Reflex Carbocation Release from Covalent Molecules by Endogenous Free Radicals.

Carbocations are pervasive in contemporary organic synthesis, so new and innocuous methods of making them are always desirable. A theoretical approach revealed that compounds in which radical generation takes place may release carbocations advantageously. The radical types and molecular substructures that promote this effect were identified. The best substructures were found to be 1,3-dicarbonyl compounds, particularly those based on the Meldrum's acid theme. Sulfate esters and dithiane rings could also be employed. Radicals generated on oxygen atoms or ethyne units were particularly effective. For these species, carbocation release could be reflex, that is, concurrent with radical generation. Only small radical enhancements were observed for release of lithium cations because of the ionic character of most of the precursors. Ethyne units could be incorporated as spacers between the radical center and the site of carbocation generation. Moreover, the enhancement was transmitted down polyethyne chains of at least six units.

Introduction

In a 1974 review, Hayon and Simic drew attention to the greater propensity of certain free radicals to deprotonate compared with parent compounds.[1] Theoretical studies have since confirmed the reality of this enhanced acidity phenomenon.[2,3] The importance of the effect as a key step in processes such as base-promoted homolytic aromatic substitution reactions[4−6] and certain one-electron redox transformations of Coenzyme A esters[7−9] has also been pointed out.

Recently, my group demonstrated that suitably sited radical centers enhanced the acidity not only of carboxylic acids but also of sulfinic and sulfonic acids. The acidity of other proton donor molecules, particularly 1,3-dicarbonyl compounds, could also be formidably increased by similar means.[10] The label “RED-shift” (for radical enhanced dissociation) was coined as a short and handy acronym to refer to the phenomenon. Radicals centered on C-, N-, and O-atoms induced RED-shifts, provided they were sufficiently close to the acid group and appropriately oriented. Huge enhancements were induced by alkoxyl radical centers and by ethynyl radical units such that 1,3-dicarbonyl compounds connected to them became carbon-based superacids.[11] Microhydration studies had revealed that acids with negative pKas, that is, pKas in the range of mineral acids, spontaneously dissociated on association with only a few (four or five) water molecules.[12] The authenticity of the computed RED-shifts of bicarbonate,[13] carboxyl, carboxyethynyl, and hydroperoxyl radicals was substantiated by computations of their microhydration behavior.[14]

The large magnitudes of many of the deprotonation enhancements suggested the intriguing possibility that radical centers might also induce dissociation of neutral species with release of a carbocation instead of a proton.

The process is generalized in Scheme where the model compound 1 consists of a potential radical center X attached to a substructure A, capable of supporting a negative (−ve) charge, connected with a potential carbocation +CR3. The corresponding radical 4 is then an intermediate for which heterolytic dissociation to the carbocation and radical anion could be significantly enhanced. A sufficiently large enhancement might lead to spontaneous release of the cation at the moment of radical generation. Carbocation generation for Friedel–Crafts and other preparative processes usually requires the use of strong and corrosive Lewis or Brønsted acids. A likely advantage of this radical-stimulated approach would be that carbocations could be generated by the “soft” initiation methods usually applied for radicals, that is, heat, photoredox catalysis, or UV–vis irradiation.

Scheme 1

Radical-Stimulated Carbocation Generation

Computational methods were employed to examine the basic premise of Scheme applied to different X–A structures and with a variety of cation types. It was found that significant enhancements were indeed predicted for release of thermodynamically stabilized cations. This paper describes a method of assessing the magnitude of the effect and an investigation of what structural features in the precursors are needed for the phenomenon to occur.

Results and Discussion

Quantification of Enhancement of Cation Production from Radical Precursors

Most radical intermediates are short-lived, so experimental methods for determination of the dynamics of their heterolytic cation generation would inevitably be problematic. A theoretical approach was therefore used to map the outlines of the structural and energetic constraints on the process. A computational method that would be applicable to n class="Chemical">free radicals and would be easy to apply was sought.

