Ketene reactions with tertiary amines.

Tertiary amines react rapidly and reversibly with arylketenes in acetonitrile forming observable zwitterions, and these undergo amine catalyzed dealkylation forming N,N-disubstituted amides. Reactions of N-methyldialkylamines show a strong preference for methyl group loss by displacement, as predicted by computational studies. Loss of ethyl groups in reactions with triethylamine also occur by displacement, but preferential loss of isopropyl groups in the phenylketene reaction with diisopropylethylamine evidently involves elimination. Quinuclidine rapidly forms long-lived zwitterions with arylketenes, providing a model for catalysis by cinchona and related alkaloids in stereoselective additions to ketenes.

The bisketene radical cation and its formation by oxidative ring-opening of cyclobutenedione.

Parent cyclobutenedione 1 was photolyzed and ionized in an Ar matrix at 10K. The bisketene 2 that results in both cases (in the form of its radical cation after ionization) was characterized by its IR spectrum and by high-level quantum chemical calculations. Experiment and theory show that the neutral bisketene has only a single conformation where the two ketene moieties are nearly perpendicular, whereas the radical cation is present in two stable planar conformations. The mechanism of the ring-opening reaction, both in the neutral and in the radical cation, is discussed on the basis of calculations. In the latter case it is a nonsynchronous process that involves an avoided crossing of states.

N-pyrrolylketene: a nonconjugated heteroarylketene.

N-Pyrrolylketene (5) is calculated to be destabilized and nonconjugated, with a preferred geometry with the pyrrolyl ring orthogonal to the ketenyl group. Ketene 5 is generated from N-pyrrolylacetic acid (7) with use of Mukaiyama's reagent, and reacts with imines forming ß-lactams 10, with a product ratio correlation of log(cis/trans) with σ(+). Photolysis of N-diazoacetylpyrrole (14) in MeOH gives methyl N-pyrrolylacetate (15) from 5 and also ester 17, evidently by trapping of 2-(1-pyrrolylketene) (21), formed by a new vinylogous Wolff rearrangement.

FRET quenching of photosensitizer singlet oxygen generation.

The development of activatable photodynamic therapy (PDT) has demonstrated a utility for effective photosensitizer quenchers. However, little is known quantitatively about Forster resonance energy transfer (FRET) quenching of photosensitizers, even though these quenchers are versatile and readily available. To characterize FRET deactivation of singlet oxygen generation, we attached various quenchers to the photosensitizer pyropheophorbide-alpha (Pyro) using a lysine linker. The linker did not induce major changes in the properties of the photosensitizer. Absorbance and emission wavelength maxima of the quenched constructs remained constant, suggesting that quenching by ground-state complex formation was minimal. All quenchers sharing moderate spectral overlap with the fluorescence emission of Pyro (J > or = 5.1 x 10(13) M(-1) cm(-1) nm4) quenched over 90% of the singlet oxygen, and quenchers with weaker spectral overlap displayed minimal quenching. A self-quenched double Pyro construct exhibited intermediate quenching. Consistent with a FRET deactivation mechanism, extension of the linker to a 10 residue polyproline peptide resulted in only the quenchers with spectral overlap almost 2 orders of magnitude higher (J > or = 3.7 x 10(15) M(-1) cm(-1) nm4) maintaining high quenching efficiency. Overall, there was good correlation (0.98) between fluorescence quenching and singlet oxygen quenching, implying that fluorescence intensity can be a convenient indicator for the singlet oxygen production status of activatable photosensitizers. Uniform singlet oxygen luminescence lifetimes of the compounds, along with minimal triplet state transient absorption were consistent with quenchers primarily deactivating the photosensitizer excited singlet state. In vitro, cells treated with well-quenched constructs demonstrated greatly reduced PDT induced toxicity, indicating that FRET-based quenchers can provide a level of quenching useful for future biological applications. The presented findings show that FRET-based quenchers can potently decrease singlet oxygen production and therefore be used to facilitate the rational design of activatable photosensitizers.

Structural effects on interconversion of oxygen-substituted bisketenes and cyclobutenediones.

