† Xiaoqi Tian

Suchaya Chaiworn

Jun Xu

Nicolas Vanthuyne

Kim K Baldridge

Jay S Siegel

Thiophene fused indenocorannulenes

Keywords: synthesis, variable emission, and exceptional chiral configurational stability

A set of thiophene fused indenocorannulenes (TFICs) was synthesized and characterized by X-ray crystallography, electrochemical, and photophysical methods. Two chiral derivatives were resolved and their absolute configurations defined by Flack analysis (12a) and by comparison of experimental VCD/ECD spectra with hybrid DFT methods (12b and 3a). The emission wavelengths of 13 compounds were compared and varied over 220 nm (emission colors from violet to red). The bowl-inversion activation barrier of 12 was determined to be 192.7 kJ mol -1 , corresponding to a configurational stability of weeks at 200 °C; on par with the highest helicene and phosphine values.

Introduction

Polynuclear aromatic hydrocarbon (PAH) networks can be seen as "Loschmidt" graphs in which cyclic 6-atom "elements" map on to the graph vertices. [START_REF] Srintana-Anant | Design of Novel Aromatics using the Loschmidt Replacement of Graphs[END_REF][START_REF] Baldridge | Of Graphs and Graphenes: Molecular Design and Chemical Studies of Aromatic Compounds[END_REF][START_REF] Loschmidt | Konstitutionsformeln der Organischen Chemie in Graphischer Darstellung[END_REF] "Isosteric" replacement of benzene by a heterocycle (e.g. thiophene) yields a set of hydrocarbon/ heterocycles appropriate for systematic structure-property comparisons. [START_REF] Burger | Isosterism and bioisosterism in drug designin[END_REF] PAHs that comprise thiophene in this manner manifest electrochemical and photochemical properties suitable for organic light-emitting diode (OLED), solar cell, conducting polymer, and field-effect transistor development. [START_REF] Cheng | Synthesis of conjugated polymers for Organic solar cell applications[END_REF][START_REF] Cinar | Thienothiophenes, dithienothiophenes, and thienoacenes: syntheses, oligomers, polymers, and properties[END_REF][START_REF] Jiang | Heteroarenes as high performance organic semiconductors[END_REF][START_REF] Kumaresan | Fused-thiophene based materials for organic photovoltaics and dye-sensitized solar cells[END_REF][START_REF] Xie | A novel thiophenefused ending group enabling an excellent small molecule acceptor for high-performance fullerene-free polymer solar cells with 11.8% efficiency[END_REF][START_REF] Zhang | Thieno[3,4-b]thiophene-based novel small-molecule optoelectronic materials[END_REF] Reports of curved-PAHs in this family are sparse in part due to synthetic effort and accessibility. [START_REF] Lu | Thiophene-fused bowl-shaped polycyclic aromatics with a dibenzo[a,g]corannulene core for organic fieldeffect transistors[END_REF][START_REF] Meng | Thiophene-fused pi-systems from diarylacetylenes and elemental sulfur[END_REF][START_REF] Rajeshkumar | A photochemical approach to aromatic extension of the corannulene nucleus[END_REF] Furthermore, the reported thiophene fused corannulenes (Fig. 1) derive from benzocorannulene graphs, which typically have shallow bowl depths and therefore small energy barriers to bowl inversion. Thiophenes derived from indenocorannulene graphs (defined here as thiophene fused indenocorannulenes or TFICs) possess deeper bowl depths and higher energy barriers to bowl inversion, due to the [a,c]-indeno fusion. Studies of the parent PAHs augur resolvable configurationally stable chiral TFICs suitable for materials research as well as for testing methods in the assignment of molecular absolute configuration.

Results and discussion

Precursors (2, 5, 8, 11) of TFICs (3, 6, 9, 12) were synthesized from iodocorannulene (1), [START_REF] Topolinski | Corannulenylferrocenes: towards a 1D, noncovalent metal-organic nanowire[END_REF][START_REF] Wang | Chiral atropisomeric indenocorannulene bowls: critique of the cahningold-prelog conception of molecular chirality[END_REF] dibromodimethylcorannulene (4), [START_REF] Wu | Multiethynyl corannulenes: synthesis, structure, and properties[END_REF] 4,9-dibromocorannulene-1,2-dicarboximide (7) [START_REF] Tian | Diindenocorannulenes : curved aromatics blending bowlin-bowl assembly and nanocarbon material properties[END_REF] and 4-bromo-9-(2-chloro-3-pyridyl)corannulene-1,2-dicarboximide (10) through Suzuki coupling reactions, [START_REF] Karroum | Methylation of imidazopyrazine, imidazoquinoxaline, and pyrazoloquinoxaline through Suzuki-Miyaura cross coupling[END_REF][START_REF] Molander | Development of the Suzuki-Miyaura cross-coupling reaction: use of air-stable potassium alkynyltrifluoroborates in aryl alkynylations[END_REF] respectively. Palladium-catalyzed intramolecular ring closure of 2, 5, 8 and 11 produced 3, 6, 9, and 12 in 85%, 35%, 35%, 40% yield (Scheme 1). It is worth mentioning that 0.1 eq. Pd(PCy 3 ) 2 Cl 2 for each indeno moiety were required in the synthesis of azaindenocorannulenes, [START_REF] Tian | Azaindenocorannulenes: Synthesis, Properties, and Chirality[END_REF] while 0.2 eq. Pd(PCy 3 ) 2 Cl 2 is required for each indeno moiety in the synthesis of the four TFICs.