A previous study of 12 radical reaction types compared results from the high-level composite ab initio G4 method,[15] with those obtained with 23 different density functional theory (DFT) functionals (plus the MP2 ab initio method).[13] The CAM-B3LYP functional[16] was found to perform best with radical species and gave lowest mean absolute deviations (MADs). A second benchmarking study was carried out, this time including second row elements, specifically sulfur.[17] Free energies were obtained for 9 diverse radical reactions with 31 different DFT functionals and compared with both G4 and the extrapolated complete basis limit of a series of CCSD(T)[18−20] calculations. Comparisons of the MADs from both high-level methods indicated that M05,[21] PBE0 (PBE1PBE),[22] and LC-ωPBE[23] were the most accurate and that CAM-B3LYP also gave very satisfactory results. The CAM-B3LYP and the PBE0 functionals were chosen for this study, and full optimizations were carried out with the 6-311+G(2d,p) basis set. Solvent effects were modeled with radii and non-electrostatic terms from Truhlar and co-workers’ solvent model density (SMD) solvation model and/or with the conductor-like polarizable continuum model (CPCM) model.[24]

The ease with which neutral radical 4 ionizes to carbocation 3 will certainly depend on the stabilization of the accompanying radical anion 5. The free energies for +CR3 production from a radical (4) (ΔG°R) and from the corresponding model (1) (ΔG°M) in which the unpaired electron (upe) had been replaced by an H-atom were computed for sets of representative molecules. The difference in these quantities, ΔΔG°, afforded a useful measure of the enhancementPositive ΔΔG° values indicate radical enhancement of cation release, whereas negative values would correspond to radical inhibition of cation release.

Search for Suitable Radical Platforms

Heterolytic generation of +CR3 carbocations from 1 will release the same radical anion •X–A– (5) as that when an acid radical •X–A–H deprotonates. As a starting point, therefore, X–A units that had been found to provide large deprotonation RED-shifts[11] were chosen for study. Scheme displays the set selected to investigate release of the t-butyl-cation. This included carbonate ester radical 6, propiolate ester radical 9, sulfonate ester radical 10, peroxyl radical 11, the 5-methylenyl-Meldrum’s acid 12, 5-oxyl-Meldrum’s acid 13 and 5-ethynyl-Meldrum’s acid 14 derivatives [5-(tert-butyl)-5-hydroxy-2,2-dimethyl-1,3-dioxane-4,6-dione derivatives], as well as the 2-ethynyl-1,3-dithiane derivative 15. The computed enthalpies ΔH°R and free energies ΔG°R for Me3C+ release are in Table , along with the enhancement factors ΔΔG°.

Scheme 2

Release of tert-Butyl Cation from Selected Radical Platforms

Table 1

Energetics of Release of the t-Butyl Cation in Water as Solventa

heterolysis	DFTb	ΔH°R	ΔG°R	ΔΔG°
6 → 6– + +CMe3	i	26.1	13.1	12.9
9 → 9– + +CMe3	i	25.9	14.4	10.3
10 → 10– + +CMe3	ii	6.3	–6.5	5.0
11 → 11– + +CMe3	ii	43.7	31.4	12.9
12 → 12– + +CMe3	i	17.5	5.2	12.9
13 → 13– + +CMe3	ii	–4.0	–19.0	38.0
14 → 14– + +CMe3	ii	–4.3	–19.1	31.3
15 → 15– + +CMe3	i	22.1	9.14	47.8

Energies in kcal/mol.

(i) CAM-B3LYP/6-311+G(2d,p); (ii) BPE1BPE/6-311+G(2d,p).

Modest enhancements (3–13 kcal/mol) were calculated for heterolytic generation of Me3C+ from carbonate radical 6, propiolate radical 9, hydrogen sulfate radical 10, peroxyl radical 11, and 5-methylenyl-Meldrum’s acid 12. However, four of these ionizations were endenthalpic and endergonic and so would not be practicable under mild conditions. t-Butyl cation release from the 2-ethynyl-1,3-dithiane radical 15 showed a very large enhancement (47.8 kcal/mol) relative to the model, but again the process was too energetically uphill for it to occur spontaneously.

On the other hand, the releases of Me3C+ by the 5-oxyl-Meldrum’s radical 13 and by 5-ethynyl-Meldrum’s radical 14 were strongly exergonic, and large enhancements (38.0 and 33.4 kcal/mol) were predicted. The Meldrum platform appeared to be the most promising as a core structure for radical-to-cation transformations. In accord with expectation, these results also indicated that significant thermodynamic stabilization of the released carbocation would be needed for spontaneous release.

