E2 elimination processes [12–15]. The advantage of the dianion methodology is that it leads to two ionic products that can
be detected by mass spectrometry, one of which is characteristic of the reaction mechanism—singly-charged, anionic nucleophiles generally give the leaving group as the product ion, which could result from either an SN2 or E2 process. In this contribution, we apply this methodology to a set of SNAr reactions. Along with exploring the intrinsic selectivity in model systems, we have examined how the internal electrostatic repulsion in the dianion can be used to fuel processes that would be significantly endothermic in singly-charged systems. A key question is how the electrostatic repulsion, which is released along an exceptionally long reaction coordinate, can be applied to the transition states, which typically would occur early on such a reaction coordinate [16]. This provides general insight into processes involving multiply-charged ions.
Methods Electronic supplementary material The online version of this article (doi:10.1007/s13361-013-0758-y) contains supplementary material, which is available to authorized users. Correspondence to: Scott Gronert; e-mail: [email protected]
Mass Spectrometry All experiments were performed in a previously-described quadrupole ion trap mass spectrometer (modified ThermoFinnigan LCQ DECA) equipped with electrospray
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
11
ionization (ESI) [15, 17]. In a typical experiment, the dianion precursor was dissolved in methanol (10–4 M) and injected through the electrospray interface at flow rates ranging from 3 to 5 μL/min. The neutral reagents were mixed into the buffer gas by injecting a constant flow of reagent (20–400 μL/h) into a measured flow of helium (1000–1500 mL/min). Reactions were monitored as a function of time at various flow rates (pressures) of the reagent and branching ratios were determined. Time delays and reagent flows were adjusted to obtain plots that covered two to three half-lives of the reactant ion. Reported rate constants were measured at three different reagent flow rates and at least nine kinetic runs were collected on 2 or more days (918 runs). In the past, we have shown that the ion trap gives reactivity at near ambient temperature [18]. All the arene reagents were obtained from commercial sources.
Calculations were done using the GAUSSIAN03 quantum mechanical package [19]. Optimizations were completed at the MP2/6-31+G(d) level. Energies were computed at the MP2/6-31+G(d,p)//MP2/6-31+G(d) level and corrected for the zero-point vibrational energies at the HF/6-31+G(d) level (ZPE, scaled by 0.9135 [20]). In the calculations of reaction surfaces, one variable was held fixed in the optimizations. Energies for the potential energy surface calculations were computed at the MP2/6-31 + G(d,p)//HF/6-31+G(d) level.
In this study, two general types of aryl bromide systems were investigated. In the first, trifluoromethyl substituents were used as electron-withdrawing groups. In the second system, multiple fluorines were used as the electronwithdrawing groups. In all cases, we employed a dianion with a 2-naphthoxide as the nucleophilic site (Scheme 2). Isolated 2-naphthoxide has a proton affinity (PA) of 344 kcal/mol [21], but it is enhanced to 376 kcal/mol (computed at MP2/6-31+G(d,p)//MP2/6-31+G(p) level) in this dianion due to internal electrostatic repulsion. Although eliminations to give benzyne products can compete with SNAr reactions, the dianion is not sufficiently basic to make this process thermodynamically viable.