Single crystals suitable for X-ray crystallographic analysis were obtained for 3, 6 (deuterated chloroform/hexane), and 12 (dichloromethane) (Fig. 2). Consistent with isosteric replacement design principle, the bowl depth and POAV angle of 3 (1.06 Å, 9.6°), 6 (1.18 Å, 10.6°), and 12 (1.18 Å, 10.5°) are larger than that of corannulene (0.875 Å, 8.3°) and approximately that of 22 (1.06 Å, 9.7°), [START_REF] Steinberg | Aromatic π-systems more curved than C 60 . the complete family of all indenocorannulenes synthesized by iterative microwave-assisted intramolecular arylations[END_REF] dimethyl diindenocorannulene 19 (1.177 Å, 10.6°), [START_REF] Shi | 1,2,3-versus 1,2-indeno ring fusions influence structure property and chirality of corannulene bowls[END_REF] N-alkylmaleimide diindenocorannulene 18 6) 1909112 (12). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1qo00596k

(1.189 Å, 10.7°), [START_REF] Tian | Diindenocorannulenes : curved aromatics blending bowlin-bowl assembly and nanocarbon material properties[END_REF] aza-diindenocorannulene 15 (1.175 Å, 10.6°), [START_REF] Tian | Azaindenocorannulenes: Synthesis, Properties, and Chirality[END_REF] respective to the number of ring fusions (Table 1).

All three compounds adopt an orthorhombic (3 -Pna2 1 , 6 -Pnma) or a monoclinic (12 -P2 1 ) space group and all show bowl-in-bowl columnar assemblies along one stacking axis (Fig. 3). Racemic 3 presents as a twin crystal in the polar orthorhombic space group Pna2 1 , with two molecules in the asymmetric unit. Although the columns are pointing in the same direction both asymmetric molecular sites are equally likely to have left as right-handed molecules without regular order. The unit cell of 6 is nonpolar in the orthorhombic space group Pnma. The packing structure comprises columns in which all the molecules in one any column are oriented along the c-axis in the same direction whereas adjacent columns point in opposing directions along the c axis.

Resolution of 12 by HPLC over chiral support (Chiralpak ID) allowed the study of a crystal from the first eluted fraction (12a). Enantiopure 12a presents in the monoclinic P2 1 space group (Z = 8) as a chiral anti-parallel columnar structure, with a Flack analysis parameter value of 0.06(4), supporting the absolute configuration assignment as shown in Fig. 7. Enantiomeric resolution of 3 by HPLC over chiral support (Chiralpak IG) did not yield crystals suitable for Flack analysis.

Having the pure enantiomers in hand raises questions of how to correlate the 3-dimensional structure to the physical samples and what if any configurational assignments can be made. Fundamental flaws in CIP nomenclature make it unsuitable for universal configurational assignments. Nonetheless, an ad hoc assignment can be made on the basis of a reference model. In the case of 3, the previously defined descriptors apply; 15 however, 12 presents additional problems, to be discuss in detail elsewhere. A convenient tetrahedral model comes from assigning the hub ring, the dicarboxyimide, the thiophene, and the pyridine, as vertices. Viewing the bowl from its convex side (from hub toward rim) the remaining three vertices can be rank ordered to distinguish enantiomeric geometries R/S (Fig. 4), without asserting any fundamental transferrable configurational classification.

A combination of experimental and theoretical ECD and VCD spectra have been used as a powerful way to assign absolute configuration in the absence of X-ray analysis. [START_REF] Freedman | Absolute Configuration Determination of Chiral Molecules in the Solution State Using Vibrational Circular Dichroism[END_REF] Accordingly, the VCD spectra of two enantiomers of 3 and 12 were measured in CHBr 3 and compared with B97-D/Def2-TZVPP(CHBr 3 ) determined spectra. Comparison of the 1200-1550 cm -1 regions in the spectra were used to make configurational assignment (Fig. 5). The calculated VCD spectra of 3and 12-S match the VCD spectra of 3a and 12b, respectively. The ECD of the two enantiomers of 3 and 12 were additionally measured in CH 3 CN and compared with TD-Scheme 1 The synthetic route for compounds 3, 6, 9 and 12. [START_REF] Steinberg | Aromatic π-systems more curved than C 60 . the complete family of all indenocorannulenes synthesized by iterative microwave-assisted intramolecular arylations[END_REF] 1.06 ± 0.05 (1.06) 9.7 ± 0.9 (9.7) P2 1 /n 19 [START_REF] Shi | 1,2,3-versus 1,2-indeno ring fusions influence structure property and chirality of corannulene bowls[END_REF] 1.18 ± 0.04 (1.22) 10.6 ± 0.6 (10.9) Cmc2 1 18 [START_REF] Tian | Diindenocorannulenes : curved aromatics blending bowlin-bowl assembly and nanocarbon material properties[END_REF] 1.19 ± 0.04 (1.22) 10.6 ± 0.7 (10.9) Pbca 15 [START_REF] Tian | Azaindenocorannulenes: Synthesis, Properties, and Chirality[END_REF] 1.18 ± 0.04 (1.22) 10.6 ± 0.7 (10.9) P1 a B97-D/Def2-TZVPP optimized results reported in parentheses. wB97xD/Def2-TZVPP(CH 3 CN) determined spectra (Fig. 6). The calculated ECD spectra of 3and 12-S agree well with the corresponding experimental spectra of 3a and 12b, respectively. From the Flack analysis of the X-ray crystal structure of 12a, the absolute configuration was assigned as 12-R, ergo the configuration of 12b as 12-S, and supporting the computational configurational assignment (Fig. 7).