Investigation of Carbocation Suitability

In view of the favorable results obtained for Me3C+ release, Meldrum’s linked radicals were chosen as platforms to study release of a range of cations with differing thermodynamic stabilizations. The computed energies and enhancement factors for release of some primary, allyl, benzyl, and tertiary carbocations by 5-oxyl-Meldrum’s 16 (process H1) and 5-ethynyl-Meldrum’s 17 (process H2) are listed in Table . Interestingly, the table demonstrates that the radical center enhances cation release in every case. No examples of radical inhibition of cation release were discovered.

Table 2

Energetics of Release of Diverse Carbocations in Water as Solventa

entry	process	R3C+	ΔH°R	ΔG°R	ΔΔG°
1	H2	FCH2+	44.0	32.3	33.5
2	H2	MeOCH2+	1.6	–10.1	33.1
3	H1	MeOCH2+	2.6	–8.7	47.3
4	H1	CH2=CHCH2+	23.3	11.1	43.2
5	H1	MeOCH5CHCH2+	–5.4	–16.1	43.3
6	H1	PhCH2+	14.7	2.6	42.6
7	H1	4-MeOC6H4CH2+	13.0	1.3	43.2
8	H2	4-MeOC6H4CH2+	6.0	–5.6	33.3
9	H1b	Me2(MeO)C+	b	b	b
10	H2	Me2(MeO)C+	–27.3	–42.1	33.3

Energies in kcal/mol; DFT with CAM-B3LYP/6-311+G(2d,p).

Dissociated straight to 13 and Me2(MeO)C+.

Although allyl and benzyl cation releases (entries 4 and 6) were strongly enhanced by the radical center, both were endergonic and so experimentally impracticable. Introduction of the electron-donating MeO group led to exergonic processes for release of the primary methoxymethyl cation (both radical platforms; entries 2 and 3). Similarly, release of the 1-methoxyallyl and 4-methoxybenzyl cations (entries 5 and 8) was also exergonic. As might be expected, introduction of the MeO group to the t-butyl cation led to very favorable energetics (entries 9 and 10). The optimization for structure 16 (CR3 = Me2(MeO)C+) led directly to the dissociation products radical anion 13– and carbocation Me2(MeO)C+. This implied that generation of radical 16 (CR3 = Me2(MeO)C+) [and probably 17 (CR3 = Me2(MeO)C+) as well] would lead to concerted (spontaneous) carbocation formation.

Effect of Solvent on Carbocation Release

The difference in solvation between the neutral radical precursors and the charged products was expected to have a considerable impact on the heterolytic cleavage. The magnitude of solvation effects was probed for two representative processes. First, release of the primary MeOCH2+ cation from the carbonate radical precursor 18 (process H3 in Table ) (together with the corresponding model) was examined. Second, the release of the t-butyl cation from the 5-oxyl-Meldrum’s radical 13 (and model) (process H4 in Table ) was studied. The SMD method, on the basis of the quantum mechanical charge density of a solute molecule interacting with a continuum description of the solvent, was employed.[24] The free energies for the two processes, for solvents ranging from water to n-heptane, as well as the enhancement factors relative to the nonradical models, are recorded in Table .

Table 3

Effect of Solvents on Heterolytic Cation Releasea

solvent	δb	MeOCH2+ (H3)		Me3C+ (H4)
		ΔG°R	ΔΔG°	ΔG°R	ΔΔG	Δr(CC)c
H2O	23.5	7.7	13.8	–19.0	38.0	0.112
MeOH	14.3	8.9	14.9	–15.9	37.0	0.115
DMSO	12.9	18.2	16.1	–9.6	38.5	0.096
MeCN	11.9	16.4	15.8	–11.6	40.3	0.097
Me2C=O	9.8	20.3	15.9
THF	9.5	31.5	16.3	0.9	38.4	0.090
n-C7H16	7.4	77.4	17.1	43.5	37.5	0.078

Energies in kcal/mol; DFT with PBE1PBE/6-311+G(2d,p).

Standard Hildebrand solvent parameters in cal1/2/cm3/2.

Extension of the bond length in Å (radical—model) from Me3C to the C atom of attachment in Meldrum’s unit.

Extension of the bond length in Å (radical—model) from n class="Chemical">Me3C to the C atom of attachment in Meldrum’s unit.