Trifluoromethyl Systems For the three model systems, the orientation of the trifluoromethyl groups, relative to the bromine, are meta/
–X
Y Y
Z X
Br
364
CF3
368
Br
369
364
Br
365
366 F3C
I
II
CF3
F
F
F
Br
F
F
F
F
IV
356 F
F
F
358
F
Br
V
F
Br
367
III
CF3
F
F Br
360
360
363
F
Br
F
F
F
VI
VII
VIII O–
–O S(CH ) O 3 2 3
naphthoxide dianion
Results and Discussion
Z
F3C
361
Computational
CF3
361
Z
X
Scheme 1. Nucleophilic aromatic substitution
Y
Scheme 2. Reaction systems. The computed ΔHacid values (MP2/6-31+G(d,p)//MP2/6-31+G(d) level) for various sites are shown (kcal/mol)
meta (I), ortho/meta (II), and ortho/para (III). Each of the doubly-substituted trifluoromethyl systems led exclusively to nucleophilic aromatic substitution with the loss of bromide. The computed ΔHacid values for I, II, and III are 361 (deprotonate C-2), 364 (deprotonate C-6), and 365 (deprotonate C-3) kcal/mol, respectively, and are well above the proton affinity of 2-naphthoxide (singly-charged analog of the dianion nucleophile). The naphthoxide dianion is basic enough to deprotonate the substrates (PA = 376 kcal/ mol), but apparently the release of electrostatic repulsion does not occur early enough on the reaction coordinate to allow proton transfer to compete with the facile substitution process. There is also no evidence of substitution leading to the loss of trifluoromethide. This process is likely to be endothermic by a few kcal/mol given the relative proton affinities of the dianion and trifluoromethide—the loss of bromide should be favored by more than 50 kcal/mol in these systems. The rate constants of the substitution reactions vary by over a factor of 6 in the order III 9 II 9 I. For III, the rate is near the collision-controlled limit. The
12
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
collision rates of these systems are problematic to characterize by standard approaches. The dianions have two widely-spaced charge sites and the application of ADO theory with a charge of 2 is not a realistic representation of the situation. Using ADO as a general guide, these reactions give predicted collision rates in the range of 2–4 × 10–9 cm3 molecule–1 s–1 [22]. The order of reactivity, ortho/para fastest and meta/meta slowest, is not surprising and follows typical patterns seen in aromatic substitution where resonance effects give activating groups the greatest impact in the ortho or para position [2].
Pentafluorophenyl Bromide (IV) and 2,3,4,5Tetrafluorophenyl Bromide (V) In the pentafluoro system, substitution is the only viable pathway and the loss of bromide is the only observed pathway (Table 1). The rate constant for IV is near the expected collision-controlled limit. With an acidic proton available in V, the reaction shifts completely to a proton transfer pathway. The rate constant drops by a small amount relative to IV. One expects an increase in the substitution barrier with one fewer activating group, but the dramatic shift in the observed products is likely related to the proton transfer having a large entropic advantage over the SNAr processes, which require the formation of more highly constrained transition states. Despite the high rate constant, V is computed to have a ΔHacid value, 350 kcal/mol, which is 6 kcal/ mol above the proton affinity of 2-naphthoxide. As a result, the reaction must be driven by the release of Coulomb repulsion in the dianion. Using a simple electrostatic model with a dielectric constant of unity [16], this requires a 3 Å increase in the charge separation in the doubly charged system to generate the energy needed to counterbalance the inadequate basicity of the 2naphthoxide base. This is a modest increase in charge separation and would occur in the part of the reaction coordinate where the developing carbanion is stabilized by hydrogen bonding to the departing 2-naphthol unit. As a result, it is not surprising that the effective basicity of the dianion would be sufficient to produce an efficient proton transfer process in this system.