The bowl inversion barrier of 3 and 12 could be determined by kinetic studies on the first order decay of optical activity. The bowl inversion energy of 3 varies slightly in differing solvents, from 114-118 kJ mol -1 (Table 2), but in good agreement with the computational data. Although the bowl depth of 12 (1.18 Å) is only about 12% larger than 3 (1.06 Å), the x 4 relationship between bowl depth and barrier would predict a 55-60% increase in the barrier (ca. 185 kJ mol -1 ). [START_REF] Seiders | Structure/Energy Correlation of Bowl Depth and Inversion Barrier in Corannulene Derivatives: Combined Experimental and Quantum Mechanical Analysis[END_REF] Kinetic studies on the first order decay of optical activity in 12a reveal a half-life of 1113 hours at 228 °C, which corresponds to a bowl inversion energy of 192.7 kJ mol -1 in good agreement with the B97-D/Def2-TZVPP prediction of 196.7 kJ mol -1 and consistent with the x 4 analytical relationship between bowl depth and inversion barrier.

Compounds 3, 6, 9 and 12 possess highly conjugated structures, the photophysical properties of which are reported in Table 3. In their absorption spectra, compounds 3 and 6 exhibit two main absorption maxima at 254 and 344 nm, respectively. Compounds 9 and 12 exhibit two main absorption maxima at 249, 337 nm and 272, 328 nm, respectively. The emission spectra shows that compound 6 has the longest emission wavelength at 657 nm, and compound 3 has the smallest emission wavelength at 606 nm (Fig. 8). The emission wavelength of these thiophene fused indenocorannulenes red shift up to 80 nm compared with the parent indenocorannulenes (18, 20) and aza-indenocorannulenes (15, 17) due to the electron-rich property of the thiophene moiety. [START_REF] Tian | Diindenocorannulenes : curved aromatics blending bowlin-bowl assembly and nanocarbon material properties[END_REF][START_REF] Tian | Azaindenocorannulenes: Synthesis, Properties, and Chirality[END_REF] Comparison of the emission wavelengths of the 13 related compounds reveal that their emission colors systematically vary over 220 nm, from violet (corannulene), to yellow ([aza]/indenocorannulenes), to red (TFICs) (Fig. 9 and10). Fluorescence quantum yields of the four compounds are all less than 0.55%.

The cyclic voltammograms of 3, 6, 9 and 12 exhibit a semireversible to reversible reduction at E 1/2 = -1.94 eV, -1.82 eV, 4). Compound 12 has the smallest first reduction potential at -1.54 eV. The first reduction potentials of 9 and 12 are much smaller than 3 and 6. Analysis of the values of I pa /I pc reveal the reversibility of 3 and 9 to be superior to that of 6 and 12.

It has been suggested that thiophene is a close analogue to benzene. [START_REF] Marino | A quantitative study of the uncatalysed halogenation of thiophene in acetic acid solution[END_REF][START_REF] Marino | Quantitative aspect of electrophilic substitution in furan, thiophene, pyrrole, and other five-membered heteroaromatic systems (Review)[END_REF][START_REF] Gol'dfarb | Researches in the thiophene series[END_REF][START_REF] Linda | Electrophilic substitution in fivemembered heterocyclic systems. Part VI. Kinetics of the bromination of the 2-methoxycarbonyl derivatives of furan, thiophen, and pyrrole in acetic acid solution[END_REF] The hypothesis can be tested in an electrochemical context for TFICs by comparing the first reduction potentials of the four compounds with the respective parent indenocorannulenes (3/22, 6/19, 9/18, 12/17). [START_REF] Tian | Diindenocorannulenes : curved aromatics blending bowlin-bowl assembly and nanocarbon material properties[END_REF][START_REF] Tian | Azaindenocorannulenes: Synthesis, Properties, and Chirality[END_REF][START_REF] Shi | 1,2,3-versus 1,2-indeno ring fusions influence structure property and chirality of corannulene bowls[END_REF] With regard to first reduction potentials, the TFICs are similar to their respective parent indenocorannulenes however the degree of reversibility seems to be worse; therefore the isosteric/isoelectronic assumption appears to hold also for this additional though limited set of compounds.