The free energy for MeOCH2+ release from radical 18 increased by nearly 70 kcal/mol (less favorable) as the polarity of the solvent decreased from water to n-heptane. No solvent was found in which this process would be exergonic. However, although the free energy of Me3C+ release from radical 13 increased by about 60 kcal/mol through the series of solvents, the reaction was favorably exergonic in methanol, dimethyl sulfoxide (DMSO), and acetonitrile, as well as in water. The enhancement factors ΔΔG° for both processes H3 and H4 were positive and very substantial for H4. Interestingly, these enhancements changed by only a small amount as the solvent was varied. Not unexpectedly therefore, the change in solvation on going from the neutral model with charged products to the neutral radical with charged products remained fairly constant, irrespective of solvent properties. Water was unquestionably the solvent of choice for advantageous energetics. However, methanol or acetonitrile could be used, with little or no diminution in enhancement, for covalent precursors insoluble in water.

The enhancement of ionic dissociation of the 5-oxyl-Meldrum’s radical (13) was accompanied by a lengthening of the bond from its CMe3 group to its Meldrum’s unit compared to that in the nonradical model (13H). Furthermore, there was a trend toward greater bond extension [Δr(CC) in Table ] as the exergonicity increased for the more polar solvents (see Table ). For the carbonate series (18) the C–O bond from the MeOCH2 group to the carbonate unit was also longer in the radical than in the model but the extension, 0.011–0.015 Å, depending on solvent, was much smaller.

Release of Acylium and Lithium Cations

Radical enhancement of release of n class="Chemical">acylium and benzoylium cations was also studied for the set of precursor radicals (and corresponding models) shown in Scheme .

Scheme 3

Radical Platforms for Release of Acyl Type Cations

The computed enthalpies, free energies, and enhancement factors are in Table . The 1,5-dihydro-2H-pyrrol-2-one unit of 19a was chosen because of the potential resonance stabilization of the anions produced on ionization. A modest enhancement of acylium release from radical 19a was obtained, but the process was impractically endergonic (Table ). Similarly, although the releases of both PhCO+ and MeCO+ were significantly enhanced for the ethynyl platforms 21a,b, the energetics were again very unfavorable. However, acylium release was exergonic from both 5-oxyl-Meldrum’s 22a and 5-ethynyl-Meldrum’s 23a precursors and large enhancement factors were observed for the radicals. Release of PhCO+ was also favorable for both 22b and 23b.

Table 4

Energetics for Release of Acylium-Type Cations in Acetonitrilea

heterolysis	R	ΔH°R	ΔG°R	ΔΔG°
19a → 19a– + RCO+	Me	65.2	52.8	13.2
21a → 21a– + RCO+	Me	54.5	45.1	19.0
21b → 21b– + RCO+	Ph	57.1	47.3	19.0
22a → 13– + RCO+	Me	0.9	–10.7	37.3
22b → 13– + RCO+	Ph	6.2	–4.5	26.4
23a → 14– + RCO+	Me	–9.6	–21.7	35.4
23b → 14– + RCO+	Ph	–8.3	–20.8	35.6

Energies in kcal/mol; PBE1PBE/6-311+G(2d,p); scrf = SMD(acetonitrile).

Because of the importance of lithium ions in battery technology, release of this alkali metal cation from carbonate 24, carboxyethynyl 25, ethynyl 26, and Meldrum’s radical-containing platforms was also examined (Scheme ). The computed energies are in Table . For all of these platforms, the heterolyses were endergonic. The smallness of the enhancement factors obtained for Li+ release from the radical forms of the carbonate and carboxyethynyl species (Table ) can be attributed to their salt-like character. The calculated long C–Li bond (2.18 Å) in model-lithiated Meldrum’s acid 27H, together with the large positive charge on Li (0.88), indicated it was virtually an ionic compound. The C–Li bond was slightly shorter (2.07 Å) in the radical 27 and the charge on Li was smaller (0.65), suggesting lower ionic character. In conformity with this, the computed ΔΔG° was actually marginally negative (−3.6). For the ethynyl-Meldrum’s platform, the minimum energy structure of the model had the Li-atom attached to one of the O-atoms and in the optimized radical 28, it was attached to the terminal ethyne C atom. Not only was the process endergonic but virtually no enhancement was found (Table ).