Trifluorophenyl Bromides (VI – VIII) In the reactions of the dianion with the trifluorophenyl bromides, a richer chemical reactivity is observed because there is a better balance between the barriers of the competing reaction pathways. In all cases, proton transfer is evident and varies from 100 % to 10 % of the observed reaction products. The range of proton transfer reactivity is broader when cast in terms of rates. The proton transfer partial rate constant peaks in 2,4,5-trifluorophenyl bromide, VI, at 1.7 × 10–9 cm3 molecule– 1 –1 s and is smallest in 2,4,6-trifluorophenyl bromide, VIII, at 1.1 × 10–11 cm3 molecule–1 s–1. The sensitivity of the proton transfer rate to the ΔHacid of the arene is surprising. The computed ΔHacid values vary only from 358 kcal/mol for VI to 360 kcal/mol for VIII. Given that the proton transfer rate for VI is very close to the collision-controlled limit and VIII is 100 times slower, the data suggest that the dianion has an effective proton affinity somewhere between them (~359 kcal/mol). The proton affinity of 2-naphthoxide is 344 kcal/mol and the dianion has a computed PA of 376 kcal/mol, so about one-half of the estimated Coulomb repulsion (15 out of 32 kcal/mol) must be available to drive the proton transfer process. This is much larger than the computed impact of Coulomb repulsion on the transition states of SN2 reactions with similar amounts of electrostatic repulsion in the starting dianion [23]. The situation is more complicated than an SN2 process because as the proton transfer progresses, the system is stabilized by hydrogen bonding between the newly-formed anionic site and the conjugate acid of the base—an interaction that is stabilizing over a reasonable distance. As a result, the full endothermicity of a proton transfer is not realized until later on the reaction coordinate than in an SN2 process. A potential energy surface is shown in Figure 1. The intrinsic endothermic nature of the
Table 1. Measured Rate Constants and Branching Ratios in Reactions of 2Naphthoxide Dianion with I -VIII ka
Substrate
I II III IV V VI VII VIII a
–10
PTb
4.2 ± 0.1 7.4 ± 0.1 27 ± 1 28 ± 3 22 ± 1 17 ± 1 0.85 ± 0.05 1.1 ± 0.1 3
–1
–1
0 0 0 0 100 100 50 10
Branching ratio (%) SNAr(Br)c
SNAr(F)c
100 100 100 100 0 0 20 0
0 0 0 0 0 0 30 90
10 cm molecule s . Uncertainties are measure of experimental precision. Absolute accuracy estimated as ±15 % b Proton transfer fraction c Aromatic substitution fraction. Leaving group given parenthetically
Figure 1. Potential energy surface for proton transfer from VIII to naphthoxide dianion. Reaction coordinate is the distance between the transferring proton and C-3 of VIII. Surface based on single path at MP2/6-31+G(d,p)//HF/631+G(d) level
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
proton transfer from VIII to 2-naphthoxide is only partially realized because hydrogen bonding along the reaction coordinate stabilizes the system while Coulomb repulsion is released, pushing the transition state to a C–H distance of about 6 Å and leading to only a small barrier on the surface at this level of theory (2 kcal/mol versus the 15 kcal/mol expected for singlycharged naphthoxide). VI only gives proton transfer but VII and VIII also give substitution products. Surprisingly, the major substitution product in each case involves the loss of fluoride (PA = 371 kcal/mol) instead of bromide (PA = 323 kcal/mol) [21]. Spectra are shown in Figure 2. In VII, fluoride loss represents about 30 % of the product yield and bromide loss represents about 20 %. In VIII, fluoride loss represents about 90 % of the total product yield and there is no evidence of bromide loss. Given the difference in proton affinities of these leaving groups, one expects that bromide loss is thermodynamically more favorable by nearly 50 kcal/ mol! In these systems, we are unable to ascertain which fluoride is lost in the reaction (see below). The fluoride-loss process would not be thermodynamically viable with singlycharged 2-naphthoxide (PA = 344 kcal/mol) and the system must take advantage of a large portion of the internal Coulomb repulsion in the naphthoxide dianion (computed PA = 376 kcal/mol) to proceed. It is true that condensedphase nucleophilic aromatic substitutions are known to have reactivity patterns that run counter to expectations based on thermodynamics. This has been called the “element effect” and can lead to attack and substitution at the carbon bearing the most electronegative group rather than the best leaving group [24]. We recently presented calculations that indicated that the “element effect” could be manifested in the gas phase for nitro-substituted arenes [25]. The competition between fluoride and bromide loss in these systems provides an experimental example of the “element effect” in the gas phase. In comparison to solution, however, the energetics are