Conclusions

A combination of a graph theory approach to the taxonomy of PAHs and the concept of isosteric replacement, led to the design and synthesis of a small set of TFICs including two chiral compounds. Three structures of these were confirmed by X-ray crystal diffraction. The two chiral derivatives 3 and 12 were resolved and in the case of 12a Flack analysis provided a suggested assignment of configuration. Configurations of the two chiral compounds were also assigned by comparison of the experimental VCD/ECD spectra with that of the computationally predicted spectra. The assignments of VCD/ECD agree well with that of the Flack analysis. The bowl inversion activation energy of 12a reaches an extraordinarily high value (192.7 kJ mol -1 ) that correlates with stability against racemization for days at 200 °C. Such configurational robustness is on par with the highest values reported for helicenes and chiral phosphines. Chiral bowls of this ilk can be prepared in a variety of patterns, and given their exceptional configurational stability, could be useful scaffolds for the development of chiral catalysts, chiroptical materials, and diagnostic/sensing agents. Their electrochemical properties are quite similar with the parent indenocorannulenes, while their emission colors can be systematically varied over 220 nm, from violet (corannulene, 13), to yellow (ICs/AICs), to red (TFICs).

Experimental section

Unless otherwise stated, all commercially available reagents and solvents were used as received without further purification. Flash chromatography was performed on silica gel 100-200 m. Thin layer chromatography (TLC) was performed on glass backed plates pre-coated with silica (GF254), which were developed using standard visualizing agents. All optical measurements were performed in HPLC grade dichloromethane. UV-Vis measurements were carried out on HITACHI U-3900. Infrared spectra (IR) were recorded on a JASCO FT/ IR-4100 Fourier Transform Infrared Spectrometer. IR frequen- cies are given in cm -1 . Signal intensities are presented as weak (w), medium (m), strong (s) and very strong (vs). NMR spectra were recorded on Bruker AV-400/600 (400/600 MHz) instruments. The chemical shift (δ) is shown in ppm and referenced against the corresponding solvent peaks (for CDCl 3 , 1 H-NMR: 7.26 ppm; [START_REF] Rajeshkumar | A photochemical approach to aromatic extension of the corannulene nucleus[END_REF] C-NMR: 77.16 ppm). Data is reported as follows: chemical shift in ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet), coupling constant ( J) in Hz, and integration. Fluorescence excitation/emission measurements were carried on Edinburgh FLS980 spectrophotometer, using 450 W Xenon arc lamp, with excitation and emission slit widths at 1 nm. Emission spectra were obtained by exciting at the longest excitation maxima wavelength. Fluorescence lifetimes were measured using nanosecond flash lamp with computercontrolled power supply, for solutions with O.D. ∼0.1. Absolute quantum yields were measured using an integrating sphere accessory. Microwave reactions were performed in a CEM Discover Microwave Reactor with integrated active cooling. All cyclic voltammetry measurements were performed using a CHI600E Electrochemical Analyzer, CH Instruments, Inc. and in THF solvent with a scan rate of 0.1 V s -1 . THF was of HPLC grade and distilled over CaH 2 prior to its use. Tetrabutylammonium hexafluorophosphate (TBAH) was used as an electrolyte. Non-Aqueous Ag/Ag + was used as reference electrode (10 mM AgNO 3 in 0.1 M Bu 4 NPF 6 in acetonitrile), platinum wire as counter electrode and glassy carbon as the working electrode for all measurements. All E 1/2 potentials are directly obtained from cyclic voltammetric curves as averages of the cathodic and anodic peak potentials. Ferrocene was used as an internal standard. The standard potential of ferrocinium/ferrocene couple in THF (+0.085 V) was used to calibrate all voltammetry plots. High-resolution mass spectra (HRMS) recorded for accurate mass analysis, were performed on Thermo scientific Q Exactive HF. The ECD spectrometer was purged with nitrogen before recording each spectrum, which was baseline subtracted. The baseline was always measured using the same solvent and in the same cell as the samples. The spectra are presented without smoothing and further data processing. VCD spectra were measured on ChiralIR-2X with 300 μm cell, CHBr 3 as solvent. The crystal structures were obtained from Rigaku XtalAB PRO MM007 DW.

Computational methods

The structural and energetic analyses of the molecular systems for all compounds described in this study were carried out with the B97-D dispersion enabled density functional method, 29,30 using an ultrafine grid, together with the Def2-TZVPP basis set. 31 Full geometry optimizations were performed and uniquely characterized via second derivatives (Hessian) analysis to establish stationary points and effects of zero point and thermal energy contributions. Absorption energies were computed in acetonitrile at the TD-wB97xD 32 /Def2-TZVPP(ACN) level of theory. From the TD-DFT results, spectra were simulated from the excitation energies and rotation lengths by overlapping Gaussian functions for each transition. VCD was performed in bromoform at the B97-D/Def2-TZVPP (CHBr 3 ) level of theory. The simulated VCD spectrum consists of a sum of Lorentzian distributions centered on the computed frequencies, with fixed width and with the height proportional to the computed rotational constant. Reduction potential data was determined in tetrahydrofuran at the B97-D/Def2-TZVPP (THF) level of theory, using E°= -ΔH/nF, where n = 1, F = 1 eV, and referenced to Ag/AgCl. The Strumm and Morgan correction [START_REF] Strumm | Aquatic Chemistry: Chemical Equilibria and Rates in Natural Waters[END_REF] for 0.1 M AgCl/Ag of 0.29 was used in combination with the value for the SHE electrode, giving 4.73 = 4.44 (SHE) + 0.29 (0.1 M AgCl/Ag), for the reference value. Effects of solvent employed the COSMO:ab initio continuum method [START_REF] Klamt | [END_REF]35 using a dielectric as in experiment, and radii of Klamt. 36 Visualization and analysis of structural and property results were obtained using Avogadro 37 and GaussView (for spectra). [START_REF] Dennington | GaussView[END_REF]