Cyclobutenediones 5 disubstituted with HO (a), MeO (b), EtO (c), i-PrO (d), t-BuO (e), PhO (f), 4-MeOC6H4O (g), 4-O2NC6H4O (h), and 3,4-bridging OCH2CH2O (i) substituents upon laser flash photolysis gave the corresponding bisketenes 6a-i, as detected by their distinctive doublet IR absorptions between 2075 and 2106 and 2116 and 2140 cm-1. The reactivities in ring closure back to the cyclobutenediones were greatest for the group 6b-e, with the highest rate constant of 2.95 x 10(7) s-1 at 25 degrees C for 6e (RO = t-BuO) in isooctane, were less for 6a (RO = OH, k = 2.57 x 10(6) s-1 in CH3CN), while 6f-i were the least reactive, with the lowest rate constant of 3.8 x 10(4) s-1 in CH3CN for 6h (RO = 4-O2NC6H4O). The significantly reduced rate constants for 6f-i are attributed to diminution of the electron-donating ability of oxygen to the cyclobutenediones 5f-h by the ArO substituents compared to alkoxy groups and to angle strain in the bridged product cyclobutenedione 5i. The reactivities of the ArO-substituted bisketenes 6f-h in CH3CN varied by a factor of 50 and gave an excellent correlation of the observed rate constants log k with the sigma p constants of the aryl substituents. Computational studies at the B3LYP/6-31G(d) level of ring-closure barriers are consistent with the measured reactivities. Photolysis of squaric acid (5a) in solution provides a convenient preparation of deltic acid (7).

Observable azacyclobutenone ylides with antiaromatic character from 2-diazoacetyl-azaaromatics.

Azacyclobutenone ylides 2 and 11 were generated in solution by laser flash photolysis of 2-diazoacetylpyridine (1) and 3-diazoacetylpyridazine (10), respectively, together with the corresponding ketenes. The ylides were identified by their characteristic IR and UV spectra: 2, nu (CH3CN) 1725 cm(-1), lambdamax 360 and 550 (br) nm; 11, nu (CH3CN) 1776 cm(-1), lambdamax 370 and 550 (br) nm. 2-Triisopropylsilyldiazoacetylpyridine 20 upon photolysis at 5 degrees C in CH3CN forms the ylide 21 as a rather persistent (T1/2 2 h at 25 degrees C) purple solution, nu (CH3CN) 1718 cm(-1), lambdamax 245, 378 and 546 (br) nm, but no ketene is observed. Quinolyl ylide 14 and pyridyl ylides 17 and 19 with Me and 2-pyridyl substituents, respectively, with characteristic IR and UV spectra were also generated. The 1H NMR spectrum of the pyridyl ring of 21 shows substantial upfield shifts relative to those of 20. Calculated nucleus-independent chemical shifts (NICS) for 2, 11, and 21 are comparable to those for benzocyclobutadiene (22) and benzocyclobutenone enolate (23), with substantial positive values for the 4-membered rings, while the NICS values for the 6-membered rings are significantly more positive than for benzene or pyridine. Significant bond alternation is also found in the calculated ylide structures, and these results suggest strong antiaromatic character for the 4-membered rings of 2, 11, 14, 17, 19, and 21, and greatly reduced aromatic character for the 6-membered rings.

Amino substituted bisketenes: generation, structure, and reactivity.

Hitherto unknown diamino-substituted bisketenes with both free (14) and tethered (16) amino substituents have been generated by using laser flash photolysis for ring opening of the corresponding cyclobutenediones. The time-resolved kinetics of ring closure of the amino bisketenes back to the cyclobutenediones were measured by IR or UV spectroscopy, and give first-order rate constants which vary by a factor of 7.5x10(4), and the bis(Me2N) bisketene 14 is the most reactive in ring closure that has been reported. Rate constants for ring closure of these and previously observed bisketenes vary by a factor of 10(13). The dialkylamino bisketenes 16 (R=Me, n-Bu) with tethered substituents and restricted geometries are less reactive than the bis(Me2N) bisketene 14 by factors of 1700 and 540, respectively. Computational results obtained with DFT methods suggest angle strain in the tethered cyclobutenediones 15 inhibits facile cyclization of bisketenes 16.

Ferrocenylketene and ferrocenyl-1,2-bisketenes: direct observation and reactivity measurements.

[Structure: see text]. Ferrocenylketene (1) is calculated to be destabilized by 1.6 kcal/mol relative to phenylketene (10) by B3LYP isodesmic comparison to the corresponding alkenes. Ketene 1 generated by Wolff rearrangement in CH3CN is identified by the IR band at 2119 cm(-1) and has a rate constant for reaction with n-BuNH2 less than that for 10 by a factor of 5. 1,2-Bisferrocenyl-1,2-bisketene 18 and 1-ferrocenyl-2-trimethylsilyl-1,2-bisketene 21 were prepared by photochemical ring opening of the corresponding cyclobutenediones, and 18 undergoes rapid ring closure 67 times faster than the corresponding 1,2-diphenyl-1,2-bisketene, while bisketene 21 is longer lived than 18 by a factor of 3.2 x 10(4).