(a)
13
much different in the gas phase. Fluoride is more basic than bromide by 48 kcal/mol in the gas phase [21], which is equivalent to about 38 pKa units at 300 K. In the condensed phase, the pKa difference is less than 15 pKa units. How can the fluoride compete in the gas phase against such a large thermodynamic bias? There are two issues to deal with in these systems. The first is the ability of fluoride loss to compete with bromide loss and the second is the exclusive nature of fluoride loss in VIII. Both of these outcomes require that the productdetermining point in the reaction process occurs early, before the disadvantage of a poor leaving group (i.e., fluoride) is manifested. In other words, the product pathway is fixed at a point when the fluoride loss process has some advantage. The key, then, is to identify a factor that would direct attack at a fluorine-bearing carbon early on the reaction coordinate. The fact that VII gives a mix of bromide and fluoride loss whereas VIII gives exclusively fluoride loss suggests that both pathways are mechanistically competitive in the trifluorophenyl bromides, but that some unique feature of VIII tips the balance completely to the fluoride loss channel. Computational data provide some insight. Transition states were computed using simpler model systems, the reaction of phenoxide with VII and VIII (the full system is too large for efficient calculations at an acceptable level). Sample transition states are given in Figure 3 and the barriers are listed in Table 2. All of the transition states are well below the entrance channel and there is a modest variation from site to site. In VII, the lowest energy transition state is for substitution at C-3 and involves the loss of fluoride. It is pictured in Figure 3a and exhibits a well-developed O–C bond and a slightly weakened C–F bond. Both are relatively close to normal lengths and the structure is similar to what would be expected for a Meisenheimer complex. In fact, the transition state leads to a stable complex that is slightly more stable. The barrier for
(b) F2Br
OH
O3S(CH2)3O
O
O3S(CH2)3O
F
F2Br
F
OH
F O
O
O3S(CH2)3O O3S(CH2)3O
O3S(CH2)3O
Figure 2. Reaction of dianion with (a) VII and (b) VIII. PT represents proton transfer and leads to two ionic products—protonated dianion (m/z 281) and deprotonated arene (m/z 209/211). Secondary product results from reaction of deprotonated arene with arene and is a fluoride complex of the arene. Structures are shown for m/z 281, 410, 471/473. For the SNAr(F) product, the regiochemistry is unknown and the product is given generically
14
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
(a)
(b) F
F
F
PhO
PhO
Br
F F
Br
F
1.688 Å
1.533 Å 2.059 Å 1.460 Å
Figure 3. Transition states for the reaction of phenoxide at (a) C-3 and (b) C-1 of VII. Carbon is green, fluorine is blue, oxygen is red, bromine is yellow, and hydrogen is white
loss of fluoride from the complex occurs late on the potential energy surface and is created by the competing effects of bond cleavage and Coulomb-repulsion release (see below). Attack at C-2 or C-5 offers similar potential energy surfaces, but the transition states are less favorable. Figure 3b is the corresponding transition state for bromide loss. It occurs earlier on the reaction coordinate and exhibits a relatively long C–O distance. This transition state is 3.5 kcal/mol less stable than the one for reaction at C-3 and is part of a concerted bromide loss process; a stable Meisenheimer intermediate could not be located. The higher barrier for bromide loss is somewhat deceptive because the surface is dropping off quickly on the addition path and the transition state is merely a shoulder on the surface; the shoulder occurs earlier on this path and, therefore, is higher in energy. In VIII, all of the transition states are about as favorable as those for VII. Again, attack at a fluorine-bearing carbon is preferred with C-2 being most favorable. Given the low barriers, the calculations are unable to give definitive guidance as to which fluoride is lost in these SNAr reactions. The computational results suggest that addition at a fluorinated carbon could compete favorably with addition at a brominated carbon, but they are not consistent with the experimental data in other ways. For example, why do the reactions have modest efficiencies? In VII, attack at C-1 to give bromide loss has a concerted transition state that is