Fig. 1

 1 Fig. 1 Representative thiophene fused corannulene structures.

Fig. 2 X

 2 Fig. 2 X-ray crystallographic structures of 3, 6 and 12, viewed from rim to hub atoms.

Fig. 3

 3 Fig. 3 Crystal packing of 3, 6 and 12a.

Fig. 5

 5 Fig. 5 Experimental and B97-D/Def2-TZVPP(CHBr 3 ) VCD spectra of 3a (red) and 12b (blue).

Fig. 6

 6 Fig. 6 Experimental and TD-wB97xD/Def2-TZVPP(CH 3 CN) ECD spectra of 3a (red) and 12b (blue).

Fig. 7 (

 7 Fig. 7 (a and b) B97-D/Def2-TZVPP optimized structures for 3a and 12b, and (c) X-ray determined crystal structure of 12a.

Fig. 8

 8 Fig. 8 UV and fluorescence spectra of 3, 6, 9 and 12.

Fig. 9

 9 Fig.9Related indenocorannulenes together with their emission wavelengths.

Fig. 10

 10 Fig. 10 Indenocorannulene derivatives (13-21, 3, 12, 9, 6) under 365 nm lamp, in THF, 2 mg mL -1 .

a

  Solvent: THF; working electrode: glassy carbon; reference electrode: Ag/Ag + in acetonitrile; counter electrode: platinum wire; scan rate: 0.1 V s -1 ; supporting electrolyte: tetrabutylammonium hexafluorophosphate (TBAPF 6 ). E * c = first reduction potential, E 1/2 = half-wave potential, I pa = peak anodic current, I pc = peak cathodic current. b Values in parentheses are B97-D/Def2-TZVPP(THF) calculated values, using E °c = -ΔH/nF -Ref Ag/AgCl , where n = 1, F = 1 eV.

Table 1

 1 Bowl depths, POAV hub angles, space group of 3, 6, 12 and related compounds

	Cmpnd	Bowl depth (Å)	POAV hub angle	Space group
	3	1.06 ± 0.02 (1.10) a	9.6 ± 0.4 (10.1)	Pna2 1
	6	1.18 ± 0.04 (1.22)	10.6 ± 0.7 (10.8)	Pnma
	12	1.18 ± 0.04 (1.21)	10.5 ± 1.0 (10.8)	P2 1
	22

Table 2

 2 Rate constants, bowl inversion barriers, and half-lives of 3 and 12

	Cmpnd	3	3	3	1 2
	k (s -1 )	6.43 × 10 -5 3.63 × 10 -5 3.72 × 10 -5 8.64 × 10 -8
	t 1/2 (hours) ΔG (kJ mol -1 ) 114.7 1.5	2.7 117.3	2.6 115.9	1113 192.7
	Calcd a	112.2	113.1	N b	196.7
	T (K)	351	354	350	501
	Solvent	EtOH	CYH	CCl 4	Ph 2 O

a B97-D/Def2-TZVPP(solvent) with solvent as in experiment. b Not determined.

Table 3

 3 Experimental photophysical properties for 3, 6, 9 and 12

	Cmpnd	Em [Ex] (QY%)	λ abs	λ onset	E g
	3	606 [342] (0.4%)	344, 306	360 ± 5	3.45 ± 0.05
	6	657 [360] (0.2%)	359, 344	375 ± 5	3.30 ± 0.05
	9	638 [336] (0.5%)	337	385 ± 5	3.20 ± 0.05
	12	629 [345] (0.3%)	328	385 ± 5	3.20 ± 0.05

-1.51 eV and -1.46 eV respectively (Table

Table 4 E

 4 * c (V), E 1/2 (V), I pa /I pc for 3, 6, 9, 12 and related compounds

	Cmpnd	E * c (eV) a	E 1/2 (eV)	I pa /I pc
	3	-2.03 (-2.02) b	-1.94	0.84
	22 20	-2.06 (-2.06)	N	N
	6	-1.87 (-1.93)	-1.82	0.45
	19 22	-1.91 (-1.89)	-1.85	0.71
	9	-1.59 (-1.54)	-1.51	0.84
	18 17	-1.60 (-1.52)	-1.51	1.15
	12	-1.54 (-1.47)	-1.46	0.42
	17 20

Acknowledgements

We thank the National Science Foundation of China (21871207) for support of this research.

Author contributions

X. T. and S. C. performed the syntheses. X. T. and V. N. did the optical resolution, J. S. S. designed, and coordinated experimental activities, and K. K. B. designed and carried out the computational studies.

Conflicts of interest

There are no conflicts to declare.


