銅催化二羥基乙酸、胺和炔三組分脫羧偶聯(lián)反應(yīng)的機理

王 欽

(吉林大學(xué) 理論化學(xué)研究所, 長春 130021)

多組分反應(yīng)(MCR)是由3個或3個以上反應(yīng)物按一定反應(yīng)方式生成一個產(chǎn)物的反應(yīng)[1]. 作為合成復(fù)雜結(jié)構(gòu)分子的多組分反應(yīng)目前已廣泛應(yīng)用于有機化學(xué)等領(lǐng)域, 如新藥開發(fā)、 天然產(chǎn)物全合成等. 經(jīng)典醛、 胺和炔三組分偶聯(lián)反應(yīng)[2-6](A3-coupling)的生成產(chǎn)物為炔丙基胺類化合物, 具有光學(xué)活性, 是一類重要的有機化合物骨架及有機合成中間體, 可用于合成各種具有廣泛生物活性和藥理作用的含氮化合物. 近年來, 利用銅作為催化劑催化三組分偶聯(lián)反應(yīng)的研究發(fā)展迅速[5]. 與鈀、 鎳等相比, 銅是一種廉價且低毒的金屬. 除銅可催化醛、 胺和炔三組分偶聯(lián)反應(yīng)外[6-7], 酮[8-9]、 缺電子炔[10-11]、 二鹵代烷烴[12-15]、 炔醛[16]、 丙炔酸[17-20]、 2-氧代乙酸[21]和α-氨基酸[22]等均可在銅催化下發(fā)生三組分偶聯(lián)反應(yīng).

在銅催化下, 二羥基乙酸可與胺和炔進行脫羧偶聯(lián)反應(yīng), 生成的產(chǎn)物為四組分偶聯(lián)產(chǎn)物, 即有兩分子的炔參與了反應(yīng), 從實驗上對其微觀反應(yīng)機理進行了猜測[23], 如圖1所示. 由圖1可見, 端炔的C—H鍵與[Cu]反應(yīng)生成炔銅中間體, 炔銅與二羥基乙酸和胺原位生成的亞胺鹽進行配位和脫羧反應(yīng)后進行質(zhì)子化生成聯(lián)烯, 最后聯(lián)烯再與炔銅中間體反應(yīng), 脫去[Cu]得到有兩分子炔參與的產(chǎn)物3-氨基-1,4-烯炔. 該催化循環(huán)中涉及脫羧反應(yīng), 且有兩分子炔參與反應(yīng), 使得反應(yīng)機理較復(fù)雜. 由于實驗未檢測到聯(lián)烯中間產(chǎn)物, 因此, 本文通過理論計算, 從原子水平研究銅催化二羥基乙酸、 胺和炔脫羧偶聯(lián)反應(yīng)的微觀機理.

圖1 實驗上提出的反應(yīng)機理Fig.1 Reaction mechanism proposed in experiments

1 計算方法

所有計算均由Gaussian 09程序[24]完成. 運用密度泛函方法B3LYP[25-27]優(yōu)化勢能面上極小點和過渡態(tài)的幾何構(gòu)型, 對金屬Cu原子采用Wachters-Hay基組6-311G(d)[28-29], 其他主族元素原子(C，H，O，N，P，Br), 除苯基采用6-31G(d)外, 均采用6-311G(d,p). 在相同水平下計算頻率, 確定極小點沒有虛頻, 過渡態(tài)有且僅有一個虛頻, 并得到298.15 K和101 325 Pa下的自由能校正. 用內(nèi)稟反應(yīng)坐標(biāo)(IRC)[30]確定過渡態(tài). 在已優(yōu)化的幾何構(gòu)型基礎(chǔ)上, 用密度泛函方法M06[31], 對Cu和其他主族元素原子分別采用6-311G(d)和6-311+G(d,p)基組, 使用SMD[32]溶劑模型, 在甲苯中計算單點能.