9.5 kcal/mol below the entrance channel and leads to a process that is favorable by over 30 kcal/mol, but it has an efficiency in the 5 % range. In addition, why would VIII be 100 % selective for fluoride loss given that attack at a brominated carbon gives a transition state that is also well below the entrance channel? Both of these outcomes can be explained by assuming that the reaction system does not give statistical behavior and that the reactions are, to some extent, dictated by nature of an initially formed complex. The electrostatic maps for the trifuorobromobenzenes indicate that the C–H bonds are the sites of the most favorable interaction with an anion. An example for 2,4,6trifluorobromobenzene is shown in Figure 4a. Here, there is a large attractive potential at the hydrogen that suggest a strong hydrogen-bonding interaction, whereas the π-system is only slightly electron-poor. For comparison, the electrostatic potential for pentafluorobromobenzene is shown in Figure 4b and, in this case, the π-system is clearly electronpoor and direct attack on the π-system would be much more
(a)
(b)
Table 2. Computed Transition State Energies for Reaction of Phenoxide with VII and VIII at the MP2/6-31+G(d,p)//MP2/6-31+G(d) level (kcal/ mol) Substrate VII
VIII
a
Transition state
F
at at at at at at at
C-1 C-2 C-3 C-5 C-1 C-2 C-4
F
Energya F
SNAr SNAr SNAr SNAr SNAr SNAr SNAr
F
-11.3 -11.6 -13.0 -9.5 -9.3 -13.5 -11.5
See Methods section for details. C-1 is the carbon bearing the bromide
Br
F
F
Br
F
F
Figure 4. Electrostatic potential maps for (a) VIII and (b) IV. Map based on MP2/6-31+G(d) calculations. Blue areas are electronpoor and red areas are electron-rich, with yellow-green representing neutral surfaces. Both surfaces use the same scaling
A. D. Eanes et al.: Nucleophilic Aromatic Substitution
favorable. It is important to note that the lowest point on the potential energy surface in Figure 1 is a hydrogen-bonded complex of the naphthoxide and a C–H bond of the trifluorobromobenzene. In the higher-level calculations on the reaction of phenoxide with VIII, the hydrogen-bonded complex is calculated to be about 10 kcal/mol below the transition states in Table 2 (it also exhibits a π-stacking interaction). These observations suggest that there is a driving force to push the system initially to an interaction between the naphthoxide and one of the C–H bonds. The next assumption is that the formation of this complex localizes the SNAr reactions to the adjacent carbons. In VIII, this would be C-2 (or C-6) and C-4, but not C-1. Because the C–H bonds are flanked only by C–F bonds in VIII, fluoride loss would be the exclusive product if the hydrogen-bonded complex directed the substitution process. In VII, the potential sites for hydrogen-bonding are flanked by C–F and C–Br bonds and, therefore, attack a fluorinated or brominated carbon would be possible. In addition, a cursory study with 3,4,5-trifluorobromobenzene and 2,3,4trifluorobromobenzene (substrates where the C–H bonds are flanked by C–F and C–Br bonds) also indicates that both fluoride and bromide loss occur, with a preference for the former. Previous gas-phase work on hydrogen/deuterium exchange with halogenated benzenes indicates that anions can become localized on the potential energy surfaces of these systems [26]. The assumption that a hydrogen-bonded intermediate directs reactivity requires non-statistical behavior and removes the constraints of the Curtin-Hammett principle. Localization in the hydrogen-bonded complex also provides an explanation for the low reaction efficiencies because proton transfer reactions for VII and VIII are expected to have barriers (see above); the system could be locked onto the proton transfer pathway and rarely explore the favorable SNAr pathways before the complex dissociates. Although it is a large system for non-statistical behavior, the rigidity can contribute to the system’s inability to fully explore the potential energy surface [27, 28]. Taken together, these rationalizations provide an explanation for the low efficiencies as well as the exclusive attack at a fluorinated carbon in VIII. The last question is how the loss of fluoride from the Meisenheimer complex can occur with a barrier that is small enough to compete with the very facile bromide loss when both pathways are possible from a hydrogen-bonded complex. In Figure 5, the potential energy surface for fluoride loss from VIII is presented. The pathway was generated by simply extending the C–F distance stepwise from the Meisenheimer complex. The pathway is surprisingly complicated and involves a number of species that could be potential intermediates (the surface is too coarse to identify transition states between these possible intermediates). The departing fluoride forms a series of hydrogen-bonded complexes with the substitution product before separation occurs. Three structures are shown in Figure 6 and each involves the fluoride forming a hydrogen bond to an aryl