Introduction

Alzheimer's Disease International (ADI) published global prevalence data on dementia in the World Alzheimer Report 2009 1 based on a systematic review of 154 studies conducted worldwide, and United Nations population projections through to the year 2050. We estimated 36 million people with dementia in 2010, nearly doubling every 20 years to 66 million by 2030 and to 115 million by 2050.

Key findings included

• 58% of those affected lived in low and middle income countries, underlining the high impact of the condition in those regions, where awareness is low, health and social care are poorly developed and social protection is limited.

• Population ageing is the main driver of projected increases.

• We assumed that age-specific prevalence would remain constant. This assumption is challenged by recent evidence suggesting a modest recent decline in dementia prevalence in some higher income countries (HIC), but an increase in prevalence in China, likely linked to recent changes in population health, particularly exposure to cardiovascular risk factors.

• Since population ageing is occurring at an unprecedentedly fast rate in middle income countries, the bulk of the increase in numbers through to 2050 will occur in those regions. By 2050 71% of those with dementia would be living in what are currently lower and middle-income countries (LMIC).

The Global Impact of Dementia 2013-2050

Results

The prevalences of dementia estimated from the recent more comprehensive review and metaanalysis of China studies 3 and our own metaanalysis of studies from sub-Saharan Africa were substantially higher than those used in the 2009 World Alzheimer Report. Age-standardised to a standard West European population, prevalence for East Asia increased from 4.98% to 6.99% and in the sub-Saharan African regions from a range of 2.07% to 4.00%, to 4.76% (Figure 1). 9 ADI and the World Health Organization have, in their joint report Dementia: a public health priority [START_REF]World Health Organization and Alzheimer's Disease International, Dementia: a public health priority[END_REF] , called upon all Governments to make dementia a public and health priority. As part of this process, all governments should initiate national debates regarding the future provision and financing of long-term care (see World Alzheimer Report 2013: Journey of Caring 15 ). However, most are woefully unprepared for the dementia epidemic with only 13 countries having funded and sought to implement a national dementia plan. Without a plan, the risk is that health and social care systems will not cope with the increase in numbers and operate in crisis mode, escalating costs even further.

10 At the eve of the G8 Dementia Summit in London, UK, it is not just the G8 countries, but all nations that must commit to a sustained increase in dementia research and a comprehensive plan for collaborative action involving all relevant government sectors, industry and civil society. International cooperation will be essential. There is a need for a collaborative, global action plan for governments, industry and non-profit organisations like Alzheimer associations. Priorities include; breaking down barriers to effective research; promoting rapid translation and ensuring equitable access to promising technologies and treatments; technical support for policymaking, health and social care service and system development.

1 Dementia, including Alzheimer's disease, is one of the biggest global public health challenges facing our generation. Newly available data suggests that the current burden and future impact of the dementia epidemic has been underestimated, particularly for the Asia East and Sub-Saharan African regions.

2 This is a global epidemic -although cases are disproportionately concentrated in the world's richest and most demographically aged countries, already the clear majority (62%) of people with dementia live in low and middle income countries where access to social protection, services, support and care are very limited.

3 In the next few decades, the global burden of dementia will shift inexorably to poorer countries, particularly rapidly developing middle income countries that are members of the G20, but not the G8.

4

The future scale of the dementia epidemic may be blunted through improvements in population health, but our best estimates suggest that only up to 10% of incidence may thus be avoided [START_REF]World Health Organization and Alzheimer's Disease International, Dementia: a public health priority[END_REF] . Public health and disease control measures targeting smoking, underactivity, obesity, hypertension and diabetes should be prioritised. Education and other factors that enhance brain and cognitive development will also improve the brain health of those entering old age, and reduce the incidence of dementia in late life.

5 Standard & Poor's has described global population ageing as the biggest threat to the sustainability of sovereign debt. Among the chronic diseases, dementia makes by far the largest single contribution to disability and needs for care among older people. The current (2010) global societal economic cost of dementia is US$ 604 billion, or 1% of global GDP 14 . Costs will escalate proportionately with numbers affected, and with increased demand for formal care services, particularly in low and middle income countries [START_REF]World Health Organization and Alzheimer's Disease International, Dementia: a public health priority[END_REF] .

6 Research must be a global priority if we are to improve the quality and coverage of care, find treatments that alter the course of the disease, and identify more options for prevention.

7 Investment in the search for a cure must be balanced with initiatives to improve access to currently available evidence-based packages of care -these include timely

Conclusions and implications

Estimation of the number of people with dementia

The new rates were applied to the new UN population estimates for each 5-years age band (60-64, to 100 and over) 2 . When rates were not available for one age-band (i.e. over 90 in SSA and over 100 in China), the rate of the nearest age-band was applied. As gender-specific estimates were available neither for China nor SSA, we applied the age-specific estimates to the whole population and to each gender separately. In the East Asia region -composed of China, Hong Kong SAR, Macao SAR, Chinese Taipei and DPR Korea -the new rates were applied to mainland China, Hong Kong SAR and Macao SAR, whereas the East Asia rates from the 2009 Word Alzheimer Report were maintained for the DPR Korea and Chinese Taipei.

