Thermal Truncation of Heptamethine Cyanine Dyes

Abstract

Cyanine dyes are a class of organic, usually cationic molecules containing two nitrogen centers linked through conjugated polymethine chains. The synthesis and reactivity of cyanine derivatives have been extensively investigated for decades. Unlike the recently described phototruncation process, the thermal truncation (chain shortening) reaction is a phenomenon that has rarely been reported for these important fluorophores. Here, we present a systematic investigation of the truncation of heptamethine cyanines (Cy7) to pentamethine (Cy5) and trimethine (Cy3) cyanines via homogeneous, acid-base-catalyzed nucleophilic exchange reactions. We demonstrate how different substituents at the C3' and C4' positions of the chain and different heterocyclic end groups, the presence of bases, nucleophiles, and oxygen, solvent properties, and temperature affect the truncation process. The mechanism of chain shortening, studied by various analytical and spectroscopic techniques, was verified by extensive ab initio calculation, implying the necessity to model catalytic reactions by highly correlated wave function-based methods. In this study, we provide critical insight into the reactivity of cyanine polyene chains and elucidate the truncation mechanism and methods to mitigate side processes that can occur during the synthesis of cyanine derivatives. In addition, we offer alternative routes to the preparation of symmetrical and unsymmetrical meso-substituted Cy5 derivatives.

Scheme 1. Reported Reactions of Polymethine Chains with Nucleophiles: (A) Nucleophilic Substitution of Halogen Atoms or Pd-Coupling Reactions, (B) Reversible Addition of Nucleophiles to the Iminium C1 Atom, (C) Addition of Methoxide to the C2′ or C4′ Chain Positions with Subsequent Fragmentation, (D) Aminolysis of the Polymethine Chain Resulting in Truncation, (E) Truncation of Merocyanines in the Presence of a Nucleophile

Scheme 2. (A) Cyanines Used in This Study, (B) Unexpected Formation of the Cy5 Product 2a Observed during the Synthesis of 1a, (C) Formation of Cy5 and Cy3 Products during Heating of Heptamethine Cyanine 1b in the Presence of Indolinium Salt 4 and Sodium Acetate

Scheme 3. Truncation Reaction Using Different Indolinium Derivatives

Scheme 4. Mechanism of 1c Truncation in the Presence of 4

Figure 1

Concentration profiles for the reactions of 1c. Reaction conditions: (A) 1c (36 mM), 4A (36 mM), and DIPA (9 mM) in acetonitrile (10 mL) stirred at 50 °C; (B) 1c (36 mM) and 4B (36 mM) in acetonitrile (10 mL) stirred at 50 °C; (C) 1c (36 mM) and DIPA (9 mM) in acetonitrile (10 mL) stirred at 50 °C.

Figure 2

Calculated electronic (red) and Gibbs (orange) free energy profiles and entropic contributions (green) at 358 K for a path following the attack of 4B to C4′ of 1c (Scheme 4, path A). “TS” stands for the corresponding transition state. The single-point electronic energies were calculated at the DLPNO–CCSD(T)/cc-pVTZ level in ethanol within the polarizable continuum model (PCM). The picture of the process did not change much with the solvent. Thermal corrections were evaluated in the gas phase at the PBE0/def2-TZVP level with a D3BJ dispersion correction. The inclusion of solvation at the DLPNO–CCSD(T) level is described in the Methodology section (Supporting Information). The structures were optimized at the same level as for the frequency calculations.

Figure 3

Gibbs free energies of the addition of 4B to 1c (Scheme 4) in ethanol at the standard state of 1 M at 358 K. The structures were optimized in the gas phase at the PBE0/def2-TZVP level with the D3BJ dispersion correction. Single-point energies were calculated at the DLPNO–CCSD(T)/cc-pVTZ level. Frequency calculations were conducted at the same level as optimization with the inclusion of solvation (at the DLPNO–CCSD(T)/cc-pVTZ level) described in the Methodology section (Supporting Information).

Scheme 5. Truncation of 1c with DIPA

Scheme 6. Exchange of Terminal Heterocycles in 2