Scheme 4

Radical Platforms for Release of Lithium Cations

Table 5

Energetics for Release of Lithium Cations in Water and THFa

heterolysis	solvent	ΔH°R	ΔG°R	ΔΔG°
24 → 6– + Li+	H2O	17.0	9.5	8.5
24 → 6– + Li+	THF	35.5	28.2	14.0
25 → 9– + Li+	THF	30.7	24.0	14.7
26 → 21– + Li+	H2O	17.8	10.1	9.6
26 → 21– + Li+	THF	32.7	25.0	10.4
27 → 27– + Li+	H2O	13.7	7.1	–3.6
28 → 14– + Li+	THF	37.3	30.46	3.3

Energies in kcal/mol; PBE1PBE/6-311+G(2d,p).

Influence of Ethyne Radicals and Multiple Ethyne Spacer Units

The cation release process was tolerant of the introduction of the two-carbon ethyne spacer between the upe and the cation (see tables above). The effect of lengthening this spacer by more ethyne units was therefore studied. Small hydrocarbon cages are known to transmit spin density across their centers.[25,26] The huge γ-H-atom hyperfine splitting in the electron paramagnetic resonance spectrum of the bicyclo[1.1.1]pent-1-yl radical pointed to its cage as by far the most effective.[27,28] This spacer unit was also investigated.

Scheme compares the computed ΔG°M and ΔG°R values and the enhancement factors ΔΔG°, for release of the 2-methoxyprop-2-yl cation from carbonate radical, with data for the analogs with a bicyclo[1.1.1]pentane or with an ethyne spacer. Cation release from the carbonate radical was exergonic and with a modest enhancement (13.5 kcal/mol) compared with the model. With the ethyne spacer, heterolytic dissociation was computed to release the 2-methoxyprop-2-yl cation but accompanied by CO2 and the C2O–• radical anion. The exergonicity was significantly increased, as was the enhancement factor. On the other hand, with the bicyclo[1.1.1]pentane spacer, ΔΔG° was close to zero such that enhancement from the upe was completely suppressed.

Scheme 5

Effect of Spacers on Release of t-Bu Cations

Computed energies with the PBE1PBE/6-311+G(2d,p) method and the SMD solvent continuum model with water.

Because the ethyne spacer was so effective, the result of increasing the number of ethyne spacer units was also explored. Release of the t-butyl cation from Meldrum’s precursor radicals with up to 6 ethyne spacers (14; n = 1–6) and release of the 2-methoxyprop-2-yl cation from similar precursors with up to 6 ethyne spacers (29) were examined. Additionally, release of 2-methoxyprop-2-yl cation from the 1,3-dithiane radicals 15 was studied. Finally, release of lithium ions from the ethynyllithium precursors 26, having up to 7 spacers, was investigated in tetrahydrofuran (THF). The computed free energies are in Tables –9 (see also the Supporting Information).

Table 6

Energetics for Release of the +CMe3 Cation (7) from Polyethynyl Meldrum’s Precursors 14

n	ΔG°M (model 14Hn)	ΔG°R (radical 14n)	ΔΔG°	r(C–C)/Åc
1a	13.48	–19.93	33.41
1b	12.26	–19.08	31.34	1.620
2b	9.34	–14.48	23.82	1.621
3b	6.63	–12.69	19.32	1.623
4b	6.87	–10.65	17.52	1.626
5b	5.12	–9.86	15.37	1.634
6b	4.70	–7.45	12.15	1.632

CAM-B3LYP/6-311+G(2d,p) with CPCN(water).

PBE1PBE/6-311+G(2d,p) with SMD(water) values in kcal/mol.

r(C–C) is length of the bond from the platform A to the leaving cation in the radicals (•XA-cation).

Table 9

Energetics for Release of the Li(+) Cation from Lithium Polyethynyl Radicals 26 in THFa

n	ΔG° (model 26Hn)	ΔG° (radical 26n)	ΔΔG°	r(C–Li)/Åb
1	35.32	24.95	10.37	1.993
2	32.80	26.29	6.51	2.003
3	31.05	25.23	5.82	2.005
4	30.48	25.25	5.22	2.005
5	29.20	25.13	4.07	2.005
6	29.75	25.67	4.08	2.003
7	29.79	22.65	7.14	2.002

PBE1PBE/6-311+G(2d,p) with SMD(THF); energy values in kcal/mol.

r(C–Li) is length of the bond from the platform A to the leaving Li cation in the radicals (•XA–Li).

CAM-B3LYP/6-311+G(2d,p) with CPCN(n class="Chemical">water).