For Sub-Saharan Africa, the new rates were applied to the countries belonging to the following Global Burden Disease (GBD) regions: SSA West, SSA Central, SSA East and SSA Southern. Based on the GBD regions, Algeria belongs to the North Africa / Middle East, so we therefore applied the EMRO B rates that are used for some of its neighbours.

For all the other regions, we applied the rates found in the 2009 World Alzheimer Report to the new population estimates from the United Nations 2 .

Annex 1: Methods

The prevalence of dementia in China and Sub-Saharan Africa

The estimates for China were revised based on the recent meta-analysis published by Chan et al. [START_REF] Chan | Epidemiology of Alzheimer's disease and other forms of dementia in China, 1990-2010: a systematic review and analysis[END_REF] . This metaanalysis included reports for dementia or Alzheimer's Disease in mainland China, published in Chinese and English between 1990 and 2010. The rates applied to the population estimates were the age-specific prevalence of dementia in 2010. A new systematic review of dementia in China has also been recently published [START_REF] Wu | Prevalence studies of dementia in mainland china, Hong Kong and taiwan: a systematic review and meta-analysis[END_REF] , together with a new large multi-centre population-based prevalence study of dementia in China 5 . These studies were not taken into account in our estimates, but will be included in any future updates.

For Sub-Saharan Africa, we conducted a systematic review of the literature on the prevalence of dementia with Pubmed / Medline up to October 2013 using a similar methodology and inclusion criteria that we used for the 2009 World Alzheimer Report 1 (see online appendix). We sought and included population-based studies of the prevalence of dementia among people aged 60 years and over for which the fieldwork started on or after 1st January 1980. Prevalence rates were extracted for seven studies covering five different countries [START_REF] Hendrie | Prevalence of Alzheimer's disease and dementia in two communities: Nigerian Africans and African Americans[END_REF][START_REF] Guerchet | Cognitive impairment and dementia in elderly people living in rural Benin, west Africa[END_REF][START_REF] Guerchet | Prevalence of dementia in elderly living in two cities of Central Africa: the EDAC survey[END_REF][START_REF] Paraiso | Prevalence of dementia among elderly people living in Cotonou, an urban area of Benin (West Africa)[END_REF][START_REF] Yusuf | Prevalence of dementia and dementia subtypes among communitydwelling elderly people in northern Nigeria[END_REF][START_REF] Longdon | The prevalence of dementia in rural Tanzania: a cross-sectional community-based study[END_REF][START_REF] Guerchet | Prevalence of dementia in two countries of Central Africa: comparison or rural and urban areas in the EPIDEMCA study[END_REF]

Figure 2

 2 Figure 2 Increase in numbers of people with dementia worldwide (2010-2050), comparing original and updated estimates

Although high income countries, including the G8, have borne the brunt of the dementia epidemic, this is a global phenomenon. Most people with dementia live in low and middle income countries, and most of the dramatic increases in numbers affected, through to 2050, will occur in those regions. In a spirit of international cooperation and solidarity we urge the G8 governments to sponsor intergovernmental action to make dementia a global priority. Crucially, this must include opening up access to diagnosis and current evidence-based treatment and care. All countries worldwide are failing in this basic objective. Action to address this problem should be balanced, as a priority, with research to improve treatment options and quality of care.

	Figure 1 Original (2009 World Alzheimer Report) and updated age-specific prevalence of dementia (%) by region,
	showing impact of new data from Asia East (China) and Sub-Saharan Africa
	The G8 Dementia Summit on 11 December
	2013 provides a timely opportunity to
	reassess and update evidence on the scale
	and the distribution of the global dementia
	epidemic, in particular its impact on more
	developed (G8, G20, OECD and 'high
	income' countries) and less developed 'low
	and middle income' countries.
	For the current update, we carried out a
	limited review, focusing on the new evidence
	emerging from China and the sub-Saharan
	African regions, and applied the new
	prevalence proportions to the latest (2012)
	UN population projections 2 . Details of the
	methodology are provided in Annex 1.
	The work on this report has been a joint
	effort of the Global Observatory for Ageing
	and Dementia Care (Prof Martin Prince,
	Dr Maëlenn Guerchet and Dr Matthew Prina),
	and the ADI office.

Since 2009, the global evidence base has expanded, most particularly with a new systematic review of the prevalence of dementia in China 3 comprising 75 studies, most published in Chinese language journals, and with seven studies from five sub-Saharan African countries, where previously only one study from Nigeria had been available.

Table 1

 1 The largest increases in projected numbers of people with dementia are those for the Asia East and Sub-Saharan African regions, accounted for by the higher age-specific prevalence of dementia estimated in our new reviews of survey data from those regions (Annex 2). Updated estimates of the number of people with dementia living in G8, G20, OECD, LMIC and HIC countries, and as a percentage of world total