2 結(jié)果與討論

圖2 催化活性體1與端炔和亞胺鹽反應(yīng)得到配合物5的勢能面Fig.2 Potential energy surfaces calculated for reaction of catalytic active species 1 with alkyne and iminium salt to form complex 5

在配合物5中, Ph取代的C與Cu相連, 經(jīng)過渡態(tài)TS5-5iso發(fā)生1,3-遷移得到NMe2取代的C與Cu成鍵的配合物5iso. TS5-5iso分別比配合物5和5iso的能壘高32.9,10.9 kJ/mol, 表明配合物5易越過過渡態(tài)TS5-5iso, 與配合物5iso達到化學(xué)平衡, 如圖3所示.

圖3 配合物5與5iso形成化學(xué)平衡的勢能面Fig.3 Potential energy surfaces of chemical equilibrium formed by complexes 5 and 5iso

配合物5有兩條質(zhì)子化反應(yīng)路徑： 1) HBr中H+加成到NMe2取代的C上, 經(jīng)過渡態(tài)TS5-6A得到炔丙基胺配位的配合物6A, 如圖4(A)所示. 2) HBr中的H+加成到Ph取代的C上, 經(jīng)過渡態(tài)TS5-6B得到聯(lián)烯配位的配合物6B, 如圖4(B)所示. 配合物5iso也有兩條質(zhì)子化反應(yīng)路徑: HBr中的H+加成到NMe2取代的C和Ph取代的C上, 分別經(jīng)過渡態(tài)TS5iso-6A和TS5iso-6B得到配合物6A(圖4(C))和6B(圖4(D)). 其中過渡態(tài)TS5-6B的能壘最低, 表明反應(yīng)更易經(jīng)過渡態(tài)TS5-6B得到配合物6B, 即后續(xù)反應(yīng)更易從聯(lián)烯配位的配合物6B開始.

圖4 配合物5和5iso分別經(jīng)兩條質(zhì)子化反應(yīng)路徑的勢能面Fig.4 Potential energy surfaces for two protonation reaction pathways of complexes 5 and 5iso respectively

配合物6B脫去聯(lián)烯重新生成催化活性體1, 如圖5所示. 由圖5可見, 催化活性體1與端炔反應(yīng)得到炔銅配合物2,1→TS1-2→2的過程與圖1過程相同, 聯(lián)烯配位到炔銅配合物2得到配合物7, 配合物7經(jīng)過渡態(tài)TS7-8發(fā)生插入反應(yīng)生成配合物8, 再進行質(zhì)子化反應(yīng)得到配合物9, 最后解離得到最終產(chǎn)物3-氨基-1,4-烯炔和催化活性體1. 配合物6B和7均為聯(lián)烯配位, 由于炔銅2比催化活性體1的能壘高61.5 kJ/mol, 配合物7比6B的能壘高65.4 kJ/mol, 過渡態(tài)TS7-8比配合物7的能壘高147.0 kJ/mol, TS7-8比6B的能壘高212.4 kJ/mol, 因此反應(yīng)需從6B越過212.4 kJ/mol的能壘才能生成最終產(chǎn)物3-氨基-1,4-烯炔. 由于實驗溫度[23]為110 ℃, 無法越過212.4 kJ/mol的能壘, 因此下面考慮該反應(yīng)是否有其他反應(yīng)機理.

圖5 配合物6B至產(chǎn)物3-氨基-1,4-烯炔的勢能面Fig.5 Potential energy surfaces from complex 6B to product 3-amino-1,4-enyne

催化活性體1與亞胺鹽反應(yīng)的過程如圖6所示. 由圖6可見, 亞胺鹽配位到Cu中心得到配合物10, 先脫去膦配體生成配合物11, 再經(jīng)過渡態(tài)TS11-12發(fā)生脫羧反應(yīng)得到配合物12. 由于脫膦和脫羧可同時經(jīng)過渡態(tài)TS10-12一步完成, TS10-12比TS11-12的能壘低29.0 kJ/mol, 因此反應(yīng)更易經(jīng)同時脫膦脫羧的路徑生成配合物12.