Release of the t-butyl cation from Meldrum’s species 15H-1 and 15-1 was investigated using both the CAM-B3LYP and PBE1PBE methods (Table , top two rows). The respectable agreement of the energies obtained demonstrates the comparability of the two methods. The tables show that ΔG°M for all model precursors became less endergonic (or more exergonic) as the length of the polyethynyl spacer increased. The dissociations of radicals 14 to Me3C+ became less exergonic as the spacer increased in length, whereas the dissociation of analogous 29 to Me2(MeO)C+ varied little in exergonicity (Tables and 7). Loss of the Me2(MeO)C+ cation from dithiane radical 15 became more exergonic as the length of the spacer increased (Table ), but ΔG°M decreased in parallel such that the enhancement decreased by only a small amount. ΔG°R for loss of Li+ from precursors 26 varied little with spacer length (Table ).

Table 7

Energetics for Release of the +C(MeO)Me2 Cation from Polyethynyl Meldrum’s Precursors 29a

n	ΔG° (model 29Hn)	ΔG° (radical 29n)	ΔΔG°	r(C–C)/Åb
1	–8.80	–42.05	33.25	1.613
2	–11.90	–46.08	34.18	1.614
3	–13.14	–46.30	33.17	1.614
4	–14.64	–46.40	31.76	1.614
5	–16.22	–47.56	31.34	1.614
6	–15.62	–45.64	30.02	1.614

CAM-B3LYP/6-311+G(2d,p) with CPCN(water); values in kcal/mol.

r(C–C) is length of the bond from the platform A to the leaving cation in the radicals (•XA-cation).

Table 8

Energetics for Release of the +C(MeO)Me2 Cation from Polyethynyl Dithiane Precursors 15 in Watera

n	ΔG° (model 15Hn)	ΔG° (radical 15n)	ΔΔG°	r(C–C)/Åb
1	36.81	–8.22	45.03	1.562
2	29.97	–11.95	41.91	1.567
3	24.12	–16.45	40.57	1.569
4	19.83	–19.00	38.83	1.569
5	16.64	–19.91	36.56	1.569
6	16.33	–22.20	38.53	1.570

PBE1PBE/6-311+G(2d,p) with SMD(water); values in kcal/mol.

r(C–C) is length of the bond from the platform A to the leaving cation in the radicals (•XA-cation).

CAM-B3LYP/6-311+G(2d,p) with CPCN(n class="Chemical">water); values in kcal/mol.

Large enhancement factors ΔΔG° were computed for dissociation of all Meldrum’s species and the dithiane precursors to carbocations. Only modest enhancements were obtained for Li+ release from the polyethynyl precursors 26. The variation in the ΔΔG° enhancements as the additional spacer units were added is illustrated in Figure .

Figure 1

Plots of enhancement factors ΔΔG° (kcal/mol) as a function of the number of C atoms (C) in the chains of ethyne spacers for radicals 14, 29, 15, and 26.

As expected, ΔΔG° decreased for the dissociations of all radical species as the length of the polyethyne spacer chains increased. However, the remarkable result that became apparent was the ability of the spacer chains to transmit the influence of the upe through more than 6 or 7 ethyne units (up to 14 C atoms!). Dissociations to carbocations were still significantly enhanced even when the upe and breaking bond were (formally) so distant. A similar ability of polyethynyl spacers to transmit RED-shift was observed in the analogous deprotonation reactions.[11]

As mentioned above, the thermodynamic stabilities of the radical anions •X–A– (5) formed on release of the cations will be a key factor. These same radical anions are, of course, released in deprotonations of acid radicals •X–A–H. The distribution of charge and spin in these species will impact both their solvation and their thermodynamic stabilization. The previously observed trend was of larger RED-shifts for radicals with charge delocalized away from their anionic centers, coupled with spin density distributed toward these centers.[10,11] This same site exchange of spin with charge, in the released radical anions, undoubtedly also plays a leading role in cation release.

It might be supposed that the length of the bond from the platform A to the leaving cation in the radicals (•XA-cation), that is, r(C–C) for 14, 29, and 15 and r(C–Li) for 26, would reflect the exergonicity of cation loss. However, the computed bond lengths for the radicals of Tables –9 (final columns) show only very minor changes and do not correlate well with the ΔG°R values.