Hydration of pyridylketenes: formation of acid enol and dihydropyridine (eneaminone) transients.

2-, 3-, and 4-Pyridylketenes 4 formed in water by photochemical Wolff rearrangements using flash photolysis undergo rapid hydration forming transient intermediates observed by UV spectroscopy. 3-Pyridylketene (3-4) formed the acid enol intermediate 3-10 which was converted to the acid 3-11, and phenylketene gave similar behavior. 4-Pyridylketene (4-4) reacted with a similar initial rate constant of 5.0 x 10(4) s(-1) for decay of an absorption at 275 nm, with concomitant formation of a strong absorption at 370 nm with the same rate constant. The intermediate absorbing at 370 nm decayed with a lifetime 2.4 x 10(3) fold longer than that of the ketene, and is identified as 4-(carboxymethylene)-1,4-dihydropyridine (4-13), resulting from conjugate 1,6-addition of H(2)O to 4-4. 2-Pyridylketene (2-4) underwent hydration with a similar rate constant of 1.1 x 10(4) s(-1) forming a transient with a UV absorption with maxima at 310 and 380 nm that decayed with biexponetial kinetics, with rate constants slower than the rate of formation by factors of 5.2 and 110, respectively. These results are interpreted as indicating the presence of two species, namely Z- and E-2-(carboxymethylene)-1,2-dihydropyridines (2-13), resulting from conjugate 1,4-addition of H(2)O to 2-4. The identifications of the 1,2- and 1,4-(carboxymethylene)dihydropyridines 2- and 4-13 were confirmed by comparison of their UV spectra with those of the corresponding N-methyl derivatives. The amination of 2-pyridylketene in CH(3)CN was reinvestigated, and spectroscopic evidence, computational studies, and preparation of the N-methyl analogue demonstrated formation of the 1,2-dihydropyridine Z-2-8f as the long-lived intermediate.

Amination of pyridylketenes: experimental and computational studies of strong amide enol stabilization by the 2-pyridyl group.

Laser flash photolyses of 2-, 3-, and 4-diazoacetylpyridines 8 give the corresponding pyridylketenes 7 formed by Wolff rearrangements, as observed by time-resolved infrared spectroscopy, with ketenyl absorptions at 2127, 2125, and 2128 cm(-1), respectively. Photolysis of 2-, 3-, and 4-8 in CH(3)CN containing n-BuNH(2) results in the formation of two transients in each case, as observed by time-resolved IR and UV spectroscopy. The initial transients are assigned as the ketenes 7, and this is confirmed by IR measurements of the decay of the ketenyl absorbance. The ketenes then form the amide enols 12, whose growth and decay are monitored by UV. Similar photolysis of diazoacetophenone leads to phenylketene (5), which forms the amide enol 17. For 3- and 4-pyridylketenes and for phenylketene, the ratios of rate constants for amination of the ketene and for conversion of the amide enol to the amide are 3.1, 7.7, and 22, respectively, while for the 2-isomer the same ratio is 1.8 x 10(7). The stability of the amide enol from 2-7 is attributed to a strong intramolecular hydrogen bond to the pyridyl nitrogen, and this is supported by the DFT calculated structures of the intermediates, which indicate this enol amide is stabilized by 12.8 kcal/mol relative to the corresponding amide enol from phenylketene. Calculations of the transition states indicate a 10.9 kcal/mol higher barrier for conversion of the 2-pyridyl amide enol to the amide as compared to that from phenylketene.

Amination of Ketenes: Kinetic and Mechanistic Studies.