				This is explained by the underestimation of
				current numbers of older people in the previous
				UN population estimates (affecting the 2013
				figures), and revision upwards of probability of
				survival into older age (affecting the 2030 and
		Hence, in		2050 projections).
	2050 we are now estimating 33.61 million people with dementia in Asia East (an increase of 49% from the previous estimate of 22.54 million) and 5.05 million older people with dementia in SSA (an increase of 136% from the previous estimate of 2.14 million). However, the new estimates of numbers of people with dementia are higher for all GBD regions than those estimated in 2009.	We now estimate that while 32% of people with dementia live in G8 countries and 38% in high income countries, 62% live in low and middle income countries (Table 1). By 2050, the proportion living in G8 countries will have shrunk to 21%, while the proportion living in what are currently low and middle income countries will have increased to 71%.
		People with dementia millions	Proportionate increase
		(% of world total)		(%)
	Region	2013	2030		2050	2013-2030	2013-2050
	G8	14.02 (32%)	20.38 (27%)	28.91 (21%)	45	106
	G20	33.93 (76%)	56.40 (75%)	96.61 (71%)	66	185
	OECD	18.08 (41%)	27.98 (37%)	43.65 (32%)	55	142
	High income	17.00 (38%)	25.86 (34%)	39.19 (29%)	52	131
	Low and middle income	27.84 (62%)	49.76 (66%)	96.27 (71%)	79	246
	World	44.35	75.62		135.46	71	205

56 65.69 115.38 44.35 75.62 135.46 71 205Table 1

 1 Numbers of people with dementia according to GBD regions (in millions, by year)

	Annex 2
		Original estimates (2009)	Updated estimates	Proportionate increases (%) for new estimates
	GBD Region	2010	2030	2050	2013	2030	2050	2013-2030	2013-2050
	Asia/Pacific	15.94	33.04	60.92	21.87	39.79	71.84	82	228
	Australasia	0.31	0.53	0.79	0.37	0.62	1.02	68	176
	Asia Pacific High Income	2.83	5.36	7.03	3.26	5.50	7.58	69	133
	Oceania	0.02	0.04	0.10	0.02	0.04	0.09	100	350
	Asia Central	0.33	0.56	1.19	0.29	0.44	0.88	52	203
	Asia East	5.49	11.93	22.54	10.46	18.83	33.61	80	221
	Asia South	4.48	9.31	18.12	4.74	8.50	16.61	79	250
	Asia Southeast	2.48	5.30	11.13	2.74	5.87	12.05	114	340
	Europe	9.95	13.95	18.65	10.93	14.8	20.75	35	90
	Europe Central	1.10	1.57	2.10	1.23	1.69	2.29	37	86
	Europe Eastern	1.87	2.36	3.10	1.86	2.03	2.44	9	31
	Europe Western	6.98	10.03	13.44	7.84	11.08	16.02	41	104
	The Americas	7.82	14.78	27.08	8.77	15.8	30.51	80	248
	North America High Income	4.38	7.13	11.01	4.58	7.28	11.74	59	156
	Caribbean	0.33	0.62	1.04	0.38	0.63	1.14	66	200
	Latin America Andean	0.25	0.59	1.29	0.31	0.64	1.46	106	371
	Latin America Central	1.19	2.79	6.37	1.38	2.95	7.07	114	412
	Latin America Southern	0.61	1.08	1.83	0.71	1.17	2.13	65	200
	Latin America Tropical	1.05	2.58	5.54	1.42	3.13	6.97	120	391
	Africa	1.86	3.92	8.74	2.78	5.24	12.35	88	344
	North Africa / Middle East	1.15	2.59	6.19	1.47	2.91	7.29	98	396
	Sub-Saharan Africa Central	0.07	0.12	0.24	0.13	0.23	0.48	77	269
	Sub-Saharan Africa East	0.36	0.69	1.38	0.55	1.06	2.45	93	345
	Sub-Saharan Africa Southern	0.10	0.17	0.20	0.19	0.29	0.49	53	158
	Sub-Saharan Africa West	0.18	0.35	0.72	0.44	0.76	1.63	73	270
	World	35.

. A random effect exponential (Poisson) model was used to assess the effects of age on the prevalence of dementia. We then applied the relevant mean ages to the coefficients estimated from the model, to estimate prevalence in five year age-bands from 65-69 years to 85 years and over, for both sexes combined.

Acknowledgements

Authors

About Alzheimer's Disease International

Alzheimer's Disease International (ADI) is the international federation of Alzheimer associations throughout the world. Each of our 79 members is a non-profit Alzheimer association supporting people with dementia and their families.

ADI was founded in 1984 and registered as a non-profit organization in the USA. Based in London, ADI is in official relations with the WHO since 1996 and has consultative status with the UN since 2012. ADI's vision is an improved quality of life for people with dementia and their families throughout the world. ADI aims to make dementia a global health priority, to build and strengthen Alzheimer associations, and to raise awareness about dementia worldwide. Stronger Alzheimer associations are better able to meet the needs of people with dementia and their carers, and to be the global voice on dementia.

Global Observatory for Ageing and Dementia Care

The Global Observatory for Ageing and Dementia Care, hosted at the Health Service and Population Research Department, King's College London, was founded in 2013. Supported by Alzheimer's Disease International and King's College London, the Observatory aims to synthesise global evidence for policymakers and the public through high impact evidence-based reports for Alzheimer's Disease International (World Alzheimer Reports 2009, 2010, 2011 and 2013), the World Health Organization (Dementia; a public health priority) and other relevant intergovernmental organisations. A particular focus is to identify and promote effective innovations in health and social care policy and practice.