Conclusions

The heterolytic dissociations of neutral covalent species were greatly enhanced for structures containing radical centers adjacent to potential cations. Such enhancements took place when the bonds breaking heterolytically were C–CR3, C–C(O), O–CR3, N–C(O), O–Li, and C–Li types. For exergonic heterolytic dissociations, tert-carbocations were required. Electron-releasing groups, particularly MeO substituents attached to the cationic centers, facilitated the process. Sulfate ester (10) and dithiane (15) radical platforms promoted exergonic releases of cations. However, the most successful substructures that gave exergonic heterolytic release of the widest variety of cations, were the 5-oxyl-Meldrum and 5-ethynyl-Meldrum radical types (16, 17 etc.). It is very probable that other 1,3-dicarbonyl core structures would work nearly as well. Spontaneous cation release, concerted with radical generation, can be anticipated for 3-methoxyallylium and 2-methoxypropylium cations from these structures. Radical enhancements of Li cation release were small for all platforms, probably because the precursors were already salt like or at least partly ionic in character. It was no surprise that cation release took place most readily in water as solvent, but methanol, DMSO, and acetonitrile also permitted large enhancements.

In every case of carbocation generation examined, the presence of an upe either enhanced the process or had little effect. No case of radical inhibition of carbocation release was found. The only retardation discovered was for Li+ cation generation from Meldrum-lithium radical ((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)lithium, 27), and that was very small.

For large enhancements, the radical center X and spacer A in the •X–A–CR3 species needed to be single C, N, or O atoms. Sizeable enhancements were also achieved for X–A = O–C–O and O–S–O. The cage bicyclo[1.1.1]pentyl structure did not transmit the enhancement, and it is safe to conclude other saturated hydrocarbon spacers would also block the effect. A remarkable finding was that the ethyne spacer in almost every radical platform led to sizeable enhancements. Notably too, polyethyne spacers gave rise to long-range enhancement. Radicals generated six or seven ethyne units away from the cationic center were still effective in enhancing cation release. It is worth mentioning the complementarity of these fragmentations to those of radical substrates that see anionic leaving groups, such as acetate anions or the loss of phosphate anions from deoxyribose radicals.[29−31]

Carbocations are extremely important in contemporary organic synthesis[32] as well as in cationic polymerizations. Friedel–Crafts alkylations and acylations are amongst the most important routes to functionalized aromatic compounds. Wagner–Meerwein skeletal rearrangements, homoallylic/cyclopropyl rearrangements, pinacol rearrangements, and others remain important in syntheses of numerous natural products. Chiral carbocation couplings with nucleophiles constitute valuable routes to asymmetric syntheses. To date, for most of these processes, either strong mineral acids or corrosive Lewis acids are required. Several of the radical platforms described above have the potential to deliver a specific carbocation as a reflex on generation of the upe. No strong acids or toxic metals need to be involved, and neutral conditions will prevail. Excellent control of initiation can be achieved when the radicals are generated photochemically or by mild heating. Practical applications of the radical-induced production of carbocations can therefore be anticipated as mild alternatives for many of these preparations.

Experimental Section

DFT calculations were carried out using the Gaussian 09 suite of programs.[33] Results were obtained with two different DFT methods. First, the CAM-B3LYP functional[16] with the 6-311+G(2d,p) basis set was employed with the CPCM continuum model[24b] with water as solvent. This model is derived from the COSMO model. Default values of the keywords Alpha, Radii, TSNUM, and TSARE were employed. On the basis of previous work with free radicals, the CAM-B3LYP functional, which combines the hybrid qualities of B3LYP with the long-range correction proposed by Tawada et al.[34] gave the best results in comparison with G4 (MAD: 2.5 kcal/mol). A second benchmarking study including second row elements indicated that M05,[21] PBE0 (PBE1PBE),[22] and LC-PBE[23] were the most accurate and that CAM-B3LYP also gave very satisfactory results. Full optimizations were carried out with the PBE1PBE/6-311+G(2d,p) method. Solvent effects were modeled with radii and non-electrostatic terms from Truhlar and co-workers’ SMD solvation model.[24a] Vibrational frequency calculations were implemented so that GS (no imaginary frequencies) and TS status could be checked (one imaginary frequency), and enthalpies and free energies were adjusted for zero point and thermal corrections to 1 atm and 298 K. The lowest energy structures of conformationally flexible molecules were, in most cases, estimated from related molecules computed previously.[10,11] The influence of the six-member ring conformation was shown previously to be small. In cases of doubt, the same conformation was employed for the model species as that for the radical species.