The rate constants for reaction of PhMe(2)SiCH=C=O (6) with amines to form amides in CH(3)CN are best fitted with a mixed second- and third-order dependence on [amine], in stark contrast to previous studies of Ph(2)C=C=O and other reactive ketenes in which only a first-order dependence on [amine] was observed in H(2)O or in CH(3)CN. Derived third-order rate constants for 6 depend on the amine basicity, with a 1.7 x 10(7) greater reactivity for n-BuNH(2) compared to CF(3)CH(2)NH(2). These kinetic results are consistent with recently reported theoretical studies for reaction of CH(2)=C=O with NH(3). For 6 the relative reactivity k(n-BuNH(2))/k(H(2)O) is estimated to be 10(13) in CH(3)CN. The crowded ketene t-Bu(2)C=C=O (10) is enormously deactivated toward amination and reacts in neat n-BuNH(2) with rates 10(12) and 2 x 10(5) times slower than those for t-BuCH=C=O and t-BuC(i-Pr)=C=O (11), respectively. The observed rate constants for 11 also show a higher than first-order dependence on [n-BuNH(2)]. The absence of higher order kinetic terms in [amine] for more reactive ketenes is attributed to irreversibility of addition of an initial amine to the ketene, while with more stable ketenes the initial step is reversible and later steps involving additional amine molecules are kinetically significant. The general acid CF(3)CH(2)NH(3)(+) catalyses the addition of CF(3)CH(2)NH(2) to 6 in a process independent of [CF(3)CH(2)NH(2)]. The reactivity of 6 with n-BuNH(2) is 370 times greater in CH(3)CN compared to isooctane, a result attributed to the polar nature of the transition state and possible catalysis of the addition by CH(3)CN.

Amination of Bis(trimethylsilyl)-1,2-bisketene to Ketenyl Amides, Succinamides, and Polyamides: Preparative and Kinetic Studies.

The reaction of the bisketene (Me(3)SiC=C=O)(2) (1) with amines is facile and proceeds by two distinct steps forming first ketenylcarboxamides 3 and then succinamides 5. Successive reaction of 1 with two different amines gives mixed succinamides, while phenylhydrazine gives succinimide 7. The reactions of 1.8 equiv of 1 with 1,4-(H(2)NCH(2))(2)C(6)H(4) gives alpha,omega-bisketenyldiamide 13, while equivalent amounts of 1 and diamines gave polymeric amides. Mixed ester amides 8 are formed by sequential reaction of 1 with an alcohol, followed by an amine, or vice versa. Kinetic studies of the amination reaction of 1 with excess amines in CH(3)CN gave rate constants k(obs) for the formation of ketenylcarboxamides that were fit by the relationship k(obs) = k(a)[amine](2) + k(b)[amine](3). Further reaction of the n-butyl ketenylcarboxamide 3b with n-BuNH(2) to give the succinamide 5b was first order in [n-BuNH(2)], while the further reaction of the CF(3)CH(2) ketenylcarboxyamide 3c with CF(3)CH(2)NH(2) to form 5c was fit by the equation k(obs) = k(c)[amine](2)/(k(d)[amine] + 1). The reaction of 3b with CH(3)OH to form the ester amide 8a is strongly accelerated compared to CH(3)OH addition to the corresponding ketenyl ester and gives significant stereoselectivity for formation of erythro product, and both these effects, as well as the absence of higher order kinetic terms in the reaction of 3b with n-BuNH(2), may arise from coordination by the carboxamido group to the nucleophile.

3-(Trifluoromethyl)indenyl Cation: Ion Pair Return in the Formation of an Antiaromatic and Electron-Deficient Doubly Destabilized Carbocation.

The solvolysis of 3-(trifluoromethyl)-3-indenyl tosylate (15) occurs with extensive isomerization to 1-(trifluoromethyl)-3-indenyl tosylate (16), which reacts in a slower process to give the substitution product 17. Kinetic analysis of a model involving an intermediate allyl cation/tosylate ion pair 18 gave a partitioning ratio in CD(3)CO(2)D at 99.6 degrees C for 18 of 7.7 for return with allylic rearrangement compared with solvent capture. Studies of 15 with specific (18)O labeling show no scrambling in recovered 15 and partial scrambling in rearrangement to 16. The m value measuring the dependence of the reactivity of 15 on the solvent-ionizing parameter Y(OTs) is 0.78, which is significantly less than that of 1.23 for the analogous 9-(trifluoromethyl)-9-fluorenyl tosylate 7. Normal salt effects in CF(3)CO(2)H predominate for 15, and the special salt effect involves no more than 14% capture of solvent-separated ion pairs by 0.551 M KO(2)CCF(3). The substrate 15 has a net diminution in reactivity of more than 10(9) relative to the secondary indanyl tosylate 22, with factors of 10(6) and 10(3) attributable to antiaromaticity and to the electron-withdrawing CF(3) group, respectively. The solvolysis of 15 is proposed to occur by formation of an ion pair with significant nucleophilic solvation at the relatively unhindered allylic carbon, but internal return occurs in preference to solvent or salt capture. Solvolysis of the rearranged tosylate 16 occurs with a strong rate retardation by the gamma-CF(3) group, a large extent of internal return, and with a normal salt effect.