15
Figure 5. Potential energy surface for nucleophilic aromatic substitution of the naphthoxide dianion at C-4 of VIII. Reaction coordinate is the distance between the fluoride leaving group and C-4 of VIII. Surface based on single path at MP2/6-31+G(d,p)//HF/6-31+G(d) level
hydrogen. In essence, the fluoride is hopping along the edge of the arene until the force from the internal Coulomb repulsion overwhelms the forces associated with hydrogen bonding. The structure with an 8 Å C–F separation in Figure 6 represents the point where the hydrogen bonding with the arene begins to break down. This pathway leads to a counterintuitive situation in that the distance between the charge centers (fluoride and sulfonate) in the ion–ion complex decreases initially before rapidly increasing once the hydrogen bonding interaction severs. The key feature of the surface is that like the proton transfer, the reaction path does not face the intrinsic endothermicity of the process immediately because interactions such as hydrogen bonding can mitigate the disadvantage of fluoride expulsion until the release of Coulomb repulsion is sufficient to drive the process forward. The path in Figures 5 and 6 is only a single example of many possible paths. The complexity, and likely variability, of the pathways for fluoride departure suggest that the transition state opens into an expansive phase space, which would make the process effectively irreversible once the C–F bond is cleaved. The absence of any opportunity for hydrogen bonding to the arene in pentafluorophenyl bromide, IV, might explain the absence of a fluoride loss channel with this substrate. Together, these assumptions lead to a situation where product determination occurs early on the surface, well before the enthalpic disadvantage of a fluoride leaving group can be fully realized. The strong hydrogen bonding that is observed on the surfaces for fluoride loss would not be likely with other leaving groups, and the fluorinated systems may be exceptional cases.
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1.80 Å
2.8 Å
3. The “element effect” is an intrinsic feature of SNAr reactions and is manifested in the gas phase. It is a powerful driving force and can outweigh the large thermodynamic disadvantage of fluoride versus bromide loss, which is many orders of magnitude more significant in the gas phase. 4. Doubly-charged systems present complicated surfaces where stabilizing interactions, such as hydrogen bonding, can mitigate the disadvantages of intrinsically endothermic processes until the combined advantages of Coulomb repulsion release and expanded phase space can drive the system to enthalpically-favorable, singly-charged products.
References 1.85 Å
2.15 Å
6.0 Å
8.0 Å
Figure 6. Selected structures on the nucleophilic aromatic substitution pathway of the naphthoxide dianion attacking C4 of VIII. Carbon is green, fluorine is blue, oxygen is red, bromine is yellow, sulfur is black, and hydrogen is white
Conclusions The reactions of a dianion nucleophile with activated aryl bromides point to a number of interesting aspects of nucleophilic aromatic substitution as well as unusual features of the reactions of doubly-charged ions. 1. In systems that are limited to SNAr reactions at a single center (i.e., the bis-trifluoromethylbromobenzenes), the reactivity follows the expected trends for activated processes. The electron-withdrawing trifluoromethyl groups are most effective in activating the SNAr reaction when they are in the ortho or para position. 2. When a sufficiently acidic proton is available, proton transfer easily out-competes an SNAr reaction. This is presumably an entropic effect. The release of Coulomb energy is efficient in proton transfer processes and the dianion has an effective proton affinity that implies up to a 50 % release of Coulomb energy at the rate-determining transition state for proton transfer.
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