圖6 催化活性體1與亞胺鹽反應(yīng)得到配合物12的勢能面Fig.6 Potential energy surfaces calculated for reaction of catalytic active species 1 with iminium salt to form complex 12

端炔配位到配合物12得到配合物14, 其過程如圖7所示. 由圖7可見, 配合物13比12的能壘低19.8 kJ/mol, 表明端炔容易配位. 再經(jīng)過渡態(tài)TS13-14, 端炔插入到Cu—C鍵生成配合物14, TS13-14比配合物13的能壘高129.8 kJ/mol.

圖7 端炔配位到配合物12進行插入得到配合物14的勢能面Fig.7 Potential energy surfaces calculated for coordination of alkyne to complex 12 and insertion to form complex 14

圖8 配合物14與端炔反應(yīng)得到最終產(chǎn)物3-氨基-1,4-烯炔的勢能面Fig.8 Potential energy surfaces calculated for reaction of complex 14 with alkyne to generate final product 3-amino-1,4-enyne

由配合物12的端炔配位插入路徑及質(zhì)子化反應(yīng)路徑可見, TS13-14比TS12-19的能壘低21.9 kJ/mol, 表明經(jīng)TS13-14生成3-氨基-1,4-烯炔產(chǎn)物的路徑更易進行, 與實驗[23]得到該產(chǎn)物的結(jié)果一致.

最優(yōu)的整個催化循環(huán)為： 從配合物11開始, 經(jīng)脫羧、 端炔配位和插入、 質(zhì)子化、 親核加成、 配體交換等步驟得到最終產(chǎn)物3-氨基-1,4-烯炔, 并重新生成配合物11, 其過程如圖10所示. 其中端炔插入為決速步驟, 能壘為129.8 kJ/mol, 與實驗上反應(yīng)溫度為110 ℃的結(jié)果一致. 從配合物11開始的脫羧反應(yīng), 若有膦配體, 則膦配體先配位, 再經(jīng)脫膦脫羧反應(yīng)生成配合物12； 若無膦配體, 則配合物11直接脫羧生成配合物12, 該步驟能壘為105.0 kJ/mol(考慮到從配合物17亞胺鹽取代最終產(chǎn)物得到配合物11需吸收23.5 kJ/mol的能量), 仍比決速步驟能壘低24.8 kJ/mol. 因此有無膦配體該反應(yīng)均可發(fā)生, 且決速步驟不變 , 均為能壘為129.8 kJ/mol的端炔插入步驟, 與文獻[23]結(jié)果相符.

圖9 配合物12與端炔反應(yīng)得到另一產(chǎn)物炔丙基胺的勢能面Fig.9 Potential energy surfaces calculated for reaction of complex 12 with alkyne to generate another product propargylamine

圖10 整個催化循環(huán)Fig.10 Whole catalytic cycle

綜上所述, 本文采用密度泛函理論方法, 對銅催化二羥基乙酸、 胺和炔的三組分反應(yīng)進行了理論研究. 先按實驗提出的反應(yīng)機理進行了計算, 即先生成聯(lián)烯, 聯(lián)烯再與炔銅反應(yīng)生成最終產(chǎn)物. 結(jié)果表明, 生成炔銅反應(yīng)需吸收61.5 kJ/mol的能量, 聯(lián)烯與炔銅發(fā)生插入反應(yīng)的能壘為147.0 kJ/mol. 炔銅不穩(wěn)定及插入能壘較高導(dǎo)致該反應(yīng)機理需越過212.4 kJ/mol的能壘才能生成最終產(chǎn)物, 與實驗結(jié)果不符. 因此提出新的反應(yīng)機理: 首先二羥基乙酸與胺原位反應(yīng)生成的亞胺鹽先配位到銅中心而發(fā)生脫羧反應(yīng), 其次端炔配位和插入, 第二個端炔C—H活化生成HBr后, HBr再提供H+進行質(zhì)子化反應(yīng), 最后親核加成以及亞胺鹽取代生成的產(chǎn)物而重新生成催化活性體. 該反應(yīng)機理的決速步驟為端炔插入步驟, 反應(yīng)能壘為129.8 kJ/mol, 與實驗上反應(yīng)溫度為110 ℃的結(jié)果